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Sample records for altered ovarian gene

  1. Alterations of c-Myc and c-erbB-2 genes in ovarian tumours

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    Pastor Tibor

    2009-01-01

    Full Text Available Introduction. According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, c-erbB-2, c-Myc and K-ras, and of the tumour suppressor gene p53, have been frequently observed in a sporadic ovarian cancer. Objective. The aim of the present study was to analyze c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process. Methods. DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. C-Myc and c-erbB-2 amplification were detected by differential PCR. The level of gene copy increase was measured using the Scion image software. Results. The amplification of both c-Myc and c-erbB-2 was detected in 26.7% of ovarian epithelial carcinoma specimens. Only one tumour specimen concomitantly showed increased gene copy number for both studied genes. Interestingly, besides amplification, gene deletion was also detected (26.7% for c-erbB-2. Most of the ovarian carcinomas with alterations in c-Myc and c-erbB-2 belonged to advanced FIGO stages. Conclusion. The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the

  2. [Alterations of c-Myc and c-erbB-2 genes in ovarian tumours].

    Science.gov (United States)

    Pastor, Tibor; Popović, Branka; Gvozdenović, Ana; Boro, Aleksandar; Petrović, Bojana; Novaković, Ivana; Puzović, Dragana; Luković, Ljiljana; Milasin, Jelena

    2009-01-01

    According to clinical and epidemiological studies, ovarian cancer ranks fifth in cancer deaths among women. The causes of ovarian cancer remain largely unknown but various factors may increase the risk of developing it, such as age, family history of cancer, childbearing status etc. This cancer results from a succession of genetic alterations involving oncogenes and tumour suppressor genes, which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, c-erbB-2, c-Myc and K-ras, and of the tumour suppressor gene p53, have been frequently observed in a sporadic ovarian cancer. The aim of the present study was to analyse c-Myc and c-erbB-2 oncogene alterations, specifically amplification, as one of main mechanisms of their activation in ovarian cancers and to establish a possible association with the pathogenic process. DNA was isolated from 15 samples of malignant and 5 benign ovarian tumours, using proteinase K digestion, followed by phenol-chloroform isoamyl extraction and ethanol precipitation. C-Myc and c-erbB-2 amplification were detected by differential PCR. The level of gene copy increase was measured using the Scion image software. The amplification of both c-Myc and c-erbB-2 was detected in 26.7% of ovarian epithelial carcinoma specimens. Only one tumour specimen concomitantly showed increased gene copy number for both studied genes. Interestingly, besides amplification, gene deletion was also detected (26.7% for c-erbB-2). Most of the ovarian carcinomas with alterations in c-Myc and c-erbB-2 belonged to advanced FIGO stages. The amplification of c-Myc and c-erbB-2 oncogenes in ovarian epithelial carcinomas is most probably a late event in the pathogenesis conferring these tumours a more aggressive biological behaviour. Similarly, gene deletions point to genomic instability in epithelial carcinomas in higher clinical stages as the result of clonal evolution and selection.

  3. Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression.

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    Veiga-Lopez, Almudena; Luense, Lacey J; Christenson, Lane K; Padmanabhan, Vasantha

    2013-05-01

    Bisphenol-A (BPA), a ubiquitous environmental endocrine disrupting chemical, is a component of polycarbonate plastic and epoxy resins. Because of its estrogenic properties, there is increasing concern relative to risks from exposures during critical periods of early organ differentiation. Prenatal BPA treatment in sheep results in low birth weight, hypergonadotropism, and ovarian cycle disruptions. This study tested the hypothesis that gestational exposure to bisphenol A, at an environmentally relevant dose, induces early perturbations in the ovarian transcriptome (mRNA and microRNA). Pregnant Suffolk ewes were treated with bisphenol A (0.5 mg/kg, sc, daily, produced ∼2.6 ng/mL of unconjugated BPA in umbilical arterial samples of BPA treated fetuses approaching median levels of BPA measured in maternal circulation) from days 30 to 90 of gestation. Expression of steroidogenic enzymes, steroid/gonadotropin receptors, key ovarian regulators, and microRNA biogenesis components were measured by RT-PCR using RNA derived from fetal ovaries collected on gestational days 65 and 90. An age-dependent effect was evident in most steroidogenic enzymes, steroid receptors, and key ovarian regulators. Prenatal BPA increased Cyp19 and 5α-reductase expression in day 65, but not day 90, ovaries. Fetal ovarian microRNA expression was altered by prenatal BPA with 45 down-regulated (>1.5-fold) at day 65 and 11 down-regulated at day 90 of gestation. These included microRNAs targeting Sry-related high-mobility-group box (SOX) family genes, kit ligand, and insulin-related genes. The results of this study demonstrate that exposure to BPA at an environmentally relevant dose alters fetal ovarian steroidogenic gene and microRNA expression of relevance to gonadal differentiation, folliculogenesis, and insulin homeostasis.

  4. Alteration of p53 gene in ovarian carcinoma: clinicopathological correlation and prognostic significance.

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    Niwa, K; Itoh, M; Murase, T; Morishita, S; Itoh, N; Mori, H; Tamaya, T

    1994-12-01

    Inactivation of the tumour-suppressor gene p53 has been demonstrated in a variety of human tumours. We extracted DNA from paraffin-embedded tissues of 67 ovarian carcinoma samples (54 primary tumours, seven metastases and six tumours obtained after chemotherapy), and analysed allelic losses and mutations of the p53 gene using single-strand conformation polymorphism (SSCP) analysis of DNA fragments amplified by a polymerase chain reaction (PCR). Allelic loss was observed in 24 of 32 informative cases. The mutation was detected in 14 of 54 primary ovarian carcinomas: eight serous cystadenocarcinomas (SCA), 42%), five endometrioid adenocarcinomas (EA, 42%) and one mucinous cystadenocarcinoma (14%). The incidence of the alteration was higher in SCA and EA than in other histological types, but the difference was not statistically significant. The incidence of p53 gene abnormalities in ovarian carcinomas tended to be increased in patients with disease advanced (over FIGO stage II). Mutations were found in exons 5 and 7 only and consisted mainly of single nucleotide substitutions [9 or 14 (64%) in exon 7; 4 of 14 (29%) in exon 5]. In 13 of 14 cases, p53 gene mutations occurred concomitantly with losses of the normal allele. The status of the p53 gene in metastases and the tumours obtained after chemotherapy was identical to that in the primary tumours. The presence of p53 gene mutation did not correlate with histological grade, response to primary therapy and survival. These findings suggest that mutational alterations of the p53 gene are involved in the development of a significant proportion of some ovarian carcinomas (SCAs or EAs), especially in advanced stages. However, they may not be a marker predicting the biological behaviour or the outcome of the disease.

  5. Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

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    Weber Mitch

    2008-03-01

    Full Text Available Abstract Background Women with polycystic ovary syndrome (PCOS are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD, which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a mice, possessing a mutation (Ay in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction. Methods Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4 or an equal volume of vehicle (DMSO; n = 4 for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression. Results Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM, and actin-related protein 6 homolog (ARP6. For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a non-mutant lean mice. Conclusion TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.

  6. Progressive obesity leads to altered ovarian gene expression in the Lethal Yellow mouse: a microarray study

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    Brannian John

    2009-08-01

    Full Text Available Abstract Background Lethal yellow (LY; C57BL/6J Ay/a mice exhibit adult-onset obesity, altered metabolic regulation, and early reproductive senescence. The present study was designed to test the hypothesis that obese LY mice possess differences in expression of ovarian genes relative to age-matched lean mice. Methods 90- and 180-day-old LY and lean black (C57BL/6J a/a mice were suppressed with GnRH antagonist (Antide®, then stimulated with 5 IU eCG. cRNA derived from RNA extracts of whole ovarian homogenates collected 36 h post-eCG were run individually on Codelink Mouse Whole Genome Bioarrays (GE Healthcare Life Sciences. Results Fifty-two genes showed ≥ 2-fold differential (p Cyp51, and steroidogenic acute regulatory protein (Star. Fewer genes showed lower expression in LY mice, e.g. angiotensinogen. In contrast, none of these genes showed differential expression in 90-day-old LY and black mice, which are of similar body weight. Interestingly, 180-day-old LY mice had a 2-fold greater expression of 11beta-hydroxysteroid dehydrogenase type 1 (Hsd11b1 and a 2-fold lesser expression of 11beta-hydroxysteroid dehydrogenase type 2 (Hsd11b2, differences not seen in 90-day-old mice. Consistent with altered Hsd11b gene expression, ovarian concentrations of corticosterone (C were elevated in aging LY mice relative to black mice, but C levels were similar in young LY and black mice. Conclusion The data suggest that reproductive dysfunction in aging obese mice is related to modified intraovarian gene expression that is directly related to acquired obesity.

  7. Alterations in gene expression during fasting-induced atresia of early secondary ovarian follicles of coho salmon, Oncorhynchus kisutch.

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    Yamamoto, Yoji; Luckenbach, J Adam; Young, Graham; Swanson, Penny

    2016-11-01

    Molecular processes that either regulate ovarian atresia or are consequences of atresia are poorly understood in teleost fishes. We hypothesized that feed restriction that perturbs normal ovarian growth and induces follicular atresia would alter ovarian gene expression patterns. Previtellogenic, two-year old coho salmon (Oncorhynchus kisutch) were subjected to prolonged fasting to induce atresia or maintained on a normal feeding schedule that would promote continued ovarian development. To identify genes that were specifically up- or down-regulated during oocyte growth in healthy, growing fish compared to fasted fish, reciprocal suppression subtractive hybridization (SSH) cDNA libraries were generated using ovaries from fed and fasted animals. Differential expression of genes identified by SSH was confirmed with quantitative PCR. The SSH library representing genes elevated in ovaries of fed fish relative to those of fasted fish contained steroidogenesis-related genes (e.g., hydroxy-delta-5-steroid dehydrogenase), Tgf-beta superfamily members (e.g., anti-Mullerian hormone) and cytoskeletal intermediate filament proteins (e.g., type I keratin s8). Overall, these genes were associated with steroid production, cell proliferation and differentiation, and ovarian epithelialization. The library representing genes elevated in ovaries of fasted fish relative to fed fish contained genes associated with apoptosis (e.g., programmed cell death protein 4), cortical alveoli (e.g., alveolin), the zona pellucida (e.g., zona pellucida protein c), and microtubules (e.g., microtubule associated protein tau). Elevated expression of this suite of genes was likely associated with the initiation of atresia and/or a reduced rate of follicle development in response to fasting. This study revealed ovarian genes involved in normal early secondary oocyte growth and potential early markers of atresia. Published by Elsevier Inc.

  8. Alteration of p53 gene in ovarian carcinoma: clinicopathological correlation and prognostic significance.

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    Niwa, K.; Itoh, M.; Murase, T.; Morishita, S.; Itoh, N.; Mori, H.; Tamaya, T.

    1994-01-01

    Inactivation of the tumour-suppressor gene p53 has been demonstrated in a variety of human tumours. We extracted DNA from paraffin-embedded tissues of 67 ovarian carcinoma samples (54 primary tumours, seven metastases and six tumours obtained after chemotherapy), and analysed allelic losses and mutations of the p53 gene using single-strand conformation polymorphism (SSCP) analysis of DNA fragments amplified by a polymerase chain reaction (PCR). Allelic loss was observed in 24 of 32 informativ...

  9. Ovarian reserve status in young women is associated with altered gene expression in membrana granulosa cells.

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    Skiadas, Christine C; Duan, Shenghua; Correll, Mick; Rubio, Renee; Karaca, Nilay; Ginsburg, Elizabeth S; Quackenbush, John; Racowsky, Catherine

    2012-07-01

    Diminished ovarian reserve (DOR) is a challenging diagnosis of infertility, as there are currently no tests to predict who may become affected with this condition, or at what age. We designed the present study to compare the gene expression profile of membrana granulosa cells from young women affected with DOR with those from egg donors of similar age and to determine if distinct genetic patterns could be identified to provide insight into the etiology of DOR. Young women with DOR were identified based on FSH level in conjunction with poor follicular development during an IVF cycle (n = 13). Egg donors with normal ovarian reserve (NOR) comprised the control group (n = 13). Granulosa cells were collected following retrieval, RNA was extracted and microarray analysis was conducted to evaluate genetic differences between the groups. Confirmatory studies were undertaken with quantitative RT-PCR (qRT-PCR). Multiple significant differences in gene expression were observed between the DOR patients and egg donors. Two genes linked with ovarian function, anti-Mullerian hormone (AMH) and luteinizing hormone receptor (LHCGR), were further analyzed with qRT-PCR in all patients. The average expression of AMH was significantly higher in egg donors (adjusted P-value = 0.01), and the average expression of LHCGR was significantly higher in DOR patients (adjusted P-value = 0.005). Expression levels for four additional genes, progesterone receptor membrane component 2 (PGRMC2), prostaglandin E receptor 3 (subtype EP3) (PTGER3), steroidogenic acute regulatory protein (StAR), and StAR-related lipid transfer domain containing 4 (StarD4), were validated in a group consisting of five NOR and five DOR patients. We conclude that gene expression analysis has substantial potential to determine which young women may be affected with DOR. More importantly, our analysis suggests that DOR patients fall into two distinct subgroups based on gene expression profiles, indicating that different

  10. PIK3CA alterations in Middle Eastern ovarian cancers

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    Uddin Shahab

    2009-07-01

    Full Text Available Abstract Background PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC. Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs. Results Fluorescence in situ hybridization (FISH technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA protein expression (p110 α, PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5% EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%; KRAS mutations in 3/154 EOC (1.9%, BRAF mutations in 3/156 EOC (1.9%, p53 mutation in 50/154 EOC (32.5%, and loss of PTEN protein expression in 33/144 EOC (22.9%. p110 α overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67. Conclusion Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.

  11. Genomic alterations detected by comparative genomic hybridization in ovarian endometriomas

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    L.C. Veiga-Castelli

    2010-08-01

    Full Text Available Endometriosis is a complex and multifactorial disease. Chromosomal imbalance screening in endometriotic tissue can be used to detect hot-spot regions in the search for a possible genetic marker for endometriosis. The objective of the present study was to detect chromosomal imbalances by comparative genomic hybridization (CGH in ectopic tissue samples from ovarian endometriomas and eutopic tissue from the same patients. We evaluated 10 ovarian endometriotic tissues and 10 eutopic endometrial tissues by metaphase CGH. CGH was prepared with normal and test DNA enzymatically digested, ligated to adaptors and amplified by PCR. A second PCR was performed for DNA labeling. Equal amounts of both normal and test-labeled DNA were hybridized in human normal metaphases. The Isis FISH Imaging System V 5.0 software was used for chromosome analysis. In both eutopic and ectopic groups, 4/10 samples presented chromosomal alterations, mainly chromosomal gains. CGH identified 11q12.3-q13.1, 17p11.1-p12, 17q25.3-qter, and 19p as critical regions. Genomic imbalances in 11q, 17p, 17q, and 19p were detected in normal eutopic and/or ectopic endometrium from women with ovarian endometriosis. These regions contain genes such as POLR2G, MXRA7 and UBA52 involved in biological processes that may lead to the establishment and maintenance of endometriotic implants. This genomic imbalance may affect genes in which dysregulation impacts both eutopic and ectopic endometrium.

  12. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer ...

    Indian Academy of Sciences (India)

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian ...

  13. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer ...

    Indian Academy of Sciences (India)

    Unknown

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the major- ity of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian ...

  14. Gene expression analysis of human fetal ovarian primordial follicle formation.

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    Fowler, Paul A; Flannigan, Samantha; Mathers, Anna; Gillanders, Kim; Lea, Richard G; Wood, Maureen J; Maheshwari, Abha; Bhattacharya, Siladitya; Collie-Duguid, Elaina S R; Baker, Paul J; Monteiro, Ana; O'Shaughnessy, Peter J

    2009-04-01

    Primordial follicle formation dictates the maximal potential female reproductive capacity and establishes the ovarian reserve. Currently, little is known about this process in the human. The aim of the study was to identify genes associated with the onset of human fetal primordial follicle formation in morphologically normal human fetuses. We conducted an observational study of the female fetal gonad, comparing gene expression before and during primordial follicle formation. The study was conducted at the Universities of Aberdeen, Glasgow, and Nottingham. Ovaries were collected from 51 morphologically normal human female fetuses of women undergoing elective termination of normal second trimester pregnancies. We performed fetal ovarian transcript expression by Affymetrix array and quantitative RT-PCR and gene product expression and localization by Western blot and immunohistochemistry. Five transcripts were down-regulated and 61 were up-regulated in ovaries from older fetuses (18-20 wk) in which primordial follicle formation had started compared with younger (15-16 wk) fetuses in which no primordial follicles were observed. The altered genes contribute to major functions, including gene expression, tissue morphology, and apoptosis, that are essential for ovarian development. NALP5, the most highly regulated transcript, is an oocyte-specific maternal effect gene that is regulated downstream of FIGLA. NALP5 probably plays a key role in the onset of human primordial follicle formation and thus the establishment of ovarian reserve in women.

  15. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium

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    Amankwah, Ernest K; Wang, Qinggang; Schildkraut, Joellen M

    2011-01-01

    Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC amo...

  16. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Amankwah, Ernest K; Wang, Qinggang; Schildkraut, Joellen M

    2011-01-01

    Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among...

  17. Tumour suppressor genes in sporadic epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Liu, Ying; Ganesan, Trivadi S

    2002-01-01

    Ovarian cancer is the most frequent cause of death from gynaecological malignancies in the western world, and sporadic epithelial ovarian cancer is its most predominant form. The aetiology of sporadic ovarian cancer remains unknown. Genetic studies have enabled a better understanding...... of the evolution of tumour progression. A major focus of research has been to identify tumour suppressor genes implicated in sporadic ovarian cancer over the past decade. Several tumour suppressor genes have been identified by strategies such as positional cloning and differential expression display. Further...... research is warranted to understand fully their contribution to the pathogenesis of sporadic ovarian cancer....

  18. B-cell translocation gene 1 is downregulated by promoter methylation in ovarian carcinoma.

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    Kim, Ji-Ye; Do, Sung-Im; Bae, Go Eun; Kim, Hyun-Soo

    2017-01-01

    A better understanding of tumor biology is important in the identification of molecules that are downregulated in malignancy and in determining their role in tumor suppression. B-cell translocation gene 1 (BTG1) has been shown to act as a tumor suppressor in several types of human malignancy. In this study, we analyzed BTG1 expression in ovarian carcinoma cell lines, and we investigated the mechanism underlying the observed alterations. The methylation status of the BTG1 promoter region was determined by methylation-specific polymerase chain reaction, and the effect of demethylation on BTG1 expression was analyzed. BTG1 protein expression in ovarian high-grade serous carcinoma tissue samples was evaluated using immunohistochemistry. BTG1 mRNA and protein expression were reduced in ovarian carcinoma cells. In BTG1-silenced ovarian cancer cells, the BTG1 promoter was highly methylated. Treatment with 5-aza-deoxycytidine significantly elevated BTG1 mRNA and protein expression. Immunostaining demonstrated that BTG1 expression was significantly lower in ovarian carcinoma tissue samples than nonpathological ovaries and fallopian tubes. We demonstrated that BTG1 silencing in ovarian carcinoma occurs through epigenetic repression and is involved in the ovarian carcinogenesis. Our data suggest that BTG1 is a potential therapeutic target for patients with ovarian carcinoma.

  19. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, Lydia; Dafou, Dimitra; Ramus, Susan J

    2009-01-01

    Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediat...

  20. Obesity alters the ovarian glucidic homeostasis disrupting the reproductive outcome of female rats.

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    Bazzano, María Victoria; Paz, Dante Agustín; Elia, Evelin Mariel

    2017-04-01

    Obesity constitutes a health problem of increasing worldwide prevalence related to many reproductive problems such as infertility, ovulation dysfunction, preterm delivery, fetal growth disorders, etc. The mechanisms linking obesity to these pathologies are not fully understood. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects western diet habits. Previously we described that CAF induces obesity associated to hyperglycemia, reduced ovarian reserve, presence of follicular cysts and ovulatory impairments. The aim of the present study was to contribute in the understanding of the physiological mechanisms altered as consequence of obesity. For that purpose, female Wistar rats were fed ad libitum with a standard diet (control group) or CAF (Obese group). We found that CAF fed-rats developed obesity, glucose intolerance and insulin resistance. Ovaries from obese rats showed decreased glucose uptake and became insulin resistant, showing decreased ovarian expression of glucotransporter type 4 and insulin receptor gene expression respect to controls. These animals showed an increased follicular nitric oxyde synthase expression that may be responsible for the ovulatory disruptions and for inflammation, a common feature in obesity. Obese rats resulted subfertile and their pups were macrosomic. We conclude that obesity alters the systemic and the ovarian glucidic homeostasis impairing the reproductive outcome. Since macrosomia is a risk factor for metabolic and obstetric disorders in adult life, we suggest that obesity is impacting not only on health and reproduction but it is also impacting on health and reproduction of the offspring. Published by Elsevier Inc.

  1. Germline EMSY sequence alterations in hereditary breast cancer and ovarian cancer families.

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    Määttä, Kirsi M; Nurminen, Riikka; Kankuri-Tammilehto, Minna; Kallioniemi, Anne; Laasanen, Satu-Leena; Schleutker, Johanna

    2017-07-24

    BRCA1 and BRCA2 mutations explain approximately one-fifth of the inherited susceptibility in high-risk Finnish hereditary breast and ovarian cancer (HBOC) families. EMSY is located in the breast cancer-associated chromosomal region 11q13. The EMSY gene encodes a BRCA2-interacting protein that has been implicated in DNA damage repair and genomic instability. We analysed the role of germline EMSY variation in breast/ovarian cancer predisposition. The present study describes the first EMSY screening in patients with high familial risk for this disease. Index individuals from 71 high-risk, BRCA1/2-negative HBOC families were screened for germline EMSY sequence alterations in protein coding regions and exon-intron boundaries using Sanger sequencing and TaqMan assays. The identified variants were further screened in 36 Finnish HBOC patients and 904 controls. Moreover, one novel intronic deletion was screened in a cohort of 404 breast cancer patients unselected for family history. Haplotype block structure and the association of haplotypes with breast/ovarian cancer were analysed using Haploview. The functionality of the identified variants was predicted using Haploreg, RegulomeDB, Human Splicing Finder, and Pathogenic-or-Not-Pipeline 2. Altogether, 12 germline EMSY variants were observed. Two alterations were located in the coding region, five alterations were intronic, and five alterations were located in the 3'untranslated region (UTR). Variant frequencies did not significantly differ between cases and controls. The novel variant, c.2709 + 122delT, was detected in 1 out of 107 (0.9%) breast cancer patients, and the carrier showed a bilateral form of the disease. The deletion was absent in 897 controls (OR = 25.28; P = 0.1) and in 404 breast cancer patients unselected for family history. No haplotype was identified to increase the risk of breast/ovarian cancer. Functional analyses suggested that variants, particularly in the 3'UTR, were located within regulatory

  2. Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

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    Angela Toss

    2015-01-01

    Full Text Available More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

  3. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    Science.gov (United States)

    Lee, Alice W.; Tyrer, Jonathan P.; Doherty, Jennifer A.; Stram, Douglas A.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G.; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B.; Shvetsov, Yurii B.; Thompson, Pamela J.; Goodman, Marc T.; Wilkens, Lynne R.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B.; Bogdanova, Natalia; Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P.; Kelley, Joseph L.; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y.; Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan; Vierkant, Robert A.; Cunningham, Julie M.; Goode, Ellen L.; Fridley, Brooke L.; Southey, Melissa C.; Giles, Graham G.; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A.T.; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A.; Weber, Rachel Palmieri; Schildkraut, Joellen M.; Iversen, Edwin S.; Berchuck, Andrew; Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.; Olson, Sara H.; Orlow, Irene; Bandera, Elisa V.; Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla; Massuger, Leon F.A.G.; Kiemeney, Lambertus A.; Aben, Katja K.H.; van Altena, Anne M.; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D.; Cook, Linda S.; Kelemen, Linda E.; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G.; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Whittemore, Alice S.; McLaughlin, John R.; Risch, Harvey A.; Phelan, Catherine M.; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C.; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B.; Pharoah, Paul D.P.; Stram, Daniel O.; Wu, Anna H.; Pearce, Celeste Leigh

    2016-01-01

    Objective Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. PMID:25528498

  4. Identification of candidate methylation-responsive genes in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Dickerson Erin B

    2007-01-01

    Full Text Available Abstract Background Aberrant methylation of gene promoter regions has been linked to changes in gene expression in cancer development and progression. Genes associated with CpG islands (CGIs are especially prone to methylation, but not all CGI-associated genes display changes in methylation patterns in cancers. Results In order to identify genes subject to regulation by methylation, we conducted gene expression profile analyses of an ovarian cancer cell line (OVCAR-3 before and after treatment with the demethylating agent 5-aza-deoxycytidine (5-aza-dC. An overlapping subset of these genes was found to display significant differences in gene expression between normal ovarian surface epithelial cells and malignant cells isolated from ovarian carcinomas. While 40% of all human genes are associated with CGIs, > 94% of the overlapping subset of genes is associated with CGIs. The predicted change in methylation status of genes randomly selected from the overlapping subset was experimentally verified. Conclusion We conclude that correlating genes that are upregulated in response to 5-aza-dC treatment of cancer cell lines with genes that are down-regulated in cancer cells may be a useful method to identify genes experiencing epigenetic-mediated changes in expression over cancer development.

  5. A Double Selection Approach to Achieve Specific Expression of Toxin Genes for Ovarian Cancer Gene Therapy

    National Research Council Canada - National Science Library

    Curiel, David T; Siegal, Gene; Wang, Minghui

    2005-01-01

    ... embodies the requisite properties of efficacy and specificity required for ovarian cancer gene therapy. This approach is based on targeting the delivered anti-cancer gene to tumor via two complimentary approaches...

  6. A Double Selection Approach to Achieve Specific Expression of Toxin Genes for Ovarian Cancer Gene Therapy

    National Research Council Canada - National Science Library

    Curiel, David T; Siegal, Gene; Wang, Minghui

    2006-01-01

    ... embodies the requisite properties of efficacy and specificity required for ovarian cancer gene therapy. This approach is based on targeting the delivered anti-cancer gene to tumor via two complimentary approaches...

  7. NOXA-induced alterations in the Bax/Smac axis enhance sensitivity of ovarian cancer cells to cisplatin.

    Directory of Open Access Journals (Sweden)

    Chao Lin

    Full Text Available Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy.

  8. NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin

    Science.gov (United States)

    Lin, Chao; Zhao, Xin-yu; Li, Lei; Liu, Huan-yi; Cao, Kang; Wan, Yang; Liu, Xin-yu; Nie, Chun-lai; Liu, Lei; Tong, Ai-ping; Deng, Hong-xin; Li, Jiong; Yuan, Zhu; Wei, Yu-quan

    2012-01-01

    Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy. PMID:22590594

  9. Relationship between promoter methylation & tissue expression of MGMT gene in ovarian cancer

    Directory of Open Access Journals (Sweden)

    V Shilpa

    2014-01-01

    Full Text Available Background & objectives: Epigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumour suppressor genes. O 6 -methyguanine-DNA methyltransferase (MGMT is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 -position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression has been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human epithelial ovarian carcinoma. Methods: A total of 88 epithelial ovarian cancer (EOC tissue samples, 14 low malignant potential (LMP tumours and 20 benign ovarian tissue samples were analysed for MGMT promoter methylation by nested methylation-specific polymerase chain reaction (MSP after bisulphite modification of DNA. A subset of 64 EOC samples, 10 LMP and benign tumours and five normal ovarian tissue samples were analysed for protein expression by immunohistochemistry. Results: The methylation frequencies of the MGMT gene promoter were found to be 29.5, 28.6 and 20 per cent for EOC samples, LMP tumours and benign cases, respectively. Positive protein expression was observed in 93.8 per cent of EOC and 100 per cent in LMP, benign tumours and normal ovarian tissue samples. Promoter hypermethylation with loss of protein expression was seen only in one case of EOC. Interpretation & conclusions: Our results suggest that MGMT promoter hypermethylation does not always reflect gene expression.

  10. Relationship between promoter methylation & tissue expression of MGMT gene in ovarian cancer.

    Science.gov (United States)

    Shilpa, V; Bhagat, Rahul; Premalata, C S; Pallavi, V R; Ramesh, G; Krishnamoorthy, Lakshmi

    2014-11-01

    Epigenetic alterations, in addition to multiple gene abnormalities, are involved in the genesis and progression of human cancers. Aberrant methylation of CpG islands within promoter regions is associated with transcriptional inactivation of various tumour suppressor genes. O 6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair gene that removes mutagenic and cytotoxic adducts from the O 6 -position of guanine induced by alkylating agents. MGMT promoter hypermethylation and reduced expression has been found in some primary human carcinomas. We studied DNA methylation of CpG islands of the MGMT gene and its relation with MGMT protein expression in human epithelial ovarian carcinoma. A total of 88 epithelial ovarian cancer (EOC) tissue samples, 14 low malignant potential (LMP) tumours and 20 benign ovarian tissue samples were analysed for MGMT promoter methylation by nested methylation-specific polymerase chain reaction (MSP) after bisulphite modification of DNA. A subset of 64 EOC samples, 10 LMP and benign tumours and five normal ovarian tissue samples were analysed for protein expression by immunohistochemistry. The methylation frequencies of the MGMT gene promoter were found to be 29.5, 28.6 and 20 per cent for EOC samples, LMP tumours and benign cases, respectively. Positive protein expression was observed in 93.8 per cent of EOC and 100 per cent in LMP, benign tumours and normal ovarian tissue samples. Promoter hypermethylation with loss of protein expression was seen only in one case of EOC. Our results suggest that MGMT promoter hypermethylation does not always reflect gene expression.

  11. Gene bionetwork analysis of ovarian primordial follicle development.

    Directory of Open Access Journals (Sweden)

    Eric E Nilsson

    2010-07-01

    Full Text Available Ovarian primordial follicles are critical for female reproduction and comprise a finite pool of gametes arrested in development. A systems biology approach was used to identify regulatory gene networks essential for primordial follicle development. Transcriptional responses to eight different growth factors known to influence primordial follicles were used to construct a bionetwork of regulatory genes involved in rat primordial follicle development. Over 1,500 genes were found to be regulated by the various growth factors and a network analysis identified critical gene modules involved in a number of signaling pathways and cellular processes. A set of 55 genes was identified as potential critical regulators of these gene modules, and a sub-network associated with development was determined. Within the network two previously identified regulatory genes were confirmed (i.e., Pdgfa and Fgfr2 and a new factor was identified, connective tissue growth factor (CTGF. CTGF was tested in ovarian organ cultures and found to stimulate primordial follicle development. Therefore, the relevant gene network associated with primordial follicle development was validated and the critical genes and pathways involved in this process were identified. This is one of the first applications of network analysis to a normal developmental process. These observations provide insights into potential therapeutic targets for preventing ovarian disease and promoting female reproduction.

  12. Molecular genetic analysis of tumor suppressor genes in ovarian cancer

    International Nuclear Information System (INIS)

    Lee, Je Ho; Park, Sang Yun

    1992-04-01

    To examine the loci of putative tumor suppressor genes in ovarian cancers, we performed the molecular genetic analysis with fresh human ovarian cancers and observed the following data. Frequent allelic losses were observed on chromosomes 4p(42%), 6p(50%), 7p(43%), 8q(31%), 12p(38%), 12q(33%), 16p(33%), 16q(37%), and 19p(34%) in addition to the previously reported 6q, 11p, and 17p in ovarian caroinomas. we have used an additional probe, TCP10 to narrow down the deleted region on chromosome 6q. TCP10 was reported to be mapped to 6q 25-27. Allelic loss was found to be 40% in epithelial ovarian caroinomas. This finding suggests that chromosome 6q 24-27 is one of putative region haboring the tumor suppressor gene of epithelial ovarian cancer (particularly serous type). To examine the association between FAL(Fractional Allelic Loss) and histopathological features, the FAL value on each phenotypically different tumor was calculated as the ratio of the number of allelic losses versus the number of cases informative in each chromosomal arm. The average FALs for each phenotypically different tumor were: serous cystoadenocarcinomas. FAL=0.31 : mucinous 0.12 : and clear cell carcinoma. FAL=0.20. (Author)

  13. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    NARCIS (Netherlands)

    Lee, A.W.; Tyrer, J.P.; Doherty, J.A.; Stram, D.A.; Kupryjanczyk, J.; Dansonka-Mieszkowska, A.; Plisiecka-Halasa, J.; Spiewankiewicz, B.; Myers, E.J.; Study, G.; Chenevix-Trench, G.; Fasching, P.A.; Beckmann, M.W.; Ekici, A.B.; Hein, A.; Vergote, I.; Nieuwenhuysen, E. Van; Lambrechts, D.; Wicklund, K.G.; Eilber, U.; Wang-Gohrke, S.; Chang-Claude, J.; Rudolph, A.; Sucheston-Campbell, L.; Odunsi, K.; Moysich, K.B.; Shvetsov, Y.B.; Thompson, P.J.; Goodman, M.T.; Wilkens, L.R.; Dork, T.; Hillemanns, P.; Durst, M.; Runnebaum, I.B.; Bogdanova, N.; Pelttari, L.M.; Nevanlinna, H.; Leminen, A.; Edwards, R.P.; Kelley, J.L.; Harter, P.; Schwaab, I.; Heitz, F.; Bois, A. du; Orsulic, S.; Lester, J.; Walsh, C.; Karlan, B.Y.; Hogdall, E.; Kjaer, S.K.; Jensen, A.; Vierkant, R.A.; Cunningham, J.M.; Goode, E.L.; Fridley, B.L.; Southey, M.C.; Giles, G.G.; Bruinsma, F.; Wu, X.; Hildebrandt, M.A.T.; Lu, K.; Liang, D.; Bisogna, M.; Levine, D.A.; Weber, R.P.; Schildkraut, J.M.; Iversen, E.S.; Berchuck, A.; Terry, K.L.; Cramer, D.W; Tworoger, S.S.; Poole, E.M.; Olson, S.H.; Orlow, I.; Bandera, E.V.; Bjorge, L.; Tangen, I.L.; Salvesen, H.B.; Krakstad, C.; Massuger, L.F.A.G.; Kiemeney, L.A.L.M.; Aben, K.K.H.; Altena, A.M. van; Bean, Y.; Pejovic, T.; Kellar, M.; Le, N.D.; Cook, L.S.; Kelemen, L.E.; Brooks-Wilson, A.; Lubinski, J.; Gronwald, J.; Cybulski, C.; Jakubowska, A.; Wentzensen, N.; Brinton, L.A.; Lissowska, J.; Yang, H.; Nedergaard, L.; et al.,

    2015-01-01

    OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of

  14. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Notaridou, Maria; Quaye, Lydia; Dafou, Dimitra

    2011-01-01

    Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines...

  15. The Prognostic 97 Chemoresponse Gene Signature in Ovarian Cancer.

    Science.gov (United States)

    Matondo, Abel; Jo, Yong Hwa; Shahid, Muhammad; Choi, Tae Gyu; Nguyen, Minh Nam; Nguyen, Ngoc Ngo Yen; Akter, Salima; Kang, Insug; Ha, Joohun; Maeng, Chi Hoon; Kim, Si-Young; Lee, Ju-Seog; Kim, Jayoung; Kim, Sung Soo

    2017-08-29

    Patient diagnosis and care would be significantly improved by understanding the mechanisms underlying platinum and taxane resistance in ovarian cancer. Here, we aim to establish a gene signature that can identify molecular pathways/transcription factors involved in ovarian cancer progression, poor clinical outcome, and chemotherapy resistance. To validate the robustness of the gene signature, a meta-analysis approach was applied to 1,020 patients from 7 datasets. A 97-gene signature was identified as an independent predictor of patient survival in association with other clinicopathological factors in univariate [hazard ratio (HR): 3.0, 95% Confidence Interval (CI) 1.66-5.44, p = 2.7E-4] and multivariate [HR: 2.88, 95% CI 1.57-5.2, p = 0.001] analyses. Subset analyses demonstrated that the signature could predict patients who would attain complete or partial remission or no-response to first-line chemotherapy. Pathway analyses revealed that the signature was regulated by HIF1α and TP53 and included nine HIF1α-regulated genes, which were highly expressed in non-responders and partial remission patients than in complete remission patients. We present the 97-gene signature as an accurate prognostic predictor of overall survival and chemoresponse. Our signature also provides information on potential candidate target genes for future treatment efforts in ovarian cancer.

  16. Effects of common germ-line genetic variation in cell cycle genes on ovarian cancer survival

    DEFF Research Database (Denmark)

    Song, H.; Hogdall, E.; Ramus, S.J.

    2008-01-01

    PURPOSE: Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could...... plausibly influence clinical characteristics of multiple tumors types. EXPERIMENTAL DESIGN: We examined associations between common germ-line genetic variation in 14 genes involved in cell cycle pathway (CCND1, CCND2, CCND3, CCNE1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDK2, CDK4, CDK6, and RB1....... CONCLUSION: It is unlikely that common variants in cell cycle pathways examined above associated with moderate effect in survival after diagnosis of ovarian cancer. Much larger studies will be needed to exclude common variants with small effects Udgivelsesdato: 2008/2/15...

  17. PDI Coamplified Genes in Ovarian Cancer

    Science.gov (United States)

    2017-08-01

    Therefore, we could not generate any data during the first year. This is a copy of our first-year progress report that goes beyond the period from 6-1-14...year we purchased several antibodies from multiple vendors and tested them in various ovarian cancer cell lines. We had to contact, test, and validate...obtained from the same mice. HE Y $ NC I$A DR $R es $ Fa t_ T$ OV CA R$ 8$ OV CA R$ 5$ SK OV 3$ TO V2 1$ Fa t$_ N$ HE Y $I nv as ion $ OV CA R$ 3$ GAPDH

  18. Polymorphisms of the p53 gene in women with ovarian or endometrial carcinoma.

    Science.gov (United States)

    Peller, S; Halperin, R; Schneider, D; Kopilova, Y; Rotter, V

    1999-01-01

    The p53 gene is frequently mutated in various human tumors. Polymorphism is an additional genetic alteration observed in exons and introns of the p53 gene of normal tissues and tumors. Distributions of alleles of three common polymorphisms of the p53 gene; a 16 bp duplication in intron 3, codon 72 of exon 4 and a sequence in intron 6, were studied in peripheral white blood cells (WBC) of patients with ovarian or endometrial carcinomas. The analysis was performed by PCR and direct sequencing. The 100% linkage observed between the most common haplotypes of each polymorphism in healthy subjects was lower in the patients. A significant difference was observed between frequencies of genotype and haplotype combinations in patients with ovarian carcinoma and endometrial carcinoma. The incidence of heterozygosity was increased in ovarian carcinoma and decreased in endometrial carcinoma. Our results suggest that the p53 gene may be involved in susceptibility and predisposition to various cancers not only by mutations but also by preferential presentation of polymorphic alleles.

  19. The Putative Role of TP53 Alterations and p53 Expression in Borderline Ovarian Tumors - Correlation with Clinicopathological Features and Prognosis: A Mini-Review

    Science.gov (United States)

    Semczuk, Andrzej; Gogacz, Marek; Semczuk-Sikora, Anna; Jóźwik, Maciej; Rechberger, Tomasz

    2017-01-01

    Borderline ovarian tumors (BOTs) represent an independent group among ovarian malignancies, being diagnosed at clinical stage earlier than invasive ovarian carcinomas (OCs) and characterized by a rather favorable outcome after careful surgical management. Data published worldwide showed a substantial discordance of p53 expression in BOTs. The purpose of this work was to present the current status of knowledge on the significance of TP53 gene and p53 protein product alterations in BOTs. In general, higher p53 expression patterns were reported for ovarian malignancies compared to BOTs. Serous, mucinous, and endometrioid BOTs differ substantially in relation to p53 immunostaining, but data concerning the relationship between the protein's immunoreactivity and other clinico-pathological variables are scarce. Finally, reports published to date support the view that TP53 alterations may not be commonly associated with the borderline phenotype of ovarian tumors but they probably occur during the development of invasive OCs. In light of these uncertainties, the impact of TP53 alterations and p53 expression on overall survival in women affected by BOTs requires further multi-institutional studies in large cohorts of patients. PMID:28928856

  20. MicroRNA genes and their target 3'-untranslated regions are infrequently somatically mutated in ovarian cancers.

    Directory of Open Access Journals (Sweden)

    Georgina L Ryland

    Full Text Available MicroRNAs are key regulators of gene expression and have been shown to have altered expression in a variety of cancer types, including epithelial ovarian cancer. MiRNA function is most often achieved through binding to the 3'-untranslated region of the target protein coding gene. Mutation screening using massively-parallel sequencing of 712 miRNA genes in 86 ovarian cancer cases identified only 5 mutated miRNA genes, each in a different case. One mutation was located in the mature miRNA, and three mutations were predicted to alter the secondary structure of the miRNA transcript. Screening of the 3'-untranslated region of 18 candidate cancer genes identified one mutation in each of AKT2, EGFR, ERRB2 and CTNNB1. The functional effect of these mutations is unclear, as expression data available for AKT2 and EGFR showed no increase in gene transcript. Mutations in miRNA genes and 3'-untranslated regions are thus uncommon in ovarian cancer.

  1. [Establishment of 5 resistant ovarian cancer cell strains and expression of resistance-related genes].

    Science.gov (United States)

    Luan, Ying-zi; Li, Li; Li, Dang-rong; Zhang, Wei; Tang, Bu-jian

    2004-06-01

    To investigate expression difference of several drug resistance related genes between sensitive and resistant ovarian carcinoma cells. Cell lines resistant to cisplatin, carboplatin and taxol were established from ovarian carcinoma cell lines of SKOV3 and A2780, and their biological features were detected. The expressions of several genes related to drug resistance were measured by RT-PCR method. (1) The values of resistance index (RI) of resistant cells to relevant drugs were elevated 3 times or more, with different degrees of cross-resistance to several other drugs (RI 2 approximately 20). They grew more slowly than primary cells (Td elongated 1.4 approximately 2.4 times, P 0.05). Intracellular concentrations of relevant drugs were reduced 2.0 approximately 8.5 times in resistant cells (P p53, lung resistance protein-1 (LRP-1), multiple drug resistance related protein-1 (MRP-1) genes were expressed at lower levels in resistant cells than in sensitive cells; while protein kinase C (PKC), topoisomerase (topo) I, and topo II beta were expressed higher, no obvious alterations were found concerning glutathione S transferase-pi (GST-pi), and topo II alpha. Expression of multiple drug resistance-1 (MDR-1) gene was either elevated or reduced in different cells. The expressions of resistance related genes were widely different in different kinds of resistant cells, suggesting more than one pathway leading to resistance transformation. This adds more difficulties for clinical management.

  2. Arched abdominal aorta and altered course of right ovarian vessels in a female cadaver: Clinical significance and embryological explanation

    Directory of Open Access Journals (Sweden)

    Sneha Guruprasad Kalthur

    2013-01-01

    Full Text Available Variations in the vascular origin of ovarian artery have been reported in the past. However, the reports on altered course of ovarian artery are very few. In the present paper, we discuss about multiple variations observed in formalin fixed female cadaver. The right ovarian artery was 22 cm long and ran unusually behind the inferior vena cava (IVC. The right ovarian vein drained in to right renal vein at right angle instead of draining into IVC directly. In addition, to these variations, the cadaver had arched abdominal aorta and retro-aortic left renal vein.

  3. The identification of new genes related to cisplatin resistance in ovarian adenocarcinoma cell line A2780

    International Nuclear Information System (INIS)

    Solar, P.; Fedorocko, P.; Sytkowski, A.; Hodorova, I.

    2006-01-01

    Ovarian cancer cells are usually sensitive to platinum-based chemotherapy, such as cisplatin (CDDP), initially but typically become resistant to the drug over time. The phenomenon of clinical drug resistance represents a serious problem for successful disease treatment, and the molecular mechanism(s) are not fully understood. In search of novel mechanisms that may lead to the development of CDDP chemoresistance we have applied subtractive hybridization based on the PCR-select cDNA subtraction. In current study we have used subtractive hybridization to identify differentially-expressed genes in CDDP resistant CP70 and C200 cells versus CDDP-sensitive A2780 human ovarian adenocarcinoma cells. We have analyzed 256 randomly selected clones. Subtraction efficiency was determined by dot blot and DNA sequencing. Confirmation of differentially expressed cDNAs was done by virtual northern blot analysis, and 17 genes that were differentially expressed in both CDDP resistant cell lines versus CDDP sensitive A2780 cells were identified. The expression of 10 of these genes was undetectable or detected with low expression in sensitive A2780 cells in comparison to resistant ones. These genes included ARHGDIB, RANBP2, ASPH, PRTFDC1, SSX2IP, MBNL1, DNAJC15, MMP10, TCTE1L and one unidentified sequence. Additional 7 genes that were more highly expressed in resistant CP70 and C200 vs. A2780 cells included ANXA2, USP8, HSPCA, TRA1, CNAP1, ATP2B1 and COX2. Interestingly, multi-drug resistance associated p-glycoprotein (p170) was not detected by the western blot in CDDP resistant CP70 and C200 cells. Our identified genes are involved in diverse processes, such as stress response, chromatin condensation, protection from protein degradation, invasiveness of cells, alterations of Ca 2+ homeostasis and others which may contribute to CDDP resistance of ovarian adenocarcinoma cells. Further characterization of these genes and gene products should yield important insights into the biology of

  4. Predisposing genes in hereditary breast and ovarian cancer

    OpenAIRE

    Huusko, P. (Pia)

    1999-01-01

    Abstract In the present study, mutations in BRCA1 and BRCA2, the two major genes predisposing individuals to hereditary breast and ovarian cancer, were screened in Finnish and Turkish cancer families. Germline BRCA1 mutations were found in 7% (6/88) and BRCA2 mutations in 6% (5/88) of the Finnish families studied in Oulu. Two distinct BRCA1 (3745delT, 4216nt-2A→G) and three BRCA2 (999delTCAAA, 6503delTT, 9346nt-2A→G) mutations were identified, all of which are recurrently found in Finland....

  5. The milk-derived fusion peptide, ACFP, suppresses the growth of primary human ovarian cancer cells by regulating apoptotic gene expression and signaling pathways.

    Science.gov (United States)

    Zhou, Juan; Zhao, Mengjing; Tang, Yigui; Wang, Jing; Wei, Cai; Gu, Fang; Lei, Ting; Chen, Zhiwu; Qin, Yide

    2016-03-24

    ACFP is an anti-cancer fusion peptide derived from bovine milk protein. This study was to investigate the anti-cancer function and underlying mechanisms of ACFP in ovarian cancer. Fresh ovarian tumor tissues were collected from 53 patients who underwent initial debulking surgery, and primary cancer cells were cultured. Normal ovarian surface epithelium cells (NOSECs), isolated from 7 patients who underwent surgery for uterine fibromas, were used as normal control tissue. Anti-viabilities of ACFP were assessed by WST-1 (water-soluble tetrazolium 1), and apoptosis was measured using a flow cytometry-based assay. Gene expression profiles of ovarian cancer cells treated with ACFP were generated by cDNA microarray, and the expression of apoptotic-specific genes, such as bcl-xl, bax, akt, caspase-3, CDC25C and cyclinB1, was assessed by real time PCR and western blot analysis. Treatment with ACFP inhibited the viability and promoted apoptosis of primary ovarian cancer cells but exhibited little or no cytotoxicity toward normal primary ovarian cells. Mechanistically, the anti-cancer effects of ACFP in ovarian cells were shown to occur partially via changes in gene expression and related signal pathways. Gene expression profiling highlighted that ACFP treatment in ovarian cancer cells repressed the expression of bcl-xl, akt, CDC25C and cyclinB1 and promoted the expression of bax and caspase-3 in a time- and dose-dependent manner. Our results suggest that ACFP may represent a potential therapeutic agent for ovarian cancer that functions by altering the expression and signaling of cancer-related pathways in ovarian cancer cells.

  6. Identifying candidate driver genes by integrative ovarian cancer genomics data

    Science.gov (United States)

    Lu, Xinguo; Lu, Jibo

    2017-08-01

    Integrative analysis of molecular mechanics underlying cancer can distinguish interactions that cannot be revealed based on one kind of data for the appropriate diagnosis and treatment of cancer patients. Tumor samples exhibit heterogeneity in omics data, such as somatic mutations, Copy Number Variations CNVs), gene expression profiles and so on. In this paper we combined gene co-expression modules and mutation modulators separately in tumor patients to obtain the candidate driver genes for resistant and sensitive tumor from the heterogeneous data. The final list of modulators identified are well known in biological processes associated with ovarian cancer, such as CCL17, CACTIN, CCL16, CCL22, APOB, KDF1, CCL11, HNF1B, LRG1, MED1 and so on, which can help to facilitate the discovery of biomarkers, molecular diagnostics, and drug discovery.

  7. Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer

    OpenAIRE

    Roy, Debarshi; Mondal, Susmita; Wang, Chen; He, Xiaoping; Khurana, Ashwani; Giri, Shailendra; Hoffmann, Robert; Jung, Deok-Beom; Kim, Sung H; Chini, Eduardo N; Periera, Juliana Camacho; Folmes, Clifford D; Mariani, Andrea; Dowdy, Sean C; Bakkum-Gamez, Jamie N

    2014-01-01

    Background Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism. Results Ingenuity pathway anal...

  8. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells

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    Matyunina Lilya V

    2009-12-01

    Full Text Available Abstract Background Accumulating evidence suggests that somatic stem cells undergo mutagenic transformation into cancer initiating cells. The serous subtype of ovarian adenocarcinoma in humans has been hypothesized to arise from at least two possible classes of progenitor cells: the ovarian surface epithelia (OSE and/or an as yet undefined class of progenitor cells residing in the distal end of the fallopian tube. Methods Comparative gene expression profiling analyses were carried out on OSE removed from the surface of normal human ovaries and ovarian cancer epithelial cells (CEPI isolated by laser capture micro-dissection (LCM from human serous papillary ovarian adenocarcinomas. The results of the gene expression analyses were randomly confirmed in paraffin embedded tissues from ovarian adenocarcinoma of serous subtype and non-neoplastic ovarian tissues using immunohistochemistry. Differentially expressed genes were analyzed using gene ontology, molecular pathway, and gene set enrichment analysis algorithms. Results Consistent with multipotent capacity, genes in pathways previously associated with adult stem cell maintenance are highly expressed in ovarian surface epithelia and are not expressed or expressed at very low levels in serous ovarian adenocarcinoma. Among the over 2000 genes that are significantly differentially expressed, a number of pathways and novel pathway interactions are identified that may contribute to ovarian adenocarcinoma development. Conclusions Our results are consistent with the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as the origin of ovarian adenocarcinoma. While our findings do not rule out the possibility that ovarian cancers may also arise from other sources, they are inconsistent with claims that ovarian surface epithelia cannot serve as the origin of ovarian cancer initiating cells.

  9. Differentially expressed genes and gene networks involved in pig ovarian follicular atresia.

    Science.gov (United States)

    Terenina, Elena; Fabre, Stephane; Bonnet, Agnès; Monniaux, Danielle; Robert-Granié, Christèle; SanCristobal, Magali; Sarry, Julien; Vignoles, Florence; Gondret, Florence; Monget, Philippe; Tosser-Klopp, Gwenola

    2017-02-01

    Ovarian folliculogenesis corresponds to the development of follicles leading to either ovulation or degeneration, this latter process being called atresia. Even if atresia involves apoptosis, its mechanism is not well understood. The objective of this study was to analyze global gene expression in pig granulosa cells of ovarian follicles during atresia. The transcriptome analysis was performed on a 9,216 cDNA microarray to identify gene networks and candidate genes involved in pig ovarian follicular atresia. We found 1,684 significantly regulated genes to be differentially regulated between small healthy follicles and small atretic follicles. Among them, 287 genes had a fold-change higher than two between the two follicle groups. Eleven genes (DKK3, GADD45A, CAMTA2, CCDC80, DAPK2, ECSIT, MSMB, NUPR1, RUNX2, SAMD4A, and ZNF628) having a fold-change higher than five between groups could likely serve as markers of follicular atresia. Moreover, automatic confrontation of deregulated genes with literature data highlighted 93 genes as regulatory candidates of pig granulosa cell atresia. Among these genes known to be inhibitors of apoptosis, stimulators of apoptosis, or tumor suppressors INHBB, HNF4, CLU, different interleukins (IL5, IL24), TNF-associated receptor (TNFR1), and cytochrome-c oxidase (COX) were suggested as playing an important role in porcine atresia. The present study also enlists key upstream regulators in follicle atresia based on our results and on a literature review. The novel gene candidates and gene networks identified in the current study lead to a better understanding of the molecular regulation of ovarian follicular atresia. Copyright © 2017 the American Physiological Society.

  10. Radiation improves gene transfer into human ovarian carcinoma cells

    International Nuclear Information System (INIS)

    Canaday, Daniel; Zeng Ming; Cerniglia, George; Stevens, Craig W.

    1997-01-01

    Purpose/Objective: Poor gene transfer is the major stumbling block to successful gene therapy today. We hypothesized that ionizing radiation might activate cellular recombination, and so improve stable gene transfer. During studies to quantitate radiation activated recombination, we also found that both plasmid and adenoviral vector transduction could be increased by irradiation. The studies presented here describe the effects of irradiation on gene transduction efficiency (both transient and stable transduction) in several human ovarian carcinoma lines, as a prelude to in vivo animal studies. Materials and Methods: The effect of irradiation on stable gene transfer efficiency was determined in human ovarian carcinoma cell lines (SKOV3, CAOV3 and PA1). Either irradiated or unirradiated cells were transfected with pRSVZ plasmid (containing a LacZ expression cassette) in either the supercoiled and linearized (XmnI) forms and β-galactosidase expression followed with time. Transfection efficiency was measured by flow cytometry following FDG staining at 0, 48, and 96 hours after irradiation. FDG is converted to a fluorescent metabolite by LacZ, and thus reflects the transfection efficiency of the LacZ containing vector. Vector quantitation was also performed by southern hybridization. Stable transduction efficiency was measured 14 -35 days after irradiation. Optimization of the time of irradiation with respect to transfection was performed. Since cells demonstrated increased stable recombination for as long as 96 hours after irradiation, continuous low dose rate and multiple radiation fractions were also tested. These experiments were repeated using the Ad5CMVlacZ. Dividing cells were exposed to Ad5CMVlacZ at an MOI of 0.1,1,5,10 and 100 to determine optimum transfection concentration. Transduction efficiency was again measured at various intervals to determine the radiation dose and interval post transfection which provides the maximum increase in transfection

  11. Polymorphic variation of genes in the fibrinolytic system and the risk of ovarian cancer.

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    Yaakov Bentov

    Full Text Available INTRODUCTION: The etiology of ovarian cancer is largely unknown. One hypothesis is that the inefficient removal of the blood clots and fibrin products which are deposited in the vicinity of the ovary by retrograde menstruation might be associated with an increased risk of ovarian cancer. Several single nucleotide polymorphisms within genes which comprise the fibrinolytic system have been shown to have functional effects on the rate of blood clot degradation. These were considered to be candidate genes in the present study. AIM: We studied the genotype distributions of 12 functional SNPs of four genes (tPA, uPA PAI1 and TAFI among 775 ovarian cancer cases and 889 controls. RESULTS: No significant associations were seen between any of the ten SNPs and the risk of ovarian cancer as a whole, or in any histologic subgroup. DISCUSSION: Germline known functional variants of genes in the fibrinolytic system are not associated with risk of ovarian cancer.

  12. Ovarian Cancer: The Interplay of Lifestyle and Genes

    NARCIS (Netherlands)

    Braem, M.G.M.

    2014-01-01

    Ovarian cancer is a highly lethal disease that is mostly diagnosed at an advanced stage. In Europe, only 36% of women with ovarian cancer can expect to survive 5 years. While our knowledge of ovarian cancer has changed substantially throughout the years, our understanding of its etiology still lacks

  13. Sulpiride-Induced Hyperprolactinemia in Mature Female Rats: Evidence for Alterations in The Reproductive System, Pituitary and Ovarian Hormones

    OpenAIRE

    Sara Mostafapour; Samad Zare; Rajab Ali Sadrkhanlou; Abbas Ahmadi; Mazdak Razi

    2014-01-01

    Background: The prevalence of hyperprolactinemia following administration of conventional antipsychotic drugs requires further investigation. The current study is designed to evaluate the effect of sulpiride (SPD)-induced hyperprolactinemia on alterations to ovarian follicular growth, gonadotropins, and ovarian hormones and to analyze the extent of potential problems in mammary glands. Materials and Methods: A total of 40 albino Wistar rats were divided into four groups: con...

  14. Neurotransmitter alteration in a testosterone propionate-induced polycystic ovarian syndrome rat model.

    Science.gov (United States)

    Chaudhari, Nirja K; Nampoothiri, Laxmipriya P

    2017-02-01

    Polycystic ovarian syndrome (PCOS), one of the leading causes of infertility seen in women, is characterized by anovulation and hyperandrogenism, resulting in ovarian dysfunction. In addition, associations of several metabolic complications like insulin resistance, obesity, dyslipidemia and psychological co-morbidities are well known in PCOS. One of the major factors influencing mood and the emotional state of mind is neurotransmitters. Also, these neurotransmitters are very crucial for GnRH release. Hence, the current study investigates the status of neurotransmitters in PCOS. A PCOS rat model was developed using testosterone. Twenty-one-day-old rats were subcutaneously injected with 10 mg/kg body weight of testosterone propionate (TP) for 35 days. The animals were validated for PCOS characteristics by monitoring estrus cyclicity, serum testosterone and estradiol levels and by histological examination of ovarian sections. Neurotransmitter estimation was carried out using fluorometric and spectrophotometric methods. TP-treated animals demonstrated increased serum testosterone levels with unaltered estradiol content, disturbed estrus cyclicity and many peripheral cysts in the ovary compared to control rats mimicking human PCOS. Norepinephrine (NE), dopamine, serotonin, γ-amino butyric acid (GABA) and epinephrine levels were significantly low in TP-induced PCOS rats compared to control ones, whereas the activity of acetylcholinesterase in the PCOS brain was markedly elevated. Neurotransmitter alteration could be one of the reasons for disturbed gonadotropin-releasing hormone (GnRH) release, consequently directing the ovarian dysfunction in PCOS. Also, decrease in neurotransmitters, mainly NE, serotonin and dopamine (DA) attributes to mood disorders like depression and anxiety in PCOS.

  15. Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers

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    Ghislain Vanessa

    2008-01-01

    Full Text Available Abstract Background The status of the EGFR and HER2-neu genes has not been fully defined in ovarian cancer. An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies. Methods We determined the tumour mutation status of the entire tyrosine kinase (TK domain of the EGFR and HER2-neu genes in a cohort of 52 patients with invasive epithelial ovarian cancer as well as the gene copy number and protein expression of both genes in 31 of these patients by DGGE and direct sequecing, immunohistochemistry and Fluorescent in Situ Hybridisation (FISH. Results The EGFR was expressed in 59% of the cases, with a 2+/3+ staining intensity in 38%. HER2-neu expression was found in 35%, with a 2/3+ staining in 18%. No mutations were found in exons 18–24 of the TK domains of EGFR and HER2-neu. High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry. Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others. Conclusion Genomic alteration of the HER2-neu and EGFR genes is frequent (25% in ovarian cancer. EGFR/HER2-neu targeted therapies should be investigated prospectively and specifically in that subset of patients.

  16. Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

    Energy Technology Data Exchange (ETDEWEB)

    Langland, Gregory T.; Yannone, Steven M.; Langland, Rachel A.; Nakao, Aki; Guan, Yinghui; Long, Sydney B.T.; Vonguyen, Lien; Chen, David J.; Gray, Joe W; Chen, Fanqing

    2009-09-07

    The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNAPK in ovarian cancer.

  17. Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids

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    Tetu Bernard

    2008-02-01

    Full Text Available Abstract Background Chemotherapy (CT resistance in ovarian cancer (OC is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155, following treatment with 10,0 μM cisplatin, 2,5 μM paclitaxel or 5,0 μM topotecan for 72 hours. Results Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism, signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes, cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses. Conclusion Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular

  18. Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids.

    Science.gov (United States)

    L'Espérance, Sylvain; Bachvarova, Magdalena; Tetu, Bernard; Mes-Masson, Anne-Marie; Bachvarov, Dimcho

    2008-02-26

    Chemotherapy (CT) resistance in ovarian cancer (OC) is broad and encompasses diverse unrelated drugs, suggesting more than one mechanism of resistance. To better understand the molecular mechanisms controlling the immediate response of OC cells to CT exposure, we have performed gene expression profiling in spheroid cultures derived from six OC cell lines (OVCAR3, SKOV3, TOV-112, TOV-21, OV-90 and TOV-155), following treatment with 10,0 microM cisplatin, 2,5 microM paclitaxel or 5,0 microM topotecan for 72 hours. Exposure of OC spheroids to these CT drugs resulted in differential expression of genes associated with cell growth and proliferation, cellular assembly and organization, cell death, cell cycle control and cell signaling. Genes, functionally involved in DNA repair, DNA replication and cell cycle arrest were mostly overexpressed, while genes implicated in metabolism (especially lipid metabolism), signal transduction, immune and inflammatory response, transport, transcription regulation and protein biosynthesis, were commonly suppressed following all treatments. Cisplatin and topotecan treatments triggered similar alterations in gene and pathway expression patterns, while paclitaxel action was mainly associated with induction of genes and pathways linked to cellular assembly and organization (including numerous tubulin genes), cell death and protein synthesis. The microarray data were further confirmed by pathway and network analyses. Most alterations in gene expression were directly related to mechanisms of the cytotoxics actions in OC spheroids. However, the induction of genes linked to mechanisms of DNA replication and repair in cisplatin- and topotecan-treated OC spheroids could be associated with immediate adaptive response to treatment. Similarly, overexpression of different tubulin genes upon exposure to paclitaxel could represent an early compensatory effect to this drug action. Finally, multicellular growth conditions that are known to alter gene

  19. Somatic copy number alterations predict response to platinum therapy in epithelial ovarian cancer.

    Science.gov (United States)

    Despierre, Evelyn; Moisse, Matthieu; Yesilyurt, Betül; Sehouli, Jalid; Braicu, Ioana; Mahner, Sven; Castillo-Tong, Dan Cacsire; Zeillinger, Robert; Lambrechts, Sandrina; Leunen, Karin; Amant, Frédéric; Moerman, Philippe; Lambrechts, Diether; Vergote, Ignace

    2014-12-01

    Platinum resistance remains an obstacle in the treatment of epithelial ovarian cancer (EOC). The goal of this study was to profile EOCs for somatic copy number alterations (SCNAs) as predictive markers of platinum response. SCNAs were assessed in a discovery (n=86) and validation cohort (n=115) of high risk stage I or stage II-IV EOCs using high-resolution SNP arrays. ASCAT and GISTIC identified all significantly overrepresented amplified or deleted chromosomal regions. Cox regression and univariate analysis assessed which SCNAs correlated with overall survival (OS), progression-free survival (PFS), platinum-free interval (PFI) and platinum response. Relevant SCNAs were also assessed in a pooled analysis involving both cohorts and published SCNA data from The Cancer Genome Atlas (TCGA; n=227). We identified 53 regions to be significantly overrepresented in EOC. Of these, 6 were associated with OS, PFS or PFI in the discovery cohort at P<0.05. In the validation cohort, amplifications of chromosomal region 14q32.33, which contains AKT1 as a potential driver gene, also correlated with OS (OR=1.670; P=0.018). In a pooled analysis of 428 tumors, involving the discovery, validation and TCGA cohorts, 14q32.33 amplifications significantly reduced OS, PFS and PFI (HR=2.69, P=1.7×10(-4); HR=1.82, P=1.9×10(-2) and HR=1.80, P=2.2×10(-2) respectively). Moreover, AKT1 mRNA expression correlated with the number of chromosomal copies of the 14q32.33 region (P=2.8×10(-11);R(2)=0.26). We established that amplifications in 14q32.33 were associated with reduced OS, PFS, PFI and platinum resistance in three independent cohorts, suggesting that AKT1 amplifications act as a potentially predictive marker for EOC treated with platinum-based chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

    NARCIS (Netherlands)

    Shen, H.; Fridley, B.L.; Song, H.; Lawrenson, K.; Cunningham, J.M.; Ramus, S.J.; Cicek, M.S.; Tyrer, J.; Stram, D.; Larson, M.C.; Kobel, M.; Ziogas, A.; Zheng, W.; Yang, H.P.; Wu, A.H.; Wozniak, E.L.; Ling Woo, Y.; Winterhoff, B.; Wik, E.; Whittemore, A.S.; Wentzensen, N.; Palmieri Weber, R.; Vitonis, A.F.; Vincent, D.; Vierkant, R.A.; Vergote, I.; Berg, D. Van den; Altena, A.M. van; Tworoger, S.S.; Thompson, P.J.; Tessier, D.C.; Terry, K.L.; Teo, S.H.; Templeman, C.; Stram, D.O.; Southey, M.C.; Sieh, W.; Siddiqui, N.; Shvetsov, Y.B.; Shu, X.O.; Shridhar, V.; Wang-Gohrke, S.; Severi, G.; Schwaab, I.; Salvesen, H.B.; Rzepecka, I.K.; Runnebaum, I.B.; Rossing, M.A.; Rodriguez-Rodriguez, L.; Risch, H.A.; Renner, S.P.; Poole, E.M.; Pike, M.C.; Phelan, C.M.; Pelttari, L.M.; Pejovic, T.; Paul, J.; Orlow, I.; Zawiah Omar, S.; Olson, S.H.; Odunsi, K.; Nickels, S.; Nevanlinna, H.; Ness, R.B.; Narod, S.A.; Nakanishi, T.; Moysich, K.B.; Monteiro, A.N.; Moes-Sosnowska, J.; Modugno, F.; Menon, U.; McLaughlin, J.R.; McGuire, V.; Matsuo, K.; Mat Adenan, N.A.; Massuger, L.F.A.G.; Lurie, G.; Lundvall, L.; Lubinski, J.; Lissowska, J.; Levine, D.A.; Leminen, A.; Lee, A.W.; Le, N.D.; Lambrechts, S.; Lambrechts, D.; Kupryjanczyk, J.; Krakstad, C.; Konecny, G.E.; Kruger Kjaer, S.; Kiemeney, L.A.L.M.; Kelemen, L.E.; Keeney, G.L.; Karlan, B.Y.; Karevan, R.; Kalli, K.R.; Kajiyama, H.; Ji, B.T.; Jensen, A.; Jakubowska, A.; Iversen, E.; Hosono, S.; Hogdall, C.K.; Hogdall, E.; Hoatlin, M.; Hillemans, P.; Heitz, F.; Hein, R.; Harter, P.; Halle, M.K.; Hall, P.; Gronwald, J.; Gore, M.; Goodman, M.T.; Giles, G.G.; Gentry-Maharaj, A.; Garcia-Closas, M.; Flanagan, J.M.; Fasching, P.A.; Ekici, A.B.; Edwards, R.; Eccles, D.; Easton, D.F.; Durst, M.; Bois, A. du; Dork, T.; Doherty, J.A.; Despierre, E.; Dansonka-Mieszkowska, A.; Cybulski, C.; Cramer, D.W; Cook, L.S.; Chen, X.; Charbonneau, B.; Chang-Claude, J.; Campbell, I.; Butzow, R.; Bunker, C.H.; Brueggmann, D.; Brown, R.; Brooks-Wilson, A.; Brinton, L.A.; Bogdanova, N.; Block, M.S.; Benjamin, E.; Beesley, J.; Beckmann, M.W.; Bandera, E.V.; Baglietto, L.; Bacot, F.; Armasu, S.M.; Antonenkova, N.; Anton-Culver, H.; Aben, K.K.; Liang, D.; et al.,

    2013-01-01

    HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we

  1. Elevated cyclooxygenase-2 expression is associated with altered expression of p53 and SMAD4, amplification of HER-2/neu, and poor outcome in serous ovarian carcinoma.

    Science.gov (United States)

    Erkinheimo, Tiina-Liisa; Lassus, Heini; Finne, Patrik; van Rees, Bastiaan P; Leminen, Arto; Ylikorkala, Olavi; Haglund, Caj; Butzow, Ralf; Ristimäki, Ari

    2004-01-15

    Cyclooxygenase-2 (COX-2) is frequently expressed in human adenocarcinomas and inhibition of COX-2 suppresses tumor formation in various animal models of carcinogenesis. We analyzed expression of COX-2 protein in human serous ovarian carcinomas by immunohistochemistry (n = 442) and by Western blotting (n = 12) and COX-2 mRNA by reverse transcriptase PCR (n = 12). COX-2 immunoreactivity was correlated to clinicopathological variables and to expression of p53 and SMAD4 as detected by immunohistochemistry and to amplification of HER-2/neu as detected by in situ hybridization. COX-2 mRNA expression was detected in 75% (9 of 12) and COX-2 protein in 42% (5 of 12) of the serous ovarian adenocarcinoma specimens as detected by reverse transcriptase-PCR and Western blot analysis, respectively. Moderate to strong (elevated) immunoreactivity for COX-2 was detected in 70% (310 of 442) of the tumors. Elevated COX-2 expression associated with reduced disease-specific survival (P = 0.0011), high histological grade (P 1 cm (P = 0.0111), and age > 57 years (P = 0.0099). Tumors with altered immunostaining pattern for p53 or SMAD4 expressed more frequently elevated levels of COX-2 when compared with the tumors with normal staining pattern of these tumor suppressor genes (P ovarian carcinomas and that expression of COX-2 may be induced in these tumors by loss of tumor suppressor genes such as p53 and SMAD4 and by amplification of HER-2/neuoncogene.

  2. High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression.

    Science.gov (United States)

    Roh, Michael H; Yassin, Yosuf; Miron, Alexander; Mehra, Karishma K; Mehrad, Mitra; Monte, Nicolas M; Mutter, George L; Nucci, Marisa R; Ning, Geng; Mckeon, Frank D; Hirsch, Michelle S; Wa, Xian; Crum, Christopher P

    2010-10-01

    High-grade endometrioid and serous carcinomas of the ovary and fallopian tube are responsible for the majority of cancer deaths and comprise a spectrum that includes early or localized (tubal intraepithelial carcinoma) and advanced (invasive or metastatic) disease. We subdivided a series of these tumors into three groups, (1) classic serous, (2) mixed serous and endometrioid and (3) endometrioid carcinomas and determined: (1) the frequencies of coexisting tubal intraepithelial carcinoma, (2) frequency of a dominant ovarian mass suggesting an ovarian origin and (3) immuno-localization of WT-1, p53, PTEN, PAX2 and p16(ink4). All tumors were analyzed for p53 mutations. Thirty six, 25 and 8% of groups 1-3 were associated with tubal intraepithelial carcinoma (P=0.09) and 34, 45 and 62% predominated in one ovary (P=0.028), respectively. Differences in frequencies of diffuse p53 immunostaining (85-93%), WT-1 (70-98%) and p16(ink4) positivity (69-75%) were not significant for all groups. Greater than 95% reduction in PAX2 and PTEN occurred in 67-75 and 5-12%, respectively; however, PAX2 and PTEN staining intensity, when present, was often heterogeneous, highlighting different tumor populations. PAX2 and PTEN expression were markedly reduced or absent in 12 of 12 and 4 of 12 tubal intraepithelial carcinomas. In summary, high-grade müllerian carcinomas share identical frequencies of altered or reduced expression of p53, PTEN and PAX2, all of which can be appreciated in tubal intraepithelial carcinomas. Because only a subset of these tumors appears to arise in the fallopian tube, attention to expression of these biomarkers in the ovary and other müllerian sites might facilitate the identification of other carcinogenic pathways. PAX2 and PTEN, in addition to p53 and p16(ink4), comprise a potentially important gene combination in high-grade pelvic carcinogenesis.

  3. Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Nicolai Skovbjerg Arildsen

    2017-05-01

    genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.

  4. Aberrant Expression of Anaplastic Lymphoma Kinase in Ovarian Carcinoma Independent of Gene Rearrangement.

    Science.gov (United States)

    Tang, Shaoxian; Yang, Fei; Du, Xiang; Lu, Yongming; Zhang, Ling; Zhou, Xiaoyan

    2016-07-01

    Ovarian carcinoma is the leading cause of death from gynecologic malignancies. The oncogenic role of anaplastic lymphoma kinase (ALK) is well characterized in many hematopoietic and solid tumors. ALK expression in ovarian carcinoma has been reported but the exact status of ALK protein and its association with clinicopathologic features requires further investigation. ALK expression was determined by immunohistochemistry in 110 primary ovarian carcinomas, including 85 cases of serous carcinoma and 25 cases of mucinous carcinoma. Fluorescence in situ hybridization (FISH) and real-time reverse transcription polymerase chain reaction (RT-PCR) were used for evaluating ALK translocation in ALK-positive ovarian carcinomas. Among 110 ovarian carcinomas, 23 (20.9%) cases were ALK positive by immunohistochemistry. All ALK-positive cases were ovarian high-grade serous carcinoma. ALK expression was detected in 23/85 (27.1%) ovarian serous carcinoma and 0/25 (0%) in ovarian mucinous carcinoma. None of the 23 ALK IHC-positive cases harbored ALK gene translocations by FISH or RT-PCR. ALK protein expression was associated with patient age, tumor stage, and histologic type. Specifically, the probability of ALK protein expression was significantly higher in high-grade serous carcinomas in older patients (above 50 y) with advanced disease (FIGO stage III and IV) compared with the low-grade serous and mucinous carcinomas in younger patients with relatively early disease. In conclusion, aberrant ALK expression is observed in ovarian serous carcinoma but not in mucinous carcinoma, is independent of gene translocation, and might be associated with progression and prognosis.

  5. Induction of autophagy by ARHI (DIRAS3) alters fundamental metabolic pathways in ovarian cancer models.

    Science.gov (United States)

    Ornelas, Argentina; McCullough, Christopher R; Lu, Zhen; Zacharias, Niki M; Kelderhouse, Lindsay E; Gray, Joshua; Yang, Hailing; Engel, Brian J; Wang, Yan; Mao, Weiqun; Sutton, Margie N; Bhattacharya, Pratip K; Bast, Robert C; Millward, Steven W

    2016-10-26

    Autophagy is a bulk catabolic process that modulates tumorigenesis, therapeutic resistance, and dormancy. The tumor suppressor ARHI (DIRAS3) is a potent inducer of autophagy and its expression results in necroptotic cell death in vitro and tumor dormancy in vivo. ARHI is down-regulated or lost in over 60 % of primary ovarian tumors yet is dramatically up-regulated in metastatic disease. The metabolic changes that occur during ARHI induction and their role in modulating death and dormancy are unknown. We employed Nuclear Magnetic Resonance (NMR)-based metabolomic strategies to characterize changes in key metabolic pathways in both cell culture and xenograft models of ARHI expression and autophagy. These pathways were further interrogated by cell-based immunofluorescence imaging, tracer uptake studies, targeted metabolic inhibition, and in vivo PET/CT imaging. Induction of ARHI in cell culture models resulted in an autophagy-dependent increase in lactate production along with increased glucose uptake and enhanced sensitivity to glycolytic inhibitors. Increased uptake of glutamine was also dependent on autophagy and dramatically sensitized cultured ARHI-expressing ovarian cancer cell lines to glutaminase inhibition. Induction of ARHI resulted in a reduction in mitochondrial respiration, decreased mitochondrial membrane potential, and decreased Tom20 staining suggesting an ARHI-dependent loss of mitochondrial function. ARHI induction in mouse xenograft models resulted in an increase in free amino acids, a transient increase in [ 18 F]-FDG uptake, and significantly altered choline metabolism. ARHI expression has previously been shown to trigger autophagy-associated necroptosis in cell culture. In this study, we have demonstrated that ARHI expression results in decreased cellular ATP/ADP, increased oxidative stress, and decreased mitochondrial function. While this bioenergetic shock is consistent with programmed necrosis, our data indicates that the accompanying up

  6. Expression Profiles of Fsh-Regulated Ovarian Genes during Oogenesis in Coho Salmon

    Science.gov (United States)

    Guzmán, José M.; Luckenbach, J. Adam; Yamamoto, Yoji; Swanson, Penny

    2014-01-01

    The function of follicle-stimulating hormone (Fsh) during oogenesis in fishes is poorly understood. Using coho salmon as a fish model, we recently identified a suite of genes regulated by Fsh in vitro and involved in ovarian processes mostly unexplored in fishes, like cell proliferation, differentiation, survival or extracellular matrix (ECM) remodeling. To better understand the role of these Fsh-regulated genes during oocyte growth in fishes, we characterized their mRNA levels at discrete stages of the ovarian development in coho salmon. While most of the transcripts were expressed at low levels during primary growth (perinucleolus stage), high expression of genes associated with cell proliferation (pim1, pcna, and mcm4) and survival (ddit4l) was found in follicles at this stage. The transition to secondary oocyte growth (cortical alveolus and lipid droplet stage ovarian follicles) was characterized by a marked increase in the expression of genes related to cell survival (clu1, clu2 and ivns1abpa). Expression of genes associated with cell differentiation and growth (wt2l and adh8l), growth factor signaling (inha), steroidogenesis (cyp19a1a) and the ECM (col1a1, col1a2 and dcn) peaked in vitellogenic follicles, showing a strong and positive correlation with transcripts for fshr. Other genes regulated by Fsh and associated with ECM function (ctgf, wapl and fn1) and growth factor signaling (bmp16 and smad5l) peaked in maturing follicles, along with increases in steroidogenesis-related gene transcripts. In conclusion, ovarian genes regulated by Fsh showed marked differences in their expression patterns during oogenesis in coho salmon. Our results suggest that Fsh regulates different ovarian processes at specific stages of development, likely through interaction with other intra- or extra-ovarian factors. PMID:25485989

  7. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    Science.gov (United States)

    Jim, Heather S.L.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Sieh, Weiva; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Vierkant, Robert A.; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Thomsen, Lotte; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Palmieri Weber, Rachel; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Schernhammer, Eva; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Amankwah, Ernest; Berchuck, Andrew; Schildkraut, Joellen M.; Kelemen, Linda E.; Ramus, Susan J.; Monteiro, Alvaro N.A.; Goode, Ellen L.; Narod, Steven A.; Gayther, Simon A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2016-01-01

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways. PMID:26807442

  8. Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma.

    Science.gov (United States)

    de Cristofaro, Tiziana; Di Palma, Tina; Soriano, Amata Amy; Monticelli, Antonella; Affinito, Ornella; Cocozza, Sergio; Zannini, Mariastella

    2016-07-05

    Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma.

  9. Early Alterations in Ovarian Surface Epithelial Cells and Induction of Ovarian Epithelial Tumors Triggered by Loss of FSH Receptor

    Directory of Open Access Journals (Sweden)

    Xinlei Chen

    2007-06-01

    Full Text Available Little is known about the behavior of the ovarian surface epithelium (OSE, which plays a central role in ovarian cancer etiology. It has been suggested that incessant ovulation causes OSE changes leading to transformation and that high gonadotropin levels during postmenopause activate OSE receptors, inducing proliferation. We examined the chronology of OSE changes, including tumor appearance, in a mouse model where ovulation never occurs due to deletion of follitropin receptor. Changes in epithelial cells were marked by pan-cytokeratin (CK staining. Histologic changes and CK staining in the OSE increased from postnatal day 2. CK staining was observed inside the ovary by 24 days and increased thereafter in tumor-bearing animals. Ovaries from a third of aged (1 year mutant mice showed CK deep inside, indicating cell migration. These tumors resembled serous papillary adenoma of human ovaries. Weak expression of GATA-4 and elevation of PCNA, cyclooxygenase-1, cyclooxygenase-2, and plateletderived growth factor receptors α and β in mutants indicated differences in cell proliferation, differentiation, and inflammation. Thus, we report that OSE changes occur long before epithelial tumors appear in FORKO mice. Our results suggest that neither incessant ovulation nor follicle-stimulating hormone receptor presence in the OSE is required for inducing ovarian tumors; thus, other mechanisms must contribute to ovarian tumorigenesis.

  10. Efficient inhibition of ovarian cancer by degradable nanoparticle-delivered survivin T34A gene

    Science.gov (United States)

    Luo, Li; Du, Ting; Zhang, Jiumeng; Zhao, Wei; Cheng, Hao; Yang, Yuping; Wu, Yujiao; Wang, Chunmei; Men, Ke; Gou, Maling

    2016-01-01

    Gene therapy has promising applications in ovarian cancer therapy. Blocking the function of the survivin protein could lead to the growth inhibition of cancer cells. Herein, we used degradable heparin–polyethyleneimine (HPEI) nanoparticles to deliver a dominant-negative human survivin T34A (hs-T34A) gene to treat ovarian cancer. HPEI nanoparticles were characterized and were found to have a dynamic diameter of 66±4.5 nm and a zeta potential of 27.1±1.87 mV. The constructed hs-T34A gene expression plasmid could be effectively delivered into SKOV3 ovarian carcinoma cells by HPEI nanoparticles with low cytotoxicity. Intraperitoneal administration of HPEI/hs-T34A complexes could markedly inhibit tumor growth in a mouse xenograft model of SKOV3 human ovarian cancer. Moreover, according to our results, apparent apoptosis of cancer cells was observed both in vitro and in vivo. Taken together, the prepared HPEI/hs-T34A formulation showed potential applications in ovarian cancer gene therapy. PMID:26893558

  11. Risk of ovarian cancer and inherited variants in relapse-associated genes.

    Directory of Open Access Journals (Sweden)

    Abraham Peedicayil

    2010-01-01

    Full Text Available We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk.Women with and without invasive ovarian cancer (749 cases, 1,041 controls were genotyped at 136 single nucleotide polymorphisms (SNPs within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog was associated with risk of serous cancer (p = 0.03; haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog were associated with risk of invasive disease (p = 0.03. MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03. SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05, and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91.Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.

  12. Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.

    Directory of Open Access Journals (Sweden)

    Carolina Vizcaíno

    Full Text Available Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK that binds to C+G-rich DNA sequences. Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death. Some of those genes have been associated with cell proliferation and poor prognosis in ovarian cancer. Sp1 transcription factor regulated most of the genes that were down-regulated by the drug, as well as the up-regulation of other genes mainly involved in response to cell stress. The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored. Some of them, such as CREB, E2F and EGR1, also recognize C/G-rich regions in gene promoters, which encompass potential DIG-MSK binding sites. DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity. This new compound might be a promising drug for the treatment of ovarian cancer.

  13. Gene expression analysis of matched ovarian primary tumors and peritoneal metastasis

    Directory of Open Access Journals (Sweden)

    Malek Joel A

    2012-06-01

    Full Text Available Abstract Background Ovarian cancer is the most deadly gynecological cancer due to late diagnosis at advanced stage with major peritoneal involvement. To date most research has focused on primary tumor. However the prognosis is directly related to residual disease at the end of the treatment. Therefore it is mandatory to focus and study the biology of meatastatic disease that is most frequently localized to the peritoneal caivty in ovarian cancer. Methods We used high-density gene expression arrays to investigate gene expression changes between matched primary and metastatic (peritoneal lesions. Results Here we show that gene expression profiles in peritoneal metastasis are significantly different than their matched primary tumor and these changes are affected by underlying copy number variation differences among other causes. We show that differentially expressed genes are enriched in specific pathways including JAK/STAT pathway, cytokine signaling and other immune related pathways. We show that underlying copy number variations significantly affect gene expression. Indeed patients with important differences in copy number variation displayed greater gene expression differences between their primary and matched metastatic lesions. Conclusions Our analysis shows a very specific targeting at both the genomic and transcriptomic level to upregulate certain pathways in the peritoneal metastasis of ovarian cancer. Moreover, while primary tumors use certain pathways we identify distinct differences with metastatic lesions. The variation between primary and metastatic lesions should be considered in personalized treatment of ovarian cancer.

  14. Evaluation the expression of three genes to epithelial ovarian ...

    African Journals Online (AJOL)

    Background: Ovarian cancer is associated with poor survival, because patients are diagnosed at an advanced stage of the disease, and in addition, tumors develop chemoresistance, which carries a poor prognosis for the patient. Material and methods: We hypothesize that high expression of SDF-1, survivin and smac is ...

  15. Ovarian Cancer Therapy by VSVMP Gene Mediated by a Paclitaxel-Enhanced Nanoparticle.

    Science.gov (United States)

    Long, Jianlin; Yang, Yuping; Kang, Tianyi; Zhao, Wei; Cheng, Hao; Wu, Yujiao; Du, Ting; Liu, Beibei; Li, Yang; Luo, Feng; Gou, Maling

    2017-11-15

    Nanoparticles have great promise for gene delivery. However, the transfection efficiency of nanoparticle-based gene delivery systems is always unsatisfied to meet the requirement of effective gene therapy. Herein, we used low-dosage paclitaxel to enhance a nanoscaled gene delivery system that was self-assembled from N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammoniummethyl sulfate and monomethoxy poly(ethylene glycol)-poly(d,l-lactide) (DPP), creating a paclitaxel-encapsulated DPP (P-DPP) nanoparticle. The encapsulated low-dosage paclitaxel significantly improved the gene delivery efficiency of the DPP nanoparticles against multiple cancer cells, in some of which the transfection efficiency is as high as 92%. By the P-DPP nanoparticle, vesicular stomatitis virus matrix protein (VSVMP) that could induce cell apoptosis was delivered to treat ovarian cancer. The encapsulation of paclitaxel in DPP nanoparticles increased the expression of VSVMP, enhancing VSVMP to induce antiproliferation and apoptosis in SKOV3 ovarian cancer cells. Intraperitoneal administration of P-DPP-delivered VSVMP effectively inhibited the intraperitoneal metastasis of SKOV3 ovarian cancer, which was more efficient than DPP-delivered VSVMP. Moreover, it was found that the tumor cell apoptosis induction, tumor cell proliferation inhibition, and tumor angiogenesis suppression were involved in the anticancer mechanism of this nanocomplex. Our data suggest that the encapsulation of low-dosage paclitaxel can enhance the gene delivery efficiency of the DPP nanoparticles against multiple cancer cells and exert a synergistic anticancer effect with VSVMP gene in ovarian cancer treatment. The VSVMP gene therapy delivered by the paclitaxel-enhanced nanoparticle has potential application in ovarian cancer therapy.

  16. Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors.

    Science.gov (United States)

    Miller, Carl W; Ikezoe, Takayuki; Krug, Utz; Hofmann, Wolf-K; Tavor, Sigal; Vegesna, Vijaya; Tsukasaki, Kunihiro; Takeuchi, Seisho; Koeffler, H Phillip

    2002-01-01

    Checkpoint genes, activated in response to DNA damage and other stresses, are frequently targeted for alteration in cancer. Checkpoint kinase 2 (CHK2, CDS1, RAD53) is activated by ataxia telangiectasia mutated (ATM) in response to gamma irradiation. Activated CHK2 stabilizes TP53, and acts on other cell cycle and stress regulators. These findings place CHK2 in the middle of a pathway frequently targeted in cancer. Because of this, and the observation that CHK2 mutations are inherited in some Li-Fraumeni cancer syndrome families, we decided to examine the role of CHK2 mutations in sporadic cancers. Exploiting the genomic sequence of chromosome 22, we looked for mutations in the exons and intron junctions of the CHK2 gene in DNA samples from 170 patients (57 osteosarcomas, 25 other sarcomas, 35 nonsmall-cell lung, 20 ovarian, and 33 breast cancers). Missense mutations affecting the forkhead and kinase domains were detected in four osteosarcomas and in one ovarian and one lung cancer. These findings of CHK2 gene mutations are consistent with osteosarcoma being a defining tumor of Li-Fraumeni syndrome. The occurrence of CHK2 mutations in sporadic cancers emphasizes the importance of the stress pathway which includes TP53.

  17. Low frequency of ESRRA-C11orf20 fusion gene in ovarian carcinomas.

    Directory of Open Access Journals (Sweden)

    Francesca Micci

    2014-02-01

    Full Text Available The identification of recurrent gene fusions in common epithelial cancers--for example, TMPRSS2/ERG in prostate cancer and EML4/ALK in nonsmall cell lung carcinomas--has raised the question of whether fusion genes are pathogenetically important also in ovarian carcinomas. The first recurrent fusion transcript in serous ovarian carcinomas was reported by Salzman et al. in 2011, who used deep paired-end sequencing to detect the fusion gene ESRRA-C11orf20 in 10 out of 67 (15% serous ovarian carcinomas examined, a finding that holds great promise for our understanding of ovarian tumorigenesis as well as, potentially, for new treatment strategies. We wanted to test how frequent the ESRRA/C11orf20 fusion is in ovarian carcinomas of all subtypes, and therefore examined a series of 230 ovarian carcinomas of which 197 were of the serous subtype and 163 of the 197 were of stages III and IV--that is, the very same carcinoma subset where the fusion transcript had been found. We performed PCR and high-throughput sequencing analyses in search of the fusion transcript. We used the same primers described previously for the detection of the fusion and the same primer combination, but found no ESRRA/C11orf20 fusion in our series. A synthetic DNA plasmid containing the reported ESRRA/C11orf20 fusion was included as a positive control for our PCR experiments. Data from high-throughput sequencing of 23 ovarian carcinomas were screened in search of alternative partner(s for the ESRRA and/or C11orf20 gene, but none was found. We conclude that the frequency of the ESRRA/C11orf20 gene fusion in serous ovarian carcinomas of stages III and IV must be considerable less than that reported previously (0/163 in our experience compared with 10/67 in the previous study. At the very least, it seems clear that the said fusion cannot be a common pathogenetic event in this tumor type.

  18. Prognostic values of DNA mismatch repair genes in ovarian cancer patients treated with platinum-based chemotherapy.

    Science.gov (United States)

    Zhao, Chuchu; Li, Saisai; Zhao, Menghuang; Zhu, Haiyan; Zhu, Xueqiong

    2018-01-01

    DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. MMR has been reported as a prognostic marker in certain cancers; however, the results are controversial. Therefore, identification of the prognostic value of MMR genes in ovarian cancer based on a large sample size is pivotal. In the current study, we systemically investigated the prognostic roles of seven MMR genes, MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2, in ovarian cancer patients treated with platinum-based chemotherapy through "The Kaplan-Meier plotter" (KM plotter) database, which contains gene expression data and survival information of ovarian cancer patients. Among seven MMR genes, high mRNA levels of MSH6, MLH1 and PMS2 were significantly associated with a better overall survival for all ovarian cancer patients treated with platinum-based chemotherapy, especially in late-stage and poor-differentiated ovarian cancer patients. Increased MSH6 and PMS2 mRNA expression was correlated with a favorable overall survival in serous ovarian cancer patients. Our results indicate that sufficient MMR system is associated with an improved survival in ovarian cancer treated with platinum-based chemotherapy. MMR gene may be a potential prognosis predictor in ovarian cancer.

  19. Ovarian cancer targeted adenoviral-mediated mda-7/IL-24 gene therapy

    NARCIS (Netherlands)

    Mahasreshti, PJ; Kataram, M; Wu, HJ; Yalavarthy, LP; Carey, D; Dent, P; Chada, S; Alvarez, RD; Haisma, HJ; Fisher, PB; Curiel, DT

    Objective. We have previously shown that adenoviral-mediated melanoma differentiation-associated gene-7 (Ad.mda-7) therapy induces apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7. The objective of this study was to

  20. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer ...

    Indian Academy of Sciences (India)

    Unknown

    Department of Biochemistry and Experimental Oncology, 1st Faculty of Medicine, Charles University,. U Nemocnice 5, 12853 Prague 2, Czech Republic. Abstract. Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly ...

  1. ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

    DEFF Research Database (Denmark)

    Hedditch, Ellen L; Gao, Bo; Russell, Amanda J

    2014-01-01

    BACKGROUND: ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. METHODS: The relationship between clinical outcomes and ABC transporter gene expression in two in...

  2. Gene expression profiles as prognostic markers in women with ovarian cancer

    DEFF Research Database (Denmark)

    Jochumsen, Kirsten M; Tan, Qihua; Høgdall, Estrid V

    2009-01-01

    toward investigations for more individualized therapies and the use of gene expression profiles in the clinical practice. RNA from tumor tissue from 43 Danish patients with serous epithelial ovarian carcinoma (11 International Federation of Gynecology and Obstetrics [FIGO] stage I/II, 32 FIGO stage III...

  3. Cytotoxic T lymphocyte associated molecule -4 (CTLA-4 gene polymorphisms in ovarian cancer patients

    Directory of Open Access Journals (Sweden)

    Sirous Naeimi

    2010-09-01

    Full Text Available Background: Ovarian cancer is a relatively common cancer among postmenopausal women. Nowadays, there is controversy about immunotherapy of ovarian cancer patients with interleukins such as interferon to reach better out come in prognosis of patients under chemotherapy. CTLA-4 is a gene, which has an important role in homeostasis and regulation of immune response. Inhibitory nature of CTLA-4 is proved to be of significance in autoimmune diseases as well as in cancer. In this study we intend to find out the relationship between polymorphisms of this gene at the sites of +49 A/G and -318 C/T and ovarian cancer.Methods: The polymorphisms of the CTLA-4 gene at the sites of +49 A/G exon and -318 C/T promoter were investigated. Blood samples of 73 patients with ovarian cancer and 115 healthy subjects used for DNA extraction. Two groups genotypes and alleles were determined using PCR method and compared by statistical t-student test.Results: There was no statistically significant difference in genotypes and alleles prevalence of +49 A/G and -317 C/T between two groups (p>0.05.Conclusion: Further researches with larger sample size while paying attention to the relation between the gene polymorphism and stage and type of tumor is recommended.

  4. Gene expression of membrane transporters: Importance for prognosis and progression of ovarian carcinoma

    Czech Academy of Sciences Publication Activity Database

    Elsnerová, K.; Mohelniková; Duchonová, B.; Čeřovská, E.; Ehrlichová, M.; Gut, I.; Rob, L.; Skapa, P.; Hruda, M.; Bartáková, A.; Bouda, J.; Vodička, Pavel; Souček, P.; Václavíková, R.

    2016-01-01

    Roč. 35, č. 4 (2016), s. 2159-2170 ISSN 1021-335X R&D Projects: GA MZd(CZ) NT14056; GA MŠk(CZ) LD14050 Institutional support: RVO:68378041 Keywords : epithelial ovarian cancer * ABC transporters * SLC transporters * gene expression * prognosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.662, year: 2016

  5. Identification of genes and pathways associated with cytotoxic T lymphocyte infiltration of serous ovarian cancer

    NARCIS (Netherlands)

    Leffers, N; Fehrmann, R S N; Gooden, M J M; Schulze, U R J; Ten Hoor, K A; Hollema, H; Boezen, H M; Daemen, T; de Jong, S.; Nijman, H W; van der Zee, A G J

    2010-01-01

    BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs)

  6. Assessing local stromal alterations in human ovarian cancer subtypes via second harmonic generation microscopy and analysis

    Science.gov (United States)

    Campbell, Kirby R.; Campagnola, Paul J.

    2017-11-01

    The collagen architecture in all human ovarian cancers is substantially remodeled, where these alterations are manifested in different fiber widths, fiber patterns, and fibril size and packing. Second harmonic generation (SHG) microscopy has differentiated normal tissues from high-grade serous (HGS) tumors with high accuracy; however, the classification between low-grade serous, endometrioid, and benign tumors was less successful. We postulate this is due to known higher genetic variation in these tissues relative to HGS tumors, which are genetically similar, and this results in more heterogeneous collagen remodeling in the respective matrix. Here, we examine fiber widths and SHG emission intensity and directionality locally within images (e.g., 10×10 microns) and show that normal tissues and HGS tumors are more uniform in fiber properties as well as in fibril size and packing than the other tissues. Moreover, these distributions are in good agreement with phase matching considerations relating SHG emission directionality and intensity. The findings show that in addition to average collagen assembly properties the intrinsic heterogeneity must also be considered as another aspect of characterization. These local analyses showed differences not shown in pure intensity-based image analyses and may provide further insight into disease etiology of the different tumor subtypes.

  7. Expression analysis and prognostic significance of the SRA1 gene, in ovarian cancer

    International Nuclear Information System (INIS)

    Leoutsakou, Theoni; Talieri, Maroulio; Scorilas, Andreas

    2006-01-01

    The SR-related-CTD-associated-factors (SCAFs) have the ability to interact with the C-terminal domain of the RNA polymerase II, linking this way transcription to splicing. SRA1 (SR-A1) gene, encoding for a human high-molecular weight SCAF protein, is located on chromosome 19, between the IRF3 and the R-RAS oncogene and it has been demonstrated from members of our group that SRA1 is constitutively expressed in most of the human tissues, while it is overexpressed in a subset of ovarian tumors. In this study, we examine the expression of SRA1 gene in 111 ovarian malignant tissues and in the human ovarian carcinoma cell lines OVCAR-3, TOV21-G, and ES-2, using a semi-quantitative RT-PCR method. SRA1 gene was overexpressed in 61/111 (55%) of ovarian carcinomas. This higher expression was positively associated to the size of the tumor (p < 0.001), the grade and the stage of the disease (p = 0.003 and p = 0.006, respectively), and the debulking success (p < 0.001). Kaplan-Meier survival analysis revealed that lower SRA1 expression increases the probability of both the longer overall and the progression free survival of the patients. Multivariate Cox regression analysis revealed that SRA1 may be used as an independent prognostic biomarker in ovarian cancer. Our results suggest that SRA1 is associated with cancer progression and may possibly be characterized as a new marker of unfavorable prognosis for ovarian cancer

  8. The Brain as a Target for Environmental Toxicants that alter Ovarian Function.

    Science.gov (United States)

    In this review we discuss the ovarian cycle of the laboratory rat in order to familiarize the reader with the well-understood timing of the neuroendocrine events controlling ovarian function. This is followed by a discussion of the location and function of the estrogen and proges...

  9. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    NARCIS (Netherlands)

    Kelemen, L.E.; Terry, K.L.; Goodman, M.T.; Webb, P.M.; Bandera, E.V.; McGuire, V.; Rossing, M.A.; Wang, Q.; Dicks, E.; Tyrer, J.P.; Song, H.; Kupryjanczyk, J.; Dansonka-Mieszkowska, A.; Plisiecka-Halasa, J.; Timorek, A.; Menon, U.; Gentry-Maharaj, A.; Gayther, S.A.; Ramus, S.J.; Narod, S.A.; Risch, H.A.; McLaughlin, J.R.; Siddiqui, N.; Glasspool, R.; Paul, J.; Carty, K.; Gronwald, J.; Lubinski, J.; Jakubowska, A.; Cybulski, C.; Kiemeney, L.A.L.M.; Massuger, L.F.A.G.; Altena, A.M. van; Aben, K.K.H.; Olson, S.H.; Orlow, I.; Cramer, D.W; Levine, D.A.; Bisogna, M.; Giles, G.G.; Southey, M.C.; Bruinsma, F.; Kjaer, S.K.; Hogdall, E.; Jensen, A.; Hogdall, C.K.; Lundvall, L.; Engelholm, S.A.; Heitz, F.; Bois, A. du; Harter, P.; Schwaab, I.; Butzow, R.; Nevanlinna, H.; Pelttari, L.M.; Leminen, A.; Thompson, P.J.; Lurie, G.; Wilkens, L.R.; Lambrechts, D.; Nieuwenhuysen, E. Van; Lambrechts, S.; Vergote, I.; Beesley, J.; Investigators, A.S.G.A.; Fasching, P.A.; Beckmann, M.W.; Hein, A.; Ekici, A.B.; Doherty, J.A.; Wu, A.H.; Pearce, C.L.; Pike, M.C.; Stram, D.; Chang-Claude, J.; Rudolph, A.; Dork, T.; Durst, M.; Hillemanns, P.; Runnebaum, I.B.; Bogdanova, N.; Antonenkova, N.; Odunsi, K.; Edwards, R.P.; Kelley, J.L.; Modugno, F.; Ness, R.B.; Karlan, B.Y.; Walsh, C.; Lester, J.; Orsulic, S.; Fridley, B.L.; Vierkant, R.A.; Cunningham, J.M.; Wu, X.; Lu, K.; Liang, D.; Hildebrandt, M.A.T.; Weber, R.P.; Iversen, E.S.

    2014-01-01

    SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND Results : Odds

  10. High-Resolution Mapping of Genomic Imbalance and Identification of Gene Expression Profiles Associated with Differential Chemotherapy Response in Serous Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Marcus Bernardini

    2005-06-01

    Full Text Available Array comparative genomic hybridization (aCGH and microarray expression profiling were used to subclassify DNA and RNA alterations associated with differential response to chemotherapy in ovarian cancer. Two to 4 Mb interval arrays were used to map genomic imbalances in 26 sporadic serous ovarian tumors. Cytobands 1p36, iq42-44, 6p22.1-p21.2, 7q32.1-q34 9q33.3-q34.3, 11p15.2, 13q12.2-q13.1, 13q21.31, 17q11.2, 17q24.2-q25.3, 18q12.2, and 21q21.2-q21.3 were found to be statistically associated with chemotherapy response, and novel regions of loss at 15g11.2q15.1 and 17q21.32-q21.33 were identified. Gene expression profiles were obtained from a subset of these tumors and identified a group of genes whose differential expression was significantly associated with drug resistance. Within this group, five genes (GAPD, HMGB2, HSC70, GRP58, and HMGB1, previously shown to form a nuclear complex associated with resistance to DNA conformation-altering chemotherapeutic drugs in in vitro systems, may represent a novel class of genes associated with in vivo drug response in ovarian cancer patients. Although RNA expression change indicated only weak DNA copy number dependence, these data illustrate the value of molecular profiling at both the RNA and DNA levels to identify small genomic regions and gene subsets that could be associated with differential chemotherapy response in ovarian cancer.

  11. RNA quality and gene expression analysis of ovarian tumor tissue undergoing repeated thaw-freezing

    DEFF Research Database (Denmark)

    Jochumsen, Kirsten Marie; Tan, Qihua; Dahlgaard, Jesper

    2007-01-01

    undergoes repeated thawing and freezing. We evaluated the influence of repeated division of tumor samples at room temperature, on RNA quality and quantity, in addition to the gene expression profile. Sixteen ovarian tumor samples were divided in three aliquots each, undergoing respectively one, two...... unsupervised, and supervised multivariate statistical methods, reliability analysis, as well as verification using published gene lists in ovarian cancer studies. RNA quality and quantity did not change during the division procedure and microarray data showed insignificant difference in gene expression. Tumor......Gene expression profiles evaluated by microarray-based quantization of RNA are used in studies of differential diagnosis and prognosis in cancer. RNA of good quality is mandatory for this evaluation. The RNA most often comes from tumor banks with limited amount of tissue, and the tissue often...

  12. The TP73 gene polymorphism (rs4648551, A>G is associated with diminished ovarian reserve.

    Directory of Open Access Journals (Sweden)

    Laura Diniz Vagnini

    Full Text Available It's known that the members of the TP53 family are involved in the regulation of female reproduction. Studies in mice showed that the TP73 gene (member of this family plays a role in the size of follicular pool, ovulation rate and maintenance of genomic stability. In the present study we analyzed data from 605 patients with ≤ 37 years attending their first intracytoplasmic sperm injection (ICSI. The association between the TP73 polymorphism (rs4648551, A>G and the following parameters related to ovarian reserve, like age, antral follicular count (AFC, anti-Mullerian hormone levels (AMH and ovarian response prediction index (ORPI was evaluated. Our results showed an association of the AA genotype with diminished ovarian reserve (AMH <1, AFC ≤9. Women presenting the AA genotype had a 2.0-fold increased risk for having AMH <1 and AFC ≤9 (OR 2.0, 95% CI 1.23-3.31, P = 0.005. Patients presenting AA genotype had the lowest levels of AMH (P = 0.02, the lowest number of antral follicles (P = 0.01 and the lowest ORPI (P = 0.007. Analyzing the alleles, we can see an enrichment of the A allele in the group of diminished ovarian reserve (OR 1.4, 95%CI 1.02-1.83, P = 0.04. To the best of our knowledge, the present study is the first to analyze this polymorphism in humans for assessing the numbers of ovarian follicles and AMH levels and, therefore, the ovarian reserve. Our findings can contribute to the use of this polymorphism as a potential marker of diminished ovarian reserve.

  13. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

    NARCIS (Netherlands)

    Hampras, S.S.; Sucheston-Campbell, L.E.; Cannioto, R.; Chang-Claude, J.; Modugno, F.; Dork, T.; Hillemanns, P.; Preus, L.; Knutson, K.L.; Wallace, P.K.; Hong, C.C.; Friel, G.; Davis, W.; Nesline, M.; Pearce, C.L.; Kelemen, L.E.; Goodman, M.T.; Bandera, E.V.; Terry, K.L.; Schoof, N.; Eng, K.H.; Clay, A.; Singh, P.K.; Joseph, J.M.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Baker, H.; Bean, Y.; Beckmann, M.W.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Cook, L.S.; Cramer, D.W; Cybulski, C.; Dansonka-Mieszkowska, A.; Dennis, J.; Despierre, E.; Dicks, E.; Doherty, J.A.; Bois, A. du; Durst, M.; Easton, D.; Eccles, D.; Edwards, R.P.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Gronwald, J.; Harrington, P.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hogdall, C.; Hogdall, E.; Hosono, S.; Iversen, E.S.; Jakubowska, A.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.L.M.; Klapdor, R.; Kolomeyevskaya, N.; Krakstad, C.; Kjaer, S.K.; Kruszka, B.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Liu, S.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.A.G.; Matsuo, K.; McGuire, V.; et al.,

    2016-01-01

    BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and

  14. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

    DEFF Research Database (Denmark)

    Hampras, Shalaka S; Sucheston-Campbell, Lara E; Cannioto, Rikki

    2016-01-01

    BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases a...

  15. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

    DEFF Research Database (Denmark)

    Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.

    2015-01-01

    contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among...... coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC....

  16. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    OpenAIRE

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K.; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S. L.; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia

    2015-01-01

    Background\\ud \\ud Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contribu...

  17. Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer

    International Nuclear Information System (INIS)

    Bragoszewski, Piotr; Kupryjanczyk, Jolanta; Bartnik, Ewa; Rachinger, Andrea; Ostrowski, Jerzy

    2008-01-01

    In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas. We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750) in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1) were quantified in 62 cancer tissues by real-time RT-PCR. Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy. In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies

  18. Limited clinical relevance of mitochondrial DNA mutation and gene expression analyses in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Rachinger Andrea

    2008-10-01

    Full Text Available Abstract Background In recent years, numerous studies have investigated somatic mutations in mitochondrial DNA in various tumours. The observed high mutation rates might reflect mitochondrial deregulation; consequently, mutation analyses could be clinically relevant. The purpose of this study was to determine if mutations in the mitochondrial D-loop region and/or the level of mitochondrial gene expression could influence the clinical course of human ovarian carcinomas. Methods We sequenced a 1320-base-pair DNA fragment of the mitochondrial genome (position 16,000-750 in 54 cancer samples and in 44 corresponding germline control samples. In addition, six transcripts (MT-ATP6, MT-CO1, MT-CYB, MT-ND1, MT-ND6, and MT-RNR1 were quantified in 62 cancer tissues by real-time RT-PCR. Results Somatic mutations in the D-loop sequence were found in 57% of ovarian cancers. Univariate analysis showed no association between mitochondrial DNA mutation status or mitochondrial gene expression and any of the examined clinicopathologic parameters. A multivariate logistic regression model revealed that the expression of the mitochondrial gene RNR1 might be used as a predictor of tumour sensitivity to chemotherapy. Conclusion In contrast to many previously published papers, our study indicates rather limited clinical relevance of mitochondrial molecular analyses in ovarian carcinomas. These discrepancies in the clinical utility of mitochondrial molecular tests in ovarian cancer require additional large, well-designed validation studies.

  19. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev

    2014-01-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer...... with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic...... for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic...

  20. Mutation and Methylation Analysis of the Chromodomain-Helicase-DNA Binding 5 Gene in Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Kylie L. Gorringe

    2008-11-01

    Full Text Available Chromodomain, helicase, DNA binding 5 (CHD5 is a member of a subclass of the chromatin remodeling Swi/Snf proteins and has recently been proposed as a tumor suppressor in a diverse range of human cancers. We analyzed all 41 coding exons of CHD5 for somatic mutations in 123 primary ovarian cancers as well as 60 primary breast cancers using high-resolution melt analysis. We also examined methylation of the CHD5 promoter in 48 ovarian cancer samples by methylation-specific single-stranded conformation polymorphism and bisulfite sequencing. In contrast to previous studies, no mutations were identified in the breast cancers, but somatic heterozygous missense mutations were identified in 3 of 123 ovarian cancers. We identified promoter methylation in 3 of 45 samples with normal CHD5 and in 2 of 3 samples with CHD5 mutation, suggesting these tumors may have biallelic inactivation of CHD5. Hemizygous copy number loss at CHD5 occurred in 6 of 85 samples as assessed by single nucleotide polymorphism array. Tumors with CHD5 mutation or methylation were more likely to have mutation of KRAS or BRAF (P = .04. The aggregate frequency of CHD5 haploinsufficiency or inactivation is 16.2% in ovarian cancer. Thus, CHD5 may play a role as a tumor suppressor gene in ovarian cancer; however, it is likely that there is another target of the frequent copy number neutral loss of heterozygosity observed at 1p36.

  1. ABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells.

    Science.gov (United States)

    Bao, Lingjie; Wu, Jianfa; Dodson, Matthew; Rojo de la Vega, Elisa Montserrat; Ning, Yan; Zhang, Zhenbo; Yao, Ming; Zhang, Donna D; Xu, Congjian; Yi, Xiaofang

    2017-06-01

    Previously, we have demonstrated that NRF2 plays a key role in mediating cisplatin resistance in ovarian cancer. To further explore the mechanism underlying NRF2-dependent cisplatin resistance, we stably overexpressed or knocked down NRF2 in parental and cisplatin-resistant human ovarian cancer cells, respectively. These two pairs of stable cell lines were then subjected to microarray analysis, where we identified 18 putative NRF2 target genes. Among these genes, ABCF2, a cytosolic member of the ABC superfamily of transporters, has previously been reported to contribute to chemoresistance in clear cell ovarian cancer. A detailed analysis on ABCF2 revealed a functional antioxidant response element (ARE) in its promoter region, establishing ABCF2 as an NRF2 target gene. Next, we investigated the contribution of ABCF2 in NRF2-mediated cisplatin resistance using our stable ovarian cancer cell lines. The NRF2-overexpressing cell line, containing high levels of ABCF2, was more resistant to cisplatin-induced apoptosis compared to its control cell line; whereas the NRF2 knockdown cell line with low levels of ABCF2, was more sensitive to cisplatin treatment than its control cell line. Furthermore, transient overexpression of ABCF2 in the parental cells decreased apoptosis and increased cell viability following cisplatin treatment. Conversely, knockdown of ABCF2 using specific siRNA notably increased apoptosis and decreased cell viability in cisplatin-resistant cells treated with cisplatin. This data indicate that the novel NRF2 target gene, ABCF2, plays a critical role in cisplatin resistance in ovarian cancer, and that targeting ABCF2 may be a new strategy to improve chemotherapeutic efficiency. © 2017 Wiley Periodicals, Inc.

  2. Absence of human papillomavirus E6-E7 transforming genes from HPV 16 and 18 in malignant ovarian carcinoma.

    Science.gov (United States)

    Chen, T R; Chan, P J; Seraj, I M; King, A

    1999-02-01

    Ovarian carcinoma is one of the frequent causes of death from malignancies in the United States. A report excited the scientific community when human papillomavirus were identified in advanced epithelial ovarian carcinoma tissues in 10 of 12 patients. A few studies also identified HPV DNA in ovarian carcinoma tissues. However, several researchers employing polymerase chain reaction techniques and using different oligonucleotide probes did not detect HPV DNA in ovarian carcinoma tissues. The objective was to determine the presence of the E6-E7 genes of HPV types 16 and 18 in archived paraffin-embedded malignant ovarian carcinoma using primers targeting. Archived human malignant ovarian cancer tissues (N = 20 cases) embedded in paraffin blocks were processed, and DNA was extracted and the presence of DNA verified by p53 amplifications. PCR analyses were performed on the extracted DNA together with appropriate controls. The results showed an absence of E6-E7 genes of HPV types 16 and 18 in ovarian carcinoma. However, the presence of other HPV types or gene regions is not ruled out and more studies are needed to resolve the question of HPV involvement in ovarian carcinogenesis. Copyright 1999 Academic Press.

  3. Aberrations of the p53 tumor suppressor gene in human epithelial ovarian carcinoma.

    Science.gov (United States)

    Kim, J W; Cho, Y H; Kwon, D J; Kim, T E; Park, T C; Lee, J M; Namkoong, S E

    1995-05-01

    Aberrations of the p53 gene in 26 surgical specimens of human epithelial ovarian carcinomas were examined by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR) products. Seven (27%) of the tumors demonstrated a SSCP band shift in exons 4 to 9 of the gene, including 5 in the region encompassing exons 5 and 6, 1 in exon 7, and 1 in the region encompassing exons 8 and 9. Mutations were clustered in exon 5 in highly conserved regions of the p53 gene. All of the abnormal DNA fragments have been further characterized by direct DNA sequencing. These include five missense mutations (five transitions), a one-base-pair deletion introducing, by frameshift, a stop codon further downstream, and a two-base-pair insertion introducing a stop codon downstream by frameshift. Most mutations were base substitutions, and were clustered in exon 5 (71%), especially codons 175 and 179. The aberrations of the p53 gene were only found in tumors of FIGO stages III and IV. Histologic grading was also reviewed with respect to p53 aberrations. The aberrations were absent in well-differentiated carcinomas. The more undifferentiated the primary tumor, the more frequent p53 mutation (P p53 gene were common in epithelial ovarian cancers and p53 aberration may occur late during ovarian cancer evolution.

  4. Gene regulatory networking reveals the molecular cue to lysophosphatidic acid-induced metabolic adaptations in ovarian cancer cells.

    Science.gov (United States)

    Ray, Upasana; Roy Chowdhury, Shreya; Vasudevan, Madavan; Bankar, Kiran; Roychoudhury, Susanta; Roy, Sib Sankar

    2017-05-01

    Extravasation and metastatic progression are two main reasons for the high mortality rate associated with cancer. The metastatic potential of cancer cells depends on a plethora of metabolic challenges prevailing within the tumor microenvironment. To achieve higher rates of proliferation, cancer cells reprogram their metabolism, increasing glycolysis and biosynthetic activities. Just why this metabolic reprogramming predisposes cells towards increased oncogenesis remains elusive. The accumulation of myriad oncolipids in the tumor microenvironment has been shown to promote the invasiveness of cancer cells, with lysophosphatidic acid (LPA) being one such critical factor enriched in ovarian cancer patients. Cellular bioenergetic studies confirm that oxidative phosphorylation is suppressed and glycolysis is increased with long exposure to LPA in ovarian cancer cells compared with non-transformed epithelial cells. We sought to uncover the regulatory complexity underlying this oncolipid-induced metabolic perturbation. Gene regulatory networking using RNA-Seq analysis identified the oncogene ETS-1 as a critical mediator of LPA-induced metabolic alterations for the maintenance of invasive phenotype. Moreover, LPA receptor-2 specific PtdIns3K-AKT signaling induces ETS-1 and its target matrix metalloproteases. Abrogation of ETS-1 restores cellular bioenergetics towards increased oxidative phosphorylation and reduced glycolysis, and this effect was reversed by the presence of LPA. Furthermore, the bioenergetic status of LPA-treated ovarian cancer cells mimics hypoxia through induction of hypoxia-inducible factor-1α, which was found to transactivate ets-1. Studies in primary tumors generated in syngeneic mice corroborated the in vitro findings. Thus, our study highlights the phenotypic changes induced by the pro-metastatic factor ETS-1 in ovarian cancer cells. The relationship between enhanced invasiveness and metabolic plasticity further illustrates the critical role of

  5. Gene expression profiles of ovarian low-grade serous carcinoma resemble those of fallopian tube epithelium.

    Science.gov (United States)

    Qiu, Chunping; Lu, Nan; Wang, Xiao; Zhang, Qing; Yuan, Cunzhong; Yan, Shi; Dongol, Samina; Li, Yingwei; Sun, Xiaomei; Sun, Chenggong; Zhang, Zhiwei; Zheng, Wenxin; Kong, Beihua

    2017-12-01

    The cell of origin of ovarian low-grade serous carcinoma (LGSC) remains unclarified. Our recent morphologic and immunophenotypic study suggests that most LGSCs may be derived from the fallopian tube. The purpose of the current study was to gain further insight into the origin of LGSC at the molecular level. RNA-seq analysis was performed on a total of 31 tissue samples including LGSC (n=6), serous borderline tumors (SBT, n=6), fallopian tube epithelia (FTE, n=5), ovarian surface epithelia (OSE, n=4), and human peritoneal mesothelia (HPM, n=4). HGSC cases (n=6) served as a positive control. Gene expression profiles were compared and analyzed. To validate the findings from the gene expression array study, we selected the highly differentially expressed genes (PAX8, CDH1, FOXA2, and ARX) as well as those corresponding proteins and examined their expression levels in tissue samples of ovarian serous tumors, fallopian tube, ovarian surface epithelia, and peritoneal mesothelia. Dendrograms revealed that OSE samples clustered with HPM, while ovarian serous tumors, including LGSC, SBT and high-grade serous carcinoma (HGSC), clustered with FTE. Furthermore, LGSC showed a significantly closer relationship with FTE than with OSE and HPM samples. PAX8, CDH1, and FOXA2 were highly and specifically expressed in serous tumors and FTE samples but not in OSE samples. In contrast, ARX was mainly expressed in OSE samples but not in FTE and serous tumors. The findings of the current study provide further evidence at a molecular level that the fallopian tube is likely the cellular source of LGSC. This finding may enable new prevention strategies, improve early detection, and allow novel therapies to be tested. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. State-related alterations of gene expression in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Vinberg, Maj; Berk, Michael

    2012-01-01

    on comprehensive database searches for studies on gene expression in patients with bipolar disorder in specific mood states, was conducted. We searched Medline, Embase, PsycINFO, and The Cochrane Library, supplemented by manually searching reference lists from retrieved publications. Results:  A total of 17......Munkholm K, Vinberg M, Berk M, Kessing LV. State-related alterations of gene expression in bipolar disorder: a systematic review. Bipolar Disord 2012: 14: 684-696. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective:  Alterations in gene expression in bipolar disorder...... have been found in numerous studies. It is unclear whether such alterations are related to specific mood states. As a biphasic disorder, mood state-related alterations in gene expression have the potential to point to markers of disease activity, and trait-related alterations might indicate...

  7. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

    Science.gov (United States)

    Notaridou, Maria; Quaye, Lydia; Dafou, Dimitra; Jones, Chris; Song, Honglin; Høgdall, Estrid; Kjaer, Susanne K.; Christensen, Lise; Høgdall, Claus; Blaakaer, Jan; McGuire, Valerie; Wu, Anna H.; Van Den Berg, David J.; Pike, Malcolm C.; Gentry-Maharaj, Aleksandra; Wozniak, Eva; Sher, Tanya; Jacobs, Ian J.; Tyrer, Jonathan; Schildkraut, Joellen M.; Moorman, Patricia G.; Iversen, Edwin S.; Jakubowska, Anna; Mędrek, Krzysztof; Lubiński, Jan; Ness, Roberta B.; Moysich, Kirsten B.; Lurie, Galina; Wilkens, Lynne R.; Carney, Michael E.; Wang-Gohrke, Shan; Doherty, Jennifer A.; Rossing, Mary Anne; Beckmann, Matthias W.; Thiel, Falk C.; Ekici, Arif B.; Chen, Xiaoqing; Beesley, Jonathan; Gronwald, Jacek; Fasching, Peter A.; Chang-Claude, Jenny; Goodman, Marc T.; Chenevix-Trench, Georgia; Berchuck, Andrew; Pearce, C. Leigh; Whittemore, Alice S.; Menon, Usha; Pharoah, Paul D.P.; Gayther, Simon A.; Ramus, Susan J.

    2011-01-01

    Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer. PMID:20635389

  8. Adiposity Alters Genes Important in Inflammation and Cell Cycle Division in Human Cumulus Granulosa Cell.

    Science.gov (United States)

    Merhi, Zaher; Polotsky, Alex J; Bradford, Andrew P; Buyuk, Erkan; Chosich, Justin; Phang, Tzu; Jindal, Sangita; Santoro, Nanette

    2015-10-01

    To determine whether obesity alters genes important in cellular growth and inflammation in human cumulus granulosa cells (GCs). Eight reproductive-aged women who underwent controlled ovarian hyperstimulation followed by oocyte retrieval for in vitro fertilization were enrolled. Cumulus GC RNA was extracted and processed for microarray analysis on Affymetrix Human Genome U133 Plus 2.0 chips. Gene expression data were validated on GCs from additional biologically similar samples using quantitative real-time polymerase chain reaction (RT-PCR). Comparison in gene expression was made between women with body mass index (BMI) cell division cycle 20 (CDC20), interleukin 1 receptor-like 1 (IL1RL1), and growth arrest-specific protein 7 (GAS7). FOXM1, CDC20, and GAS7 were downregulated while FGF-12 and PPM1L were upregulated in group 2 when compared to group 1. Validation with RT-PCR confirmed the microarray data except for ZFPM2 and IL1RL. As BMI increased, expression of FOXM1 significantly decreased (r = -.60, P = .048). Adiposity is associated with changes in the expression of genes important in cellular growth, cell cycle progression, and inflammation. The upregulation of the metabolic regulator gene PPM1L suggests that adiposity induces an abnormal metabolic follicular environment, potentially altering folliculogenesis and oocyte quality. © The Author(s) 2015.

  9. Combined comparative genomic hybridization and transcriptomic analyses of ovarian granulosa cell tumors point to novel candidate driver genes.

    Science.gov (United States)

    Caburet, Sandrine; Anttonen, Mikko; Todeschini, Anne-Laure; Unkila-Kallio, Leila; Mestivier, Denis; Butzow, Ralf; Veitia, Reiner A

    2015-04-10

    Ovarian granulosa cell tumors (GCTs) are the most frequent sex cord-stromal tumors. Several studies have shown that a somatic mutation leading to a C134W substitution in the transcription factor FOXL2 appears in more than 95% of adult-type GCTs. Its pervasive presence suggests that FOXL2 is the main cancer driver gene. However, other mutations and genomic changes might also contribute to tumor formation and/or progression. We have performed a combined comparative genomic hybridization and transcriptomic analyses of 10 adult-type GCTs to obtain a picture of the genomic landscape of this cancer type and to identify new candidate co-driver genes. Our results, along with a review of previous molecular studies, show the existence of highly recurrent chromosomal imbalances (especially, trisomy 14 and monosomy 22) and preferential co-occurrences (i.e. trisomy 14/monosomy 22 and trisomy 7/monosomy 16q). In-depth analyses showed the presence of recurrently broken, amplified/duplicated or deleted genes. Many of these genes, such as AKT1, RUNX1 and LIMA1, are known to be involved in cancer and related processes. Further genomic explorations suggest that they are functionally related. Our combined analysis identifies potential candidate genes, whose alterations might contribute to adult-type GCT formation/progression together with the recurrent FOXL2 somatic mutation.

  10. Somatic Activation of rasK Gene in a Human Ovarian Carcinoma

    Science.gov (United States)

    Feig, L. A.; Bast, R. C.; Knapp, R. C.; Cooper, G. M.

    1984-02-01

    A tumor isolate from a patient with serous cystadenocarcinoma of the ovary contained an activated rasK gene detected by transfection of NIH/3T3 cells. In contrast, DNA from normal cells of the same patient lacked transforming activity, indicating that activation of this transforming gene was the consequence of somatic mutation in the neoplastic cells. The transforming gene product displayed an electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that differed from the mobilities of rasK transforming proteins in other tumors, indicating that a previously undescribed mutation was responsible for activation of rasK in this ovarian carcinoma.

  11. p53 gene mutations and codon 72 polymorphism in ovarian carcinoma patients from Serbia.

    Science.gov (United States)

    Malisic, E; Jankovic, R; Slavkovic, D; Milovic-Kovacevic, M; Radulovic, S

    2010-01-01

    Ovarian cancer is the leading cause of death from gynecological malignancies. The early stages of this disease are asymptomatic and more than 75% of the cases are diagnosed with regional or distant metastases. p53 gene is frequently mutated in some histological subtypes of ovarian carcinomas. The role of p53 mutations and polymorphic variant of codon 72 in the prognosis of disease is still unclear. The aim of this study was to determine the frequency of p53 mutations and polymorphic variants of codon 72 among ovarian carcinoma patients and to correlate them with clinicopathological characteristics of disease. 54 ovarian carcinoma patients were included in the study. DNA was isolated from tumor tissue by the salting- out method. p53 mutations in exons 4-8 were detected by PCR-SSCP (polymerase chain reaction - single-stranded conformational polymorphism) electrophoresis. Codon 72 polymorphism was assessed by RFLP (restriction fragment-length polymorphism) method. p53 mutations were present in 11 out of 54 patients (20.4%). Twenty-four patients (44.4%) exhibited Arg/ Arg, 24 patients (44.4%) Arg/Pro and 6 patients (11.2%) Pro/ Pro genotype of 72 codon polymorphism. Correlations between p53 mutations and various clinicopathological characteristics were not found. However, we observed that the frequency of Pro/Pro genotype was increasing with higher histological grade as well as in advanced compared to localized disease, but without statistical significance. Distribution of p53 gene mutations between Pro/Pro genotype and Arg/Pro plus Arg/Arg genotypes was not statistically significant. Our study suggests that Pro/Pro genotype of 72 codon polymorphism could be an independent prognostic marker in ovarian carcinomas.

  12. Association between MTHFR gene polymorphism and the risk of ovarian cancer: a meta-analysis of the literature.

    Science.gov (United States)

    Pu, Danhua; Jiang, Shi-Wen; Wu, Jie

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme for DNA biosynthesis and the epigenetic process of DNA methylation. MTHFR gene polymorphisms have been implicated as risk factors for several types of cancers. However, reports on the association of MTHFR polymorphisms with ovarian cancers are inconclusive. The aim of this study is to summarize on the reported data and meta-analytically investigate the relationship between the MTHFR C677T and A1298C polymorphism and the risk of ovarian cancer. We searched for all published articles indexed in MEDLINE (1950-2012), EMBASE (1974-2012), and CNKI (1994-2012). Case-control or cohort studies that relating to MTHFR polymorphism and ovarian cancer women were included and data were extracted independently by two reviewers. The search yielded 21 articles, from which 7 studies met the inclusion criteria. We performed a metaanalysis involving 3493 patients with ovarian cancer and 3863 controls with Review Manager 5.1 software. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate the ovarian cancer risk. All the available data considered together, no association between the MTHFR C677T polymorphism and ovarian cancer risk was found in any genetic variations. However, in the subgroup analysis by ethnicity of Asian and Caucasian, MTHFR 677T was associated with significantly increased ovarian cancer risk among Asian [T allele vs. C allele: OR=1.50, 95% CI: 1.25-1.81, PA1298C polymorphism, no marked association was found in either group of Caucasian population, while no data was available to analyze in Asian population. The C677T polymorphism of the MTHFR gene is associated with the susceptibility of ovarian cancer in Asian population, suggesting that TT genotype may serve as a risk factor of ovarian cancer among Asian but not Caucasians. In addition, there is no association between A1298C gene polymorphism and ovarian cancer, including Caucasian and Asian women.

  13. The use of genetic transformation in the study of ovarian-specific gene expression

    International Nuclear Information System (INIS)

    Manzi, A.; Andone, S.; Rotoli, D.; Capua, M.R.; Gargiulo, G.; Graziani, F.; Malva, C.

    1998-01-01

    We are using genetic and molecular approaches to understand the mechanisms controlling the establishment of the cellular specificity of expression during oogenesis. Female-sterile mutations have been isolated and the molecular analysis is revealing interesting cell-cell interaction systems that work not only during oogenesis but also at other developmental stages. We will review in this paper our most recent studies on genes involved in ovarian development. (author)

  14. BRCA1 gene-related hereditary susceptibility to breast and ovarian cancer in Latvia.

    Science.gov (United States)

    Tihomirova, Laima; Vaivade, Iveta; Fokina, Oksana; Peculis, Raitis; Mandrika, Ilona; Sinicka, Olga; Stengrevics, Aivars; Krilova, Anna; Keire, Guntars; Petrevics, Janis; Eglitis, Janis; Timofejevs, Mihails; Leja, Marcis

    2014-03-01

    In this report, we summarise data on BRCA1 gene analysis in Latvia to characterise criteria of genetic testing for breast and ovarian cancer susceptibility. Analysis by SSCP/HD, MALDI-TOF mass spectrometry or DNA sequencing was used for mutation detection. Mutations identified were confirmed by direct DNA sequencing. Out of 1068 breast and 231 ovarian cancer patients from different families: 58 carried the c.5266dupC and 43 carried the c.4035delA mutations. Every 4th patient in our study did not report cancer in the family. The breast cancer was diagnosed earlier in carriers of the c.5266dupC than in carriers of the c.4035delA (p=0.003). The incidence of breast or ovarian cancer does not differ among the 2 mutation carriers in our patient group. The nature of the c.5266dupC mutation might be more deleterious. We recommend the screening of 4 founder BRCA1 mutations in all breast and ovarian cancer patients in Latvia at diagnosis of disease regardless of family history or age. The BRCA1 screening can be carried out efficiently using the MALDI-TOF mass spectrometry mutation detection method developed in the Biomedical Research and Study Centre (Riga, Latvia). Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

  15. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

    DEFF Research Database (Denmark)

    Shen, Hui; Fridley, Brooke L; Song, Honglin

    2013-01-01

    HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we ...

  16. Prolactin Alters the Mammary Epithelial Hierarchy, Increasing Progenitors and Facilitating Ovarian Steroid Action

    Directory of Open Access Journals (Sweden)

    Kathleen A. O'Leary

    2017-10-01

    Full Text Available Hormones drive mammary development and function and play critical roles in breast cancer. Epidemiologic studies link prolactin (PRL to increased risk for aggressive cancers that express estrogen receptor α (ERα. However, in contrast to ovarian steroids, PRL actions on the mammary gland outside of pregnancy are poorly understood. We employed the transgenic NRL-PRL model to examine the effects of PRL alone and with defined estrogen/progesterone exposure on stem/progenitor activity and regulatory networks that drive epithelial differentiation. PRL increased progenitors and modulated transcriptional programs, even without ovarian steroids, and with steroids further raised stem cell activity associated with elevated canonical Wnt signaling. However, despite facilitating some steroid actions, PRL opposed steroid-driven luminal maturation and increased CD61+ luminal cells. Our findings demonstrate that PRL can powerfully influence the epithelial hierarchy alone and temper the actions of ovarian steroids, which may underlie its role in the development of breast cancer.

  17. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    Science.gov (United States)

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Amankwah, Ernest K.; Qu, Xiaotao; Tsai, Ya-Yu; Jim, Heather S. L.; Chen, Zhihua; Chen, Ann Y.; Permuth-Wey, Jennifer; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kelemen, Linda E.; Kellar, Mellissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Pike, Malcolm C.; Poole, Elizabeth M.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Lotte; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vierkant, Robert A.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Hasmad, Hanis N.; Berchuck, Andrew; Iversen, Edwin S.; Schildkraut, Joellen M.; Ramus, Susan J.; Goode, Ellen L.; Monteiro, Alvaro N. A.; Gayther, Simon A.; Narod, Steven A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2015-01-01

    Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR qtransporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (ptransport gene variants and risk of EOC histologic subtypes. PMID:26091520

  18. Altered levels of acylcarnitines, phosphatidylcholines, and sphingomyelins in peritoneal fluid from ovarian endometriosis patients.

    Science.gov (United States)

    Vouk, Katja; Ribič-Pucelj, Martina; Adamski, Jerzy; Rižner, Tea Lanišnik

    2016-05-01

    Endometriosis is a complex, polygenic, and estrogen-dependent disease that affects 6% to 10% of women of reproductive age, and 30% to 50% of women with infertility and/or pelvic pain. Surgical diagnosis of endometriosis is still the gold standard, as there are currently no diagnostic biomarkers available. Due to the invasive diagnostics, it can take up to 11 years before affected women are diagnosed and receive the appropriate treatment. We performed a targeted metabolomics study to search for potential semi-invasive biomarkers in peritoneal fluid from endometriosis patients. Our case-control study comprised 29 ovarian endometriosis patients and 36 healthy control women. The 148 metabolites included acylcarnitines, glycerophospholipids, and sphingolipids, which were quantified by electrospray ionization tandem mass spectrometry. The strength of association between the metabolites and the metabolite ratios and disease was assessed using crude and adjusted odds ratios. The best combination of biomarkers was then selected by performing step-wise logistic regression. Our analysis reveals significantly decreased concentrations of 10 metabolites, of carnitine and acylcarnitines (C0, C8:1, C6C4:1 DC, C10:1), phosphatidylcholines (PC aa C38:3, PC aa C38:4, PC aa C40:4, PC aa C40:5), and sphingomyelins (SM C16:1, SM C18:1), and 125 significantly altered metabolite ratios in patients versus control women. The best model includes two ratios: a carnitine to a phosphatidylcholine (C0/PC ae C36:0); and between two phosphatidylcholines (PC aa C30:0/PC ae C32:2). When adjusted for age, this provides sensitivity of 82.8% and specificity of 94.4%, with AUC of 0.944. Our study supports the importance of carnitine, phosphatidylcholine, and sphingomyelin metabolites in the pathophysiology of endometriosis, and confirms the potential for the combination of individual metabolite ratios to provide biomarkers for semi-invasive diagnostics. Copyright © 2016 Elsevier Ltd. All rights

  19. Ovarian characteristics in sheep with multiple fecundity genes.

    Science.gov (United States)

    McNatty, Kenneth P; Heath, Derek A; Clark, Zaramasina; Reader, Karen; Juengel, Jennifer L; Pitman, Janet L

    2017-02-01

    Ewes heterozygous for combinations of the Inverdale (FecX I ; I+), Booroola (FecB; B+) and Woodlands (FecX2 W ; W+) mutations have ovulation rates higher than each mutation separately. The aims of the experiments described herein were to examine the ovarian phenotypes in I+B+ and I+B+W+ ewes and to compare these with the appropriate ++ (controls), I+ and BB animals available for this study. The mean ± s.e.m. ovulation rates in the ++ (n = 23), I+ (10), I+B+ (7), I+B+W+ (10) and BB (3) animals were 1.8 ± 0.1, 2.5 ± 0.2, 6.6 ± 1.0, 9.6 ± 0.9 and 9.7 ± 0.9 respectively. The maximum number of granulosa cells per follicle in the ++ and I+ genotypes was accumulated after exceeding 5 mm diameter, whereas in I+B+, I+B+W+ and BB animals, this was achieved when follicles reached >2-3 mm. The number of putative preovulatory follicles, as assessed from those with LH-responsive granulosa cells, 24 h after the induction of luteolysis, was higher (P Reproduction and Fertility.

  20. Clock genes alterations and endocrine disorders.

    Science.gov (United States)

    Angelousi, Anna; Kassi, Eva; Nasiri-Ansari, Narjes; Weickert, Martin O; Randeva, Harpal; Kaltsas, Gregory

    2018-03-25

    Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock. We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases. Various human single nucleotide polymorphisms of BMAL1 and CLOCK genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue specific way whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK, and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscilliations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2 as well as between prolactin and CLOCK was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility whereas estradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers. Clock genes are associated with various endocrine disorders through complex mechanisms. However data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  1. Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an estrogen receptor-dependent pathway.

    Science.gov (United States)

    Kim, Joo-Young; Yi, Bo-Rim; Go, Ryeo-Eun; Hwang, Kyung-A; Nam, Ki-Hoan; Choi, Kyung-Chul

    2014-05-01

    Methoxychlor and triclosan are emergent or suspected endocrine-disrupting chemicals (EDCs). Methoxychlor [MXC; 1,1,1-trichlor-2,2-bis (4-methoxyphenyl) ethane] is an organochlorine pesticide that has been primarily used since dichlorodiphenyltrichloroethane (DDT) was banned. In addition, triclosan (TCS) is used as a common component of soaps, deodorants, toothpastes, and other hygiene products at concentrations up to 0.3%. In the present study, the potential impact of MXC and TCS on ovarian cancer cell growth and underlying mechanism(s) was examined following their treatments in BG-1 ovarian cancer cells. As results, MXC and TCS induced BG-1 cell growth via regulating cyclin D1, p21 and Bax genes related with cell cycle and apoptosis. A methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay confirmed that the proliferation of BG-1 ovarian cancer cells was stimulated by MXC (10(-6), 10(-7), 10(-8), and 10(-9)M) or TCS (10(-6), 10(-7), 10(-8), and 10(-9)M). Treatment of BG-1 cells with MXC or TCS resulted in the upregulation of cyclin D1 and downregulation of p21 and Bax transcriptions. In addition, the protein level of cyclin D1 was increased by MXC or TCS while p21 and Bax protein levels appeared to be reduced in these cells. Furthermore, MXC- or TCS-induced alterations of these genes were reversed in the presence of ICI 182,780 (10(-7)M), suggesting that the changes in these gene expressions may be regulated by an ER-dependent signaling pathway. In conclusion, the results of our investigation indicate that two potential EDCs, MXC and TCS, may stimulate ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an ER-dependent pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Phelan, Catherine M; Tsai, Ya-Yu; Goode, Ellen L

    2010-01-01

    Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism...... in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming...... the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication...

  3. Distinct and competitive regulatory patterns of tumor suppressor genes and oncogenes in ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Min Zhao

    Full Text Available So far, investigators have found numerous tumor suppressor genes (TSGs and oncogenes (OCGs that control cell proliferation and apoptosis during cancer development. Furthermore, TSGs and OCGs may act as modulators of transcription factors (TFs to influence gene regulation. A comprehensive investigation of TSGs, OCGs, TFs, and their joint target genes at the network level may provide a deeper understanding of the post-translational modulation of TSGs and OCGs to TF gene regulation.In this study, we developed a novel computational framework for identifying target genes of TSGs and OCGs using TFs as bridges through the integration of protein-protein interactions and gene expression data. We applied this pipeline to ovarian cancer and constructed a three-layer regulatory network. In the network, the top layer was comprised of modulators (TSGs and OCGs, the middle layer included TFs, and the bottom layer contained target genes. Based on regulatory relationships in the network, we compiled TSG and OCG profiles and performed clustering analyses. Interestingly, we found TSGs and OCGs formed two distinct branches. The genes in the TSG branch were significantly enriched in DNA damage and repair, regulating macromolecule metabolism, cell cycle and apoptosis, while the genes in the OCG branch were significantly enriched in the ErbB signaling pathway. Remarkably, their specific targets showed a reversed functional enrichment in terms of apoptosis and the ErbB signaling pathway: the target genes regulated by OCGs only were enriched in anti-apoptosis and the target genes regulated by TSGs only were enriched in the ErbB signaling pathway.This study provides the first comprehensive investigation of the interplay of TSGs and OCGs in a regulatory network modulated by TFs. Our application in ovarian cancer revealed distinct regulatory patterns of TSGs and OCGs, suggesting a competitive regulatory mechanism acting upon apoptosis and the ErbB signaling pathway through

  4. Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells

    Directory of Open Access Journals (Sweden)

    Ulises Urzúa

    2016-10-01

    Full Text Available Abstract Background Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE. Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. Results At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05 comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1, Birc5 (Survivin, Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms. Interestingly, the earliest discrete segmental aneuploidies arose by passage 18 in chromosomes 7, 10, 11, 13, 15, 17 and 19. By passage 23, when MOSE cells express the malignant phenotype, the dysregulated gene expression repertoire expanded, DNA imbalances enlarged in size and covered additional loci. Conclusion Prior to early aneuploidies, overexpression of genes coding for the mitotic apparatus in passage-14 pre-malignant MOSE cells indicate an increased proliferation rate suggestive of replicative stress. Concomitant down-regulation of nuclear bodies and RNA processing related genes

  5. A correlation between altered O-GlcNAcylation, migration and with changes in E-cadherin levels in ovarian cancer cells

    International Nuclear Information System (INIS)

    Jin, Feng-zhen; Yu, Chao; Zhao, De-zhang; Wu, Ming-jun; Yang, Zhu

    2013-01-01

    O-GlcNAcylation is a dynamic and reversible posttranslational modification of nuclear and cytoplasmic proteins. In recent years, the roles of O-GlcNAcylation in several human malignant tumors have been investigated, and O-GlcNAcylation was found to be linked to cellular features relevant to metastasis. In this study, we modeled four diverse ovarian cancer cells and investigated the effects of O-GlcNAcylation on ovarian cancer cell migration. We found that total O-GlcNAcylation level was elevated in HO-8910PM cells compared to OVCAR3 cells. Additionally, through altering the total O-GlcNAcylation level by OGT silencing or OGA inhibition, we found that the migration of OVCAR3 cells was dramatically enhanced by PUGNAc and Thiamet G treatment, and the migration ability of HO-8910PM cells was significantly inhibited by OGT silencing. Furthermore, we also found that the expression of E-cadherin, an O-GlcNAcylated protein in ovarian cancer cells, was reduced by OGA inhibition in OVCAR3 cells and elevated by OGT silencing in HO-8910PM cells. These results indicate that O-GlcNAcylation could enhance ovarian cancer cell migration and decrease the expression of E-cadherin. Our studies also suggest that O-GlcNAcylation might become another potential target for the therapy of ovarian cancer. -- Highlights: • We examine the migration potential of diverse ovarian cancer cells. • We examine the total O-GlcNAcylation level of diverse ovarian cancer cells. • Increasing O-GlcNAcylation level will enhance the migration of ovarian cancer cells. • Reducing O-GlcNAcylation level will inhibit the migration of ovarian cancer cells. • The mechanism explains O-GlcNAcylation enhance ovarian cancer cell migration

  6. A correlation between altered O-GlcNAcylation, migration and with changes in E-cadherin levels in ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Feng-zhen [Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, 76 Lin Jiang Road, Chongqing 400010, PR China. (China); Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China. (China); Yu, Chao; Zhao, De-zhang; Wu, Ming-jun [Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China. (China); Yang, Zhu, E-mail: cqyangz@vip.163.com [Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, 76 Lin Jiang Road, Chongqing 400010, PR China. (China); Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, PR China. (China)

    2013-06-10

    O-GlcNAcylation is a dynamic and reversible posttranslational modification of nuclear and cytoplasmic proteins. In recent years, the roles of O-GlcNAcylation in several human malignant tumors have been investigated, and O-GlcNAcylation was found to be linked to cellular features relevant to metastasis. In this study, we modeled four diverse ovarian cancer cells and investigated the effects of O-GlcNAcylation on ovarian cancer cell migration. We found that total O-GlcNAcylation level was elevated in HO-8910PM cells compared to OVCAR3 cells. Additionally, through altering the total O-GlcNAcylation level by OGT silencing or OGA inhibition, we found that the migration of OVCAR3 cells was dramatically enhanced by PUGNAc and Thiamet G treatment, and the migration ability of HO-8910PM cells was significantly inhibited by OGT silencing. Furthermore, we also found that the expression of E-cadherin, an O-GlcNAcylated protein in ovarian cancer cells, was reduced by OGA inhibition in OVCAR3 cells and elevated by OGT silencing in HO-8910PM cells. These results indicate that O-GlcNAcylation could enhance ovarian cancer cell migration and decrease the expression of E-cadherin. Our studies also suggest that O-GlcNAcylation might become another potential target for the therapy of ovarian cancer. -- Highlights: • We examine the migration potential of diverse ovarian cancer cells. • We examine the total O-GlcNAcylation level of diverse ovarian cancer cells. • Increasing O-GlcNAcylation level will enhance the migration of ovarian cancer cells. • Reducing O-GlcNAcylation level will inhibit the migration of ovarian cancer cells. • The mechanism explains O-GlcNAcylation enhance ovarian cancer cell migration.

  7. Detection of circulating methylated opioid binding protein/cell adhesion molecule-like gene as a biomarker for ovarian carcinoma.

    Science.gov (United States)

    Zhou, Feng; Ma, Min; Tao, Guohua; Chen, Xiang; Xie, Wei; Wang, Ying; Cao, Xingjian

    2014-01-01

    Hypermethylation of the opioid binding protein/cell adhesion molecule-like (OPCML) gene is frequently observed in ovarian carcinoma. We evaluated the detection of circulating hypermethylated OPCML for detecting ovarian carcinoma and assessing its prognosis. We studied 85 tissue samples including 45 ovarian cancer tissues and 40 normal ovarian tissues and blood samples from 45 ovarian cancer patients and 20 healthy individuals. Bisulfite sequencing and methylation-sensitive restriction enzyme-PCR (MSRE-PCR) were used to detect the frequency of OPCML hypermethylation. We detected that the frequency of OPCML hypermethylation for tissue and serum samples in ovarian carcinoma were 86.7% (39/45) and 80.0% (36/45), respectively, but none was detected in ovarian tissue and serum of healthy individuals. The frequency of OPCML hypermethylation in endometrioid carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, clear cell carcinoma, and undifferentiated carcinoma were 80.0%, 85.5%, 50.0%, 80.0%, and 100%, respectively (p > 0.05). The frequencies of OPCML hypermethylation in patients were also different in terms of tumor differentiation degree. We detected hypermethylated OPCML in the sera of 50% of well differentiated, 62.5% of moderately differentiated, 93.1% of poorly differentiated tumors (p ovarian carcinoma diagnosis.

  8. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

    Science.gov (United States)

    Hedditch, Ellen L; Gao, Bo; Russell, Amanda J; Lu, Yi; Emmanuel, Catherine; Beesley, Jonathan; Johnatty, Sharon E; Chen, Xiaoqing; Harnett, Paul; George, Joshy; Williams, Rebekka T; Flemming, Claudia; Lambrechts, Diether; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Karlan, Beth; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Fasching, Peter; Beckmann, Matthias W; Ekici, Arif B; Hein, Alexander; Matsuo, Keitaro; Hosono, Satoyo; Nakanishi, Toru; Yatabe, Yasushi; Pejovic, Tanja; Bean, Yukie; Heitz, Florian; Harter, Philipp; du Bois, Andreas; Schwaab, Ira; Hogdall, Estrid; Kjaer, Susan K; Jensen, Allan; Hogdall, Claus; Lundvall, Lene; Engelholm, Svend Aage; Brown, Bob; Flanagan, James; Metcalf, Michelle D; Siddiqui, Nadeem; Sellers, Thomas; Fridley, Brooke; Cunningham, Julie; Schildkraut, Joellen; Iversen, Ed; Weber, Rachel P; Berchuck, Andrew; Goode, Ellen; Bowtell, David D; Chenevix-Trench, Georgia; deFazio, Anna; Norris, Murray D; MacGregor, Stuart; Haber, Michelle; Henderson, Michelle J

    2014-07-01

    ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid

  9. Impact of Panel Gene Testing for Hereditary Breast and Ovarian Cancer on Patients.

    Science.gov (United States)

    Lumish, Heidi S; Steinfeld, Hallie; Koval, Carrie; Russo, Donna; Levinson, Elana; Wynn, Julia; Duong, James; Chung, Wendy K

    2017-10-01

    Recent advances in next generation sequencing have enabled panel gene testing, or simultaneous testing for mutations in multiple genes for a clinical condition. With more extensive and widespread genetic testing, there will be increased detection of genes with moderate penetrance without established clinical guidelines and of variants of uncertain significance (VUS), or genetic variants unknown to either be disease-causing or benign. This study surveyed 232 patients who underwent genetic counseling for hereditary breast and ovarian cancer to examine the impact of panel gene testing on psychological outcomes, patient understanding, and utilization of genetic information. The survey used standardized instruments including the Impact of Event Scale (IES), Multidimensional Impact of Cancer Risk Assessment (MICRA), Satisfaction with Decision Instrument (SWD), Ambiguity Tolerance Scale (AT-20), genetics knowledge, and utilization of genetic test results. Study results suggested that unaffected individuals with a family history of breast or ovarian cancer who received positive results were most significantly impacted by intrusive thoughts, avoidance, and distress. However, scores were also modestly elevated among unaffected patients with a family history of breast and ovarian cancer who received VUS, highlighting the impact of ambiguous results that are frequent among patients undergoing genetic testing with large panels of genes. Potential risk factors for increased genetic testing-specific distress in this study included younger age, black or African American race, Hispanic origin, lower education level, and lower genetic knowledge and highlight the need for developing strategies to provide effective counseling and education to these communities, particularly when genetic testing utilizes gene panels that more commonly return VUS. More detailed pre-test education and counseling may help patients appreciate the probability of various types of test results and how results

  10. Ovarian dysfunction and gene-expressed characteristics of female mice caused by long-term exposure to titanium dioxide nanoparticles.

    Science.gov (United States)

    Gao, Guodong; Ze, Yuguan; Li, Bing; Zhao, Xiaoyang; Zhang, Ting; Sheng, Lei; Hu, Ringhu; Gui, Suxin; Sang, Xuezi; Sun, Qingqing; Cheng, Jie; Cheng, Zhe; Wang, Ling; Tang, Meng; Hong, Fashui

    2012-12-01

    Although numerous studies have described the accumulation of titanium dioxide nanoparticles (TiO(2) NPs) in the liver, kidneys, lung, spleen, and brain, and the corresponding damage, it is unclear whether or not TiO(2) NPs can be translocated to the ovary and cause ovarian injury, thus impairing fertility. In the current study, ovarian injury and gene-expressed characteristics in female mice induced by intragastric administration of TiO(2) NPs (10mg/kg) for 90 consecutive days were investigated. Our findings indicated that TiO(2) NPs can accumulate in the ovary and result in ovarian damage, cause an imbalance of mineral element distribution and sex hormones, decrease fertility or the pregnancy rate and oxidative stress in mice. Microarray analysis showed that in ovaries from mice treated with TiO(2) NPs compared to controls, 223 genes of known function were up-regulated, while 65 ovarian genes were down-regulated. The increased expression of Cyp17a1 following TiO(2) NPs treatment suggested that the increase in estradiol biosynthesis may be a consequence of increased TiO(2) NPs. In addition, the elevated expression of Akr1c18 implied that progesterone metabolism was accelerated, thus causing a decrease in the progesterone concentration. Taken together, the apparent regulation of key ovarian genes supports the hypothesis that TiO(2) NPs directly affects ovarian function. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  11. Effect of p53 gene functional status on radiosensitivity of ovarian cancer cell lines

    International Nuclear Information System (INIS)

    Lu Hongmei; Qiang Yizhong; Shi Qin; Gu Huixin; Zhang Xueguang

    2001-01-01

    In the present study, the functional status of p53 in three ovarian cancer cell lines were analyzed by PCR-SSCP, the differences of their proliferative capacity and apoptosis in vitro were measured respectively by MTT and cytometric analysis after 1-10 Gy 60 Co γ irradiation. The results show that A2780 cell line with wild-type p53 presented a higher rate of growth inhibition and apoptosis after 60 Co γ irradiation; while A2780 with p53 mutation and SKOV3 with p53 deletion exhibited higher radioresistance in vitro. The results mentioned above indicate that the functional status of p53 gene in human ovarian cancer cell lines directly affects their sensitivities to γ irradiation

  12. Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation

    International Nuclear Information System (INIS)

    Cui, Juan; Miner, Brooke M; Eldredge, Joanna B; Warrenfeltz, Susanne W; Dam, Phuongan; Xu, Ying; Puett, David

    2011-01-01

    Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic targets, may reflect a positive

  13. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

    Science.gov (United States)

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

    2014-01-01

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

  14. Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes.

    Science.gov (United States)

    Fang, Xiefan; Mei, Wenbin; Barbazuk, William B; Rivkees, Scott A; Wendler, Christopher C

    2014-12-15

    Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20-60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3-65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. Copyright © 2014 the American Physiological Society.

  15. Feed intake alters immune cell functions and ovarian infiltration in broiler hens: implications for reproductive performance.

    Science.gov (United States)

    Liu, Zu-Chen; Xie, Yi-Lun; Chang, Chai-Ju; Su, Chia-Ming; Chen, Yu-Hui; Huang, San-Yuan; Walzem, Rosemary L; Chen, Shuen-Ei

    2014-06-01

    Leukocytes are known to participate in ovarian activities in several species, but there is a surprising lack of information for the common chicken. Broiler hens consuming feed ad libitum (AL) exhibit a number of ovarian irregularities, but leukocyte functions are unstudied. In contrast to feed-restricted (R) hens, AL feeding for 7 wk significantly reduced egg production and clutch length while increasing pause length and atretic follicle numbers (P hens contained less progesterone, and follicle walls were thicker with loose fibrous morphology and had less collagenase-3-like gelatinolytic activity but more IL-1beta (P hen peripheral heterophils and monocytes (P hens. © 2014 by the Society for the Study of Reproduction, Inc.

  16. The genetic alteration of retinoblastoma gene in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Jae Il; Shim, Yung Mok; Kim, Chang Min [Korea Cancer Center Hospital of Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1994-12-01

    Retinoblastoma(RB) gene is the prototype of tumor suppressor gene and it`s alteration have been frequently observed in a large number of human tumors. To investigate the role of RB in esophageal cancer, we studied 36 esophageal cancer tissues with Southern blot analysis to detect gross LOH and PCR-SSCP method to find minute LOH and mutation, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. Allelic loss of chromosome 13q14 occurred in 20 out of 32 informative cases (62.5%) by Southern analysis. Furthermore, PCR-LOH added three positive cases. Mobility shift by PCR-SSCP was observed in one case at exon 22, which showed 1 bp deletion in codon 771 of RB gene resulting in frame shift mutation. Besides, nine PCR-band alteration in tumor tissue compared with normal tissue were observed in exon 14 and 22, but mutation was not found on sequencing analysis suggesting the epigenetic alteration in tumor tissue. Analysis of the clinical data did not show any difference depending upon RB alteration. However, the total incidence of RB gene may play an important role in the development of esophageal cancer. The main genetic alteration of RB gene was deletion detected by Southern blot and one bp deletion leading to frame shift was also observed. 8 figs, 5 tabs. (Author).

  17. Sulpiride-induced hyperprolactinemia in mature female rats: evidence for alterations in the reproductive system, pituitary and ovarian hormones.

    Science.gov (United States)

    Mostafapour, Sara; Zare, Samad; Sadrkhanlou, Rajab Ali; Ahmadi, Abbas; Razi, Mazdak

    2014-07-01

    The prevalence of hyperprolactinemia following administration of conven- tional antipsychotic drugs requires further investigation. The current study is designed to evaluate the effect of sulpiride (SPD)-induced hyperprolactinemia on alterations to ovarian follicular growth, gonadotropins, and ovarian hormones and to analyze the extent of potential problems in mammary glands. A total of 40 albino Wistar rats were divided into four groups: control (no treatment), control-sham (0.3 ml olive oil), low dose SPD (20 mg/kg) and high dose SPD (40 mg/kg). All compounds were intraperitoneally (IP) administered for a period of 28 days. After 28 days, we dissected the rats' ovarian tissues, uterine horns and mammary glands which were sent for histological analyses. We counted the numbers of normal, atretic follicles and corpora lutea (CL). Serum levels of prolactin (PRL), estradiol, progesterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were evaluated. SPD-administered animals showed sporadic follicular atresia in different sizes associated with higher numbers of CL on the ovaries. The mammary glands exhibited features of galactorrhea. There was remarkable (p<0.05) elevation in SPD-administered animals' uterine horn endometrium, myometrium and perimetrium thicknesses. The serum levels of PRL and progesterone significantly (p<0.05) increased, while the serum concentration of estradiol, LH and FSH notably (p<0.05) decreased according to the SPD administered dose. No histological and biological changes occurred in control-sham animals. SPD-induced animals had unsuccessful attempts at mating and decreased pregnancy rates. The present findings suggest that SPD-induced disturbances depend on PRL level. In addition, an increased PRL level is largely dependent on the administered doses of SPD.

  18. Sulpiride-Induced Hyperprolactinemia in Mature Female Rats: Evidence for Alterations in The Reproductive System, Pituitary and Ovarian Hormones

    Directory of Open Access Journals (Sweden)

    Sara Mostafapour

    2014-07-01

    Full Text Available Background: The prevalence of hyperprolactinemia following administration of conventional antipsychotic drugs requires further investigation. The current study is designed to evaluate the effect of sulpiride (SPD-induced hyperprolactinemia on alterations to ovarian follicular growth, gonadotropins, and ovarian hormones and to analyze the extent of potential problems in mammary glands. Materials and Methods: A total of 40 albino Wistar rats were divided into four groups: control (no treatment, control-sham (0.3 ml olive oil, low dose SPD (20 mg/kg and high dose SPD (40 mg/kg. All compounds were intraperitoneally (IP administered for a period of 28 days. Results: After 28 days, we dissected the rats’ ovarian tissues, uterine horns and mammary glands which were sent for histological analyses. We counted the numbers of normal, atretic follicles and corpora lutea (CL. Serum levels of prolactin (PRL, estradiol, progesterone, follicle stimulating hormone (FSH and luteinizing hormone (LH were evaluated. SPD-administered animals showed sporadic follicular atresia in different sizes associated with higher numbers of CL on the ovaries. The mammary glands exhibited features of galactorrhea. There was remarkable (p<0.05 elevation in SPD-administered animals’ uterine horn endometrium, myometrium and perimetrium thicknesses. The serum levels of PRL and progesterone significantly (p<0.05 increased, while the serum concentration of estradiol, LH and FSH notably (p<0.05 decreased according to the SPD administered dose. No histological and biological changes occurred in control-sham animals. SPD-induced animals had unsuccessful attempts at mating and decreased pregnancy rates. Conclusion: The present findings suggest that SPD-induced disturbances depend on PRL level. In addition, an increased PRL level is largely dependent on the administered doses of SPD.

  19. p53 Gene status and response to topotecan-containing chemotherapy in advanced ovarian carcinoma.

    Science.gov (United States)

    Oggionni, M; Pilotti, S; Suardi, S; Ditto, A; Luoni, C; Mariani, L; Scambia, G; Fanfani, F; Zunino, F

    2005-01-01

    Since the p53 gene has been identified as a determinant of response to chemotherapy in ovarian carcinoma in previous studies, we investigated the significance of the p53 status in response to topotecan as second-line therapy. Twenty-eight patients with advanced ovarian carcinoma, pretreated with standard platinum/paclitaxel chemotherapy, received topotecan as single-agent second-line therapy. Tumors were investigated by molecular analysis for p53 mutations in tumor samples obtained at primary surgery (i.e. before first-line therapy). Wild-type p53 tumors responsive to first-line therapy maintained substantial responsiveness to topotecan. In contrast, p53 mutation was associated with a low responsiveness to second-line therapy. The better outcome in relapsed patients with wild-type p53 suggests that the presence of a functional wild-type p53 confers stability of the drug-sensitive phenotype. This outcome is consistent with the clinical observation that the efficacy of topotecan in the treatment of relapsed ovarian carcinoma patients is dependent on platinum sensitivity, because platinum-sensitive tumors are expected to carry wild-type p53. Although untreated mutant p53 tumors may be responsive to first-line paclitaxel-containing therapy, it is likely that loss of p53 leads to genomic instability resulting in rapid progression to drug resistance.

  20. Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Phelan, Catherine M; Tsai, Ya-Yu; Goode, Ellen L

    2010-01-01

    Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism...... sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies....

  1. Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma

    DEFF Research Database (Denmark)

    Arildsen, Nicolai Skovbjerg; Jönsson, Jenny-Maria; Bartuma, Katarina

    2017-01-01

    OBJECTIVE: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyondARID1A, which...... and ultimately improve patient outcome. METHODS: Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1;n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays...... ovarian cancer subtypes. However, overexpression ofERBB2was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct...

  2. Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis

    DEFF Research Database (Denmark)

    Cunningham, J M; Vierkant, R A; Sellers, T A

    2009-01-01

    BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin...... in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion...

  3. DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk

    Directory of Open Access Journals (Sweden)

    Rabiau Nadège

    2008-05-01

    Full Text Available Abstract Breast and ovarian cancers increased in the last decades. Except rare cases with a genetic predisposition and high penetrance, these pathologies are viewed as a polygenic disease. In this concept, association studies look for genetic variations such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damages have been shown to have significantly reduced. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study, 2 functional polymorphisms in a DNA repair gene ERCC2 were analyzed. The population included 911 breast cancer cases, 51 ovarian cancer cases and 1000 controls. The genotyping of 2 SNP (Single Nucleotide Polymorphism was carried out on the population with the MGB (Minor Groove Binder probe technique which consists of the use of the allelic discrimination with the Taqman® method. This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio (WHR > 0.85 for Asn homozygous for ERCC2 312.

  4. Is there peripheral or ovarian insulin action alteration in broiler breeder hens fed ad libitum?

    Science.gov (United States)

    Métayer, S; Tesseraud, S; Cassy, S; Taouis, M; Williams, J; Picard, M; Rideau, N

    2006-06-01

    We investigated whether a change in peripheral glucose homeostasis, a local change in the insulin-related ovarian regulatory system, or both occurred in ad libitum-fed broiler breeder hens compared with feed-restricted counterparts. Feed-restricted (R, from 5 to 16 wk of age) and ad libitum-fed (A) hens from a standard commercial line (S) and an experimental dwarf genotype (E) were studied. Basal and stimulated plasma insulin and glucose concentrations were measured during the prebreeding and laying periods. In the basal state (after 16 h fasting) plasma glucose concentrations were significantly lower in SA chickens (-5% at 17 wk, -7.5% at 32 wk) compared with EA, SR, and ER chickens, with no difference in plasma insulin concentrations (n = 16). In 17-wk-old SA birds, 30 min after oral glucose loading, plasma glucose concentrations increased significantly compared with the basal state and were also significantly lower as compared with SR but did not differ significantly from EA and ER. Plasma insulin concentrations did not differ significantly between genotypes or regimens (n = 16). A potential modification of intracellular mediators involved in the regulation of cell growth and survival in small follicles that were overrecruited in SA compared with SR was also investigated in SA and SR hens at 32 wk. There was no effect of food restriction in phospho-Akt, Akt, phospho-ERK, and phospho-S6 in the small white ovarian follicles (n = 6) in the basal state and after 30 min of refeeding. In conclusion, the present study does not demonstrate any evidence of glucose intolerance during the prebreeding period, specific change in the ovarian small follicle insulin signalling pathway, or both, in laying broiler breeders fed ad libitum compared with feed-restricted hens.

  5. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk

    DEFF Research Database (Denmark)

    Usset, Joseph L; Raghavan, Rama; Tyrer, Jonathan P

    2016-01-01

    BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese......, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. RESULTS: SNPs in the following...... candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408...

  6. Bioinformatics analysis to screen the key prognostic genes in ovarian cancer.

    Science.gov (United States)

    Li, Li; Cai, Shengyun; Liu, Shengnan; Feng, Hao; Zhang, Junjie

    2017-04-13

    Ovarian cancer (OC) is a gynecological oncology that has a poor prognosis and high mortality. This study is conducted to identify the key genes implicated in the prognosis of OC by bioinformatic analysis. Gene expression data (including 568 primary OC tissues, 17 recurrent OC tissues, and 8 adjacent normal tissues) and the relevant clinical information of OC patients were downloaded from The Cancer Genome Atlas database. After data preprocessing, cluster analysis was conducted using the ConsensusClusterPlus package in R. Using the limma package in R, differential analysis was performed to identify feature genes. Based on Kaplan-Meier (KM) survival analysis, prognostic seed genes were selected from the feature genes. After key prognostic genes were further screened by cluster analysis and KM survival analysis, they were performed functional enrichment analysis and multivariate survival analysis. Using the survival package in R, cox regression analysis was conducted for the microarray data of GSE17260 to validate the key prognostic genes. A total of 3668 feature genes were obtained, among which 75 genes were identified as prognostic seed genes. Then, 25 key prognostic genes were screened, including AXL, FOS, KLF6, WDR77, DUSP1, GADD45B, and SLIT3. Especially, AXL and SLIT3 were enriched in ovulation cycle. Multivariate survival analysis showed that the key prognostic genes could effectively differentiate the samples and were significantly associated with prognosis. Additionally, GSE17260 confirmed that the key prognostic genes were associated with the prognosis of OC. AXL, FOS, KLF6, WDR77, DUSP1, GADD45B, and SLIT3 might affect the prognosis of OC.

  7. Altered expression of histamine signaling genes in autism spectrum disorder.

    Science.gov (United States)

    Wright, C; Shin, J H; Rajpurohit, A; Deep-Soboslay, A; Collado-Torres, L; Brandon, N J; Hyde, T M; Kleinman, J E; Jaffe, A E; Cross, A J; Weinberger, D R

    2017-05-09

    The histaminergic system (HS) has a critical role in cognition, sleep and other behaviors. Although not well studied in autism spectrum disorder (ASD), the HS is implicated in many neurological disorders, some of which share comorbidity with ASD, including Tourette syndrome (TS). Preliminary studies suggest that antagonism of histamine receptors 1-3 reduces symptoms and specific behaviors in ASD patients and relevant animal models. In addition, the HS mediates neuroinflammation, which may be heightened in ASD. Together, this suggests that the HS may also be altered in ASD. Using RNA sequencing (RNA-seq), we investigated genome-wide expression, as well as a focused gene set analysis of key HS genes (HDC, HNMT, HRH1, HRH2, HRH3 and HRH4) in postmortem dorsolateral prefrontal cortex (DLPFC) initially in 13 subjects with ASD and 39 matched controls. At the genome level, eight transcripts were differentially expressed (false discovery rate effect on any of the individual HS genes but expression of the gene set of HNMT, HRH1, HRH2 and HRH3 was significantly altered. Curated HS gene sets were also significantly differentially expressed. Differential expression analysis of these gene sets in an independent RNA-seq ASD data set from DLPFC of 47 additional subjects confirmed these findings. Understanding the physiological relevance of an altered HS may suggest new therapeutic options for the treatment of ASD.

  8. PARK2, a Large Common Fragile Site Gene, is Part of a Stress Response Network in Normal Cells That is Disrupted During the Development of Ovarian Cancer

    National Research Council Canada - National Science Library

    Smith, David I; Zhu, Yu

    2007-01-01

    .... The central two questions that we want to address with this work are what role does inactivation of Parkin and other large CFS genes play in the development of ovarian cancer and whether these genes...

  9. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

    International Nuclear Information System (INIS)

    Pylkäs, Katri; Erkko, Hannele; Nikkilä, Jenni; Sólyom, Szilvia; Winqvist, Robert

    2008-01-01

    BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families. Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA) method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative. We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13) in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2. In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility

  10. Neonatal thymulin gene therapy prevents ovarian dysgenesis and attenuates reproductive derangements in nude female mice.

    Science.gov (United States)

    Reggiani, Paula C; Barbeito, Claudio G; Zuccolilli, Gustavo O; Cónsole, Gloria M; Flamini, Alicia M; Dardenne, Mireille; Goya, Rodolfo G

    2012-08-01

    Congenitally athymic (nude) female mice show severe ovarian dysgenesis after puberty, which seems to be consequential to a number of neuroendocrine derangements described in these mutants. Thus, considerable evidence suggests that thymulin, a thymic peptide, may be involved in thymus-pituitary communication. In order to clarify the relevance of thymulin for the maturation of the female reproductive system, we assessed at hypothalamic, pituitary, ovarian, and uterine level the preventive action of neonatal thymulin gene therapy (NTGT) on the changes that typically occur after puberty in congenitally athymic female mice. We injected (im) an adenoviral vector harboring a synthetic DNA sequence encoding a biologically active analog of thymulin, methionine-serum thymic factor, in newborn nude mice (which are thymulin deficient) and killed the animals at 70-71 d of age. NTGT in the athymic mice restored the serum thymulin levels. Morphometric analysis revealed that athymic nudes have reduced numbers of brain GnRH neurons and pituitary gonadotropic cells as compared with heterozygous controls. NTGT prevented these changes and also rescued the premature ovarian failure phenotype typically observed in athymic nude mice (marked reduction in the number of antral follicles and corpora lutea, increase in atretic follicles). Serum estrogen, but not progesterone, levels were low in athymic nudes, a reduction that was partially prevented by NTGT. Little to no morphological changes were observed in the endometrium of female nudes. The delay in the age of vaginal opening that occurs in athymic nudes was significantly prevented by NTGT. Our results suggest that thymulin plays a relevant physiologic role in the thymus-hypothalamo-pituitary-gonadal axis.

  11. Identification of reference genes in human myelomonocytic cells for gene expression studies in altered gravity.

    Science.gov (United States)

    Thiel, Cora S; Hauschild, Swantje; Tauber, Svantje; Paulsen, Katrin; Raig, Christiane; Raem, Arnold; Biskup, Josefine; Gutewort, Annett; Hürlimann, Eva; Unverdorben, Felix; Buttron, Isabell; Lauber, Beatrice; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Layer, Liliana E; Ullrich, Oliver

    2015-01-01

    Gene expression studies are indispensable for investigation and elucidation of molecular mechanisms. For the process of normalization, reference genes ("housekeeping genes") are essential to verify gene expression analysis. Thus, it is assumed that these reference genes demonstrate similar expression levels over all experimental conditions. However, common recommendations about reference genes were established during 1 g conditions and therefore their applicability in studies with altered gravity has not been demonstrated yet. The microarray technology is frequently used to generate expression profiles under defined conditions and to determine the relative difference in expression levels between two or more different states. In our study, we searched for potential reference genes with stable expression during different gravitational conditions (microgravity, normogravity, and hypergravity) which are additionally not altered in different hardware systems. We were able to identify eight genes (ALB, B4GALT6, GAPDH, HMBS, YWHAZ, ABCA5, ABCA9, and ABCC1) which demonstrated no altered gene expression levels in all tested conditions and therefore represent good candidates for the standardization of gene expression studies in altered gravity.

  12. DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1

    Directory of Open Access Journals (Sweden)

    Connor Joseph P

    2012-05-01

    Full Text Available Abstract Background Overcoming platinum resistance is a major obstacle in the treatment of Epithelial Ovarian Cancer (EOC. In our previous work Decoy Receptor 3 (DcR3 was found to be related to platinum resistance. The major objective of this work was to define the cellular interaction of DcR3 with EOC and to explore its effects on platinum responsiveness. Methods We studied cell lines and primary cultures for the expression of and the cells ability to bind DcR3. Cells were cultured with DcR3 and then exposed to platinum. Cell viability was determined by MTT assay. Finally, the cells molecular response to DcR3 was studied using real time RT-PCR based differential expression arrays, standard RT-PCR, and Western blot. Results High DcR3 in the peritoneal cavity of women with EOC is associated with significantly shorter time to first recurrence after platinum based therapy (p = 0.02. None-malignant cells contribute DcR3 in the peritoneal cavity. The cell lines studied do not secrete DcR3; however they all bind exogenous DcR3 to their surface implying that they can be effected by DcR3 from other sources. DcR3s protein binding partners are minimally expressed or negative, however, all cells expressed the DcR3 binding Heparan Sulfate Proteoglycans (HSPGs Syndecans-2, and CD44v3. DcR3 binding was inhibited by heparin and heparinase. After DcR3 exposure both SKOV-3 and OVCAR-3 became more resistant to platinum with 15% more cells surviving at high doses. On the contrary CaOV3 became more sensitive to platinum with 20–25% more cell death. PCR array analysis showed increase expression of BRCA1 mRNA in SKOV-3 and OVCAR-3 and decreased BRCA1 expression in CaOV-3 after exposure to DcR3. This was confirmed by gene specific real time PCR and Western blot analysis. Conclusions Non-malignant cells contribute to the high levels of DcR3 in ovarian cancer. DcR3 binds readily to EOC cells via HSPGs and alter their responsiveness to platinum chemotherapy. The

  13. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC Risk.

    Directory of Open Access Journals (Sweden)

    Ganna Chornokur

    Full Text Available Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC, we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC. Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS. SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020; this SNP was also associated with the borderline/low malignant potential (LMP tumors (P = 0.021. Other genes significantly associated with EOC histological subtypes (p<0.05 included the UGT1A (endometrioid, SLC25A45 (mucinous, SLC39A11 (low malignant potential, and SERPINA7 (clear cell carcinoma. In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4.These results, generated on a large cohort of women, revealed associations between inherited cellular

  14. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    NARCIS (Netherlands)

    Lawrenson, K.; Li, Q.; Kar, S.; Seo, J.H.; Tyrer, J.; Spindler, T.J.; Lee, J. van der; Chen, Y; Karst, A.; Drapkin, R.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Baker, H.; Bandera, E.V.; Bean, Y.; Beckmann, M.W.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A; Chen, Z.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Eccles, D.; Easton, D.T.; Edwards, R.P.; Eilber, U.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Grownwald, J.; Harrington, P.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Iversen, E.S.; Jakubowska, A.; James, P.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kjaer, S. Kruger; Kelemen, L.E.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.; et al.,

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions

  15. Microsatellite instability, promoter methylation and protein expression of the DNA mismatch repair genes in epithelial ovarian cancer.

    Science.gov (United States)

    V, Shilpa; Bhagat, Rahul; C S, Premalata; V R, Pallavi; Krishnamoorthy, Lakshmi

    2014-10-01

    The role of defective mismatch repair (MMR) system in ovarian carcinoma is not well defined. The purpose of the study was to determine the relationship between microsatellite instability (MSI), promoter methylation and protein expression of MMR genes in epithelial ovarian carcinoma (EOC). MSI and promoter methylation of MLH1, MSH2 and PMS2 genes were studied using PCR methods in the study cohort. A small subset of samples was used to analyze the protein expression by immunohistochemistry (IHC). MSI was observed in >60% of tumor samples and 47% of normal ovaries. MLH1 was methylated in 37.5% and 64.3% EOCs and LMP tumors. The loss of immunoexpression of MMR genes was not seen in ovarian tumors. There was no correlation between MSI, promoter methylation and protein expression of the MMR genes suggesting that each may function independently. MSI is a common event in ovarian carcinoma and may increase the clinical awareness of the subset of tumors. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Gene expression profiling of bovine ovarian follicular and luteal cells provides insight into cellular identities and functions

    Science.gov (United States)

    After ovulation, somatic cells of the ovarian follicle (theca and granulosa cells) become the small and large luteal cells of the corpus luteum. Aside from known cell type-specific receptors and steroidogenic enzymes, little is known about the differences in the gene expression profiles of these fou...

  17. The ligand binding domain of GCNF is not required for repression of pluripotency genes in mouse fetal ovarian germ cells.

    Directory of Open Access Journals (Sweden)

    Leah M Okumura

    Full Text Available In mice, successful development and reproduction require that all cells, including germ cells, transition from a pluripotent to a differentiated state. This transition is associated with silencing of the pluripotency genes Oct4 and Nanog. Interestingly, these genes are repressed at different developmental timepoints in germ and somatic cells. Ovarian germ cells maintain their expression until about embryonic day (E 14.5, whereas somatic cells silence them much earlier, at about E8.0. In both somatic cells and embryonic stem cells, silencing of Oct4 and Nanog requires the nuclear receptor GCNF. However, expression of the Gcnf gene has not been investigated in fetal ovarian germ cells, and whether it is required for silencing Oct4 and Nanog in that context is not known. Here we demonstrate that Gcnf is expressed in fetal ovarian germ cells, peaking at E14.5, when Oct4 and Nanog are silenced. However, conditional ablation of the ligand-binding domain of Gcnf using a ubiquitous, tamoxifen-inducible Cre indicates that Gcnf is not required for the down-regulation of pluripotency genes in fetal ovarian germ cells, nor is it required for initiation of meiosis and oogenesis. These results suggest that the silencing of Oct4 and Nanog in germ cells occurs via a different mechanism from that operating in somatic cells during gastrulation.

  18. Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

    DEFF Research Database (Denmark)

    Charbonneau, Bridget; Moysich, Kirsten B; Kalli, Kimberly R

    2014-01-01

    The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL...

  19. Molecular Alterations of TP53 are a Defining Feature of Ovarian High-Grade Serous Carcinoma: A Rereview of Cases Lacking TP53 Mutations in The Cancer Genome Atlas Ovarian Study.

    Science.gov (United States)

    Vang, Russell; Levine, Douglas A; Soslow, Robert A; Zaloudek, Charles; Shih, Ie-Ming; Kurman, Robert J

    2016-01-01

    The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data are the subject of this report. Only 1 case (Case 5), which contained a homozygous deletion of TP53, had unanimous interobserver agreement for a diagnosis of pure HGSC. In 1 case (Case 3), all 5 observers (100%) rendered a diagnosis of HGSC; however, 3 observers (60%) noted that the histologic features were not classic for HGSC and suggested this case may have arisen from a low-grade serous carcinoma (arisen from an alternate pathway compared with the usual HGSC). In 2 cases (Cases 4 and 12), only 3 observers (60%) in each case, respectively, interpreted it as having a component of HGSC. In the remaining 10 (71%) of tumors (Cases 1, 2, 6-11, 13, and 14), the consensus diagnosis was not HGSC, with individual diagnoses including low-grade serous carcinoma, high-grade endometrioid carcinoma, HGSC, metastatic carcinoma, clear cell carcinoma, atypical proliferative (borderline) serous tumor, and adenocarcinoma, not otherwise specified. Therefore, 13 (93%) of the tumors (Cases 1-4 and 6-14) were either not a pure HGSC or represented a diagnosis other than HGSC, all with molecular results not characteristic of HGSC. Accordingly, our review of the TP53 wild-type HGSCs reported in The Cancer Genome Atlas suggests that 100% of de novo HGSCs contain TP53 somatic mutations or deletions, with the exception of the rare HGSCs that develop from a low-grade serous tumor precursor. We, therefore, propose that lack of molecular alterations of TP53 are essentially inconsistent with the

  20. Identification of differentially expressed genes using an annealing control primer system in stage III serous ovarian carcinoma

    International Nuclear Information System (INIS)

    Kim, Yun-Sook; Hwan Do, Jin; Bae, Sumi; Bae, Dong-Han; Shick Ahn, Woong

    2010-01-01

    Most patients with ovarian cancer are diagnosed with advanced stage disease (i.e., stage III-IV), which is associated with a poor prognosis. Differentially expressed genes (DEGs) in stage III serous ovarian carcinoma compared to normal tissue were screened by a new differential display method, the annealing control primer (ACP) system. The potential targets for markers that could be used for diagnosis and prognosis, for stage III serous ovarian cancer, were found by cluster and survival analysis. The ACP-based reverse transcriptase polymerase chain reaction (RT PCR) technique was used to identify DEGs in patients with stage III serous ovarian carcinoma. The DEGs identified by the ACP system were confirmed by quantitative real-time PCR. Cluster analysis was performed on the basis of the expression profile produced by quantitative real-time PCR and survival analysis was carried out by the Kaplan-Meier method and Cox proportional hazards multivariate model; the results of gene expression were compared between chemo-resistant and chemo-sensitive groups. A total of 114 DEGs were identified by the ACP-based RT PCR technique among patients with stage III serous ovarian carcinoma. The DEGs associated with an apoptosis inhibitory process tended to be up-regulated clones while the DEGs associated with immune response tended to be down-regulated clones. Cluster analysis of the gene expression profile obtained by quantitative real-time PCR revealed two contrasting groups of DEGs. That is, a group of genes including: SSBP1, IFI6 DDT, IFI27, C11orf92, NFKBIA, TNXB, NEAT1 and TFG were up-regulated while another group of genes consisting of: LAMB2, XRCC6, MEF2C, RBM5, FOXP1, NUDCP2, LGALS3, TMEM185A, and C1S were down-regulated in most patients. Survival analysis revealed that the up-regulated genes such as DDAH2, RNase K and TCEAL2 might be associated with a poor prognosis. Furthermore, the prognosis of patients with chemo-resistance was predicted to be very poor when genes such

  1. Inherited variants in regulatory T cell genes and outcome of ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Ellen L Goode

    Full Text Available Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL and sequence-based tagging single nucleotide polymorphisms (tagSNPs for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p=2.7×10(-5, LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p=4.5×10(-4, and rs3753348, p=9.0×10(-4, respectively, and CD80 (endometrioid, rs13071247, p=8.0×10(-4. Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p=0.006. An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p=8.1×10(-4 among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.

  2. Effects of deletion of the prolactin receptor on ovarian gene expression

    Directory of Open Access Journals (Sweden)

    Kelly Paul A

    2003-02-01

    Full Text Available Abstract Prolactin (PRL exerts pleiotropic physiological effects in various cells and tissues, and is mainly considered as a regulator of reproduction and cell growth. Null mutation of the PRL receptor (R gene leads to female sterility due to a complete failure of embryo implantation. Pre-implantatory egg development, implantation and decidualization in the mouse appear to be dependent on ovarian rather than uterine PRLR expression, since progesterone replacement permits the rescue of normal implantation and early pregnancy. To better understand PRL receptor deficiency, we analyzed in detail ovarian and corpora lutea development of PRLR-/- females. The present study demonstrates that the ovulation rate is not different between PRLR+/+ and PRLR-/- mice. The corpus luteum is formed but an elevated level of apoptosis and extensive inhibition of angiogenesis occur during the luteal transition in the absence of prolactin signaling. These modifications lead to the decrease of LH receptor expression and consequently to a loss of the enzymatic cascades necessary to produce adequate levels of progesterone which are required for the maintenance of pregnancy.

  3. Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Joellen M Schildkraut

    Full Text Available BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS, a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio(per allele = 0.66; 95% credible interval (CI = 0.44-1.00 and rs6005835 (median OR(per allele = 0.69; 95% CI = 0.53-0.91 in CHEK2, rs2078486 (median OR(per allele = 1.65; 95% CI = 1.21-2.25 and rs12951053 (median OR(per allele = 1.65; 95% CI = 1.20-2.26 in TP53, rs411697 (median OR (rare homozygote = 0.53; 95% CI = 0.35 - 0.79 in BACH1 and rs10131 (median OR( rare homozygote = not estimable in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.

  4. Low concentrations of o,p'-DDT inhibit gene expression and prostaglandin synthesis by estrogen receptor-independent mechanism in rat ovarian cells.

    Directory of Open Access Journals (Sweden)

    Jing Liu

    Full Text Available o,p'-DDT is an infamous xenoestrogen as well as a ubiquitous and persistent pollutant. Biomonitoring studies show that women have been internally exposed to o,p'-DDT at range of 0.3-500 ng/g (8.46×10(-10 M-1.41×10(-6 M in blood and other tissues. However, very limited studies have investigated the biological effects and mechanism(s of o,p'-DDT at levels equal to or lower than current exposure levels in human. In this study, using primary cultures of rat ovarian granulosa cells, we determined that very low doses of o,p'-DDT (10(-12-10(-8 M suppressed the expression of ovarian genes and production of prostaglandin E2 (PGE2. In vivo experiments consistently demonstrated that o,p'-DDT at 0.5-1 mg/kg inhibited the gene expression and PGE2 levels in rat ovary. The surprising results from the receptor inhibitors studies showed that these inhibitory effects were exerted independently of either classical estrogen receptors (ERs or G protein-coupled receptor 30 (GPR30. Instead, o,p'-DDT altered gene expression or hormone action via inhibiting the activation of protein kinase A (PKA, rather than protein kinase C (PKC. We further revealed that o,p'-DDT directly interfered with the PKA catalytic subunit. Our novel findings support the hypothesis that exposure to low concentrations of o,p'-DDT alters gene expression and hormone synthesis through signaling mediators beyond receptor binding, and imply that the current exposure levels of o,p'-DDT observed in the population likely poses a health risk to female reproduction.

  5. RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Bignone, P A; Lee, K Y; Liu, Y

    2007-01-01

    -activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells....... Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced...

  6. Protein levels and gene expressions of the epidermal growth factor receptors, HER1, HER2, HER3 and HER4 in benign and malignant ovarian tumors

    DEFF Research Database (Denmark)

    Dahl Steffensen, Karina; Waldstrøm, Marianne; Fredslund Andersen, Rikke

    2008-01-01

    , but this is not elucidated in detail in ovarian tissue. High tumor-to-normal-tissue concentration ratios would be favorable for molecular targeted anti-cancer treatment. The primary aim of the study was to analyze the potential differential protein content and gene expression of the four receptors in benign and malignant...... ovarian tumors. Tissue from 207 patients (101 malignant, 19 borderline, 64 benign ovarian tumors and 23 normal ovaries) were analyzed by quantitative ELISA for HER1-HER4 protein concentrations and by real-time PCR for HER1-HER4 gene expression. HER2 was also analyzed by immunohistochemistry. The HER2......-4 receptor protein content and the median gene expression level was significantly higher in ovarian cancer patients compared to patients with benign ovarian tumors and normal ovaries (povarian cancer compared to borderline...

  7. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

    Science.gov (United States)

    Hampras, Shalaka S.; Sucheston-Campbell, Lara E.; Cannioto, Rikki; Chang-Claude, Jenny; Modugno, Francesmary; Dörk, Thilo; Hillemanns, Peter; Preus, Leah; Knutson, Keith L.; Wallace, Paul K.; Hong, Chi-Chen; Friel, Grace; Davis, Warren; Nesline, Mary; Pearce, Celeste L.; Kelemen, Linda E.; Goodman, Marc T.; Bandera, Elisa V.; Terry, Kathryn L.; Schoof, Nils; Eng, Kevin H.; Clay, Alyssa; Singh, Prashant K.; Joseph, Janine M.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Cook, Linda S.; Cramer, Daniel W.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; du Bois, Andreas; Dürst, Matthias; Easton, Doug; Eccles, Diana; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hogdall, Claus; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Klapdor, Rüdiger; Kolomeyevskaya, Nonna; Krakstad, Camilla; Kjaer, Susanne K.; Kruszka, Bridget; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashikant; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Liu, Song; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valeria; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Moes-Sosnowska, Joanna; Narod, Steven A.; Nedergaard, Lotte; Nevanlinna, Heli; Nickels, Stefan; Olson, Sara H.; Orlow, Irene; Weber, Rachel Palmieri; Paul, James; Pejovic, Tanja; Pelttari, Liisa M.; Perkins, Barbara; Permuth-Wey, Jenny; Pike, Malcolm C.; Plisiecka-Halasa, Joanna; Poole, Elizabeth M.; Risch, Harvey A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schmitt, Kristina; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Tangen, Ingvild L.; Teo, Soo-Hwang; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; Tyrer, Jonathan; van Altena, Anna M.; Vergote, Ignace; Vierkant, Robert A.; Walsh, Christine; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Gayther, Simon A.; Ramus, Susan J.; Sellers, Thomas A.; Schildkraut, Joellen M.; Phelan, Catherine M.; Berchuck, Andrew; Chenevix-Trench, Georgia; Cunningham, Julie M.; Pharoah, Paul P.; Ness, Roberta B.; Odunsi, Kunle; Goode, Ellen L.; Moysich, Kirsten B.

    2016-01-01

    Background Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with (p = 0.001) and clear cell EOC. Gene associations with histotypes at< 0.05 included:(p = 0.005 and = 0.008, serous and high-grade serous, respectively), (p = 0.035, endometrioid and mucinous), (p = 0.03, mucinous), (p = 0.022, clear cell), (p = 0.021 endometrioid) and (p = 0.017 and = 0.025, endometrioid and mucinous, respectively). Conclusions Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients. PMID:27533245

  8. Collagen type I alpha 1 gene polymorphism in premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Vujović Svetlana

    2013-01-01

    Full Text Available Introduction. Premature ovarian failure (POF is characterized by amenorrhea, hypergonadotropism and hypoestrogenism in women bellow 40 years. Osteoporosis is one of the late complications of POF. Objective. To correlate collagen type I alpha1 (COLIA1 gene polymorphism with bone mineral density (BMD in women with POF. Methods. We determined the COLIA1 genotypes SS, Ss, ss in 66 women with POF. Single nucleotide polymorphism (G to T substitution within the Sp 1-binding site in the first intron of the COLIA1 gene was assessed by polymerase chain reaction (PCR followed by single-stranded conformation polymorphism (SSCP analysis. Bone mineral density (BMD was measured at the lumbar spine region by dual X-ray absorptiometry. Statistics: Kruskal-Wallis ANOVA, Chisquare test, Spearman correlation test. Results. The relative distribution of COLIA1 genotype alleles was SS - 54.4%, Ss - 41.0% and ss - 4.5%. No significant differences were found between genotype groups in body mass index, age, duration of amenorrhea or BMD. A significant positive correlation was observed between BMI and parity. Conclusion. The COLIA1 gene is just one of many genes influencing bone characteristics. It may act as a marker for differences in bone quantity and quality, bone fragility and accelerated bone loss in older women. However, in young women with POF, COLIA1 cannot identify those at higher risk for osteoporosis. [Projekat Ministarstva nauke Republike Srbije, br. ON 173056

  9. Alterations in opioid parameters in the hypothalamus of rats with estradiol-induced polycystic ovarian disease

    Energy Technology Data Exchange (ETDEWEB)

    Desjardins, G.C.; Beaudet, A.; Brawer, J.R. (McGill Univ., Quebec (Canada))

    1990-12-01

    The distribution and density of selectively labeled mu-, delta-, and kappa-opioid binding sites were examined by in vitro radioautography in the hypothalamus of normal, estradiol valerate (EV)-injected, and estradiol (E2)-implanted female rats. Hypothalamic beta-endorphin concentration was also examined by RIA in these three groups of animals. Quantitative analysis of film radioautographs demonstrated a selective increase in mu-opioid binding in the medial preoptic area of EV-treated, but not of E2-implanted rats. However, both these estrogenized groups exhibited a reduction in the density of delta-opioid binding in the suprachiasmatic nucleus. Statistically significant changes between either estrogenized groups were not observed for kappa-opioid binding. Results on the hypothalamic concentration of beta-endorphin indicated a marked reduction in EV-injected animals with respect to controls. In contrast, the E2-implanted animals exhibited beta-endorphin concentrations similar to controls. The present results confirm the increase in opioid receptor binding previously reported in the hypothalamus of EV-treated rats and further demonstrate that this increase is confined to the medial preoptic area and exclusively concerns mu-opioid receptors. The concomitant reduction in beta-endorphin levels observed in the same group of animals suggests that the observed increase in mu-opioid binding could reflect a chronic up-regulation of the receptor in response to compromised beta-endorphin input. Given the restriction of this effect to the site of origin of LHRH neurons and the demonstrated inhibitory role of opioids on LHRH release, it is tempting to postulate that such up-regulation could lead to the suppression of the plasma LH pattern that characterizes polycystic ovarian disease in the EV-treated rat.

  10. Alterations in opioid parameters in the hypothalamus of rats with estradiol-induced polycystic ovarian disease

    International Nuclear Information System (INIS)

    Desjardins, G.C.; Beaudet, A.; Brawer, J.R.

    1990-01-01

    The distribution and density of selectively labeled mu-, delta-, and kappa-opioid binding sites were examined by in vitro radioautography in the hypothalamus of normal, estradiol valerate (EV)-injected, and estradiol (E2)-implanted female rats. Hypothalamic beta-endorphin concentration was also examined by RIA in these three groups of animals. Quantitative analysis of film radioautographs demonstrated a selective increase in mu-opioid binding in the medial preoptic area of EV-treated, but not of E2-implanted rats. However, both these estrogenized groups exhibited a reduction in the density of delta-opioid binding in the suprachiasmatic nucleus. Statistically significant changes between either estrogenized groups were not observed for kappa-opioid binding. Results on the hypothalamic concentration of beta-endorphin indicated a marked reduction in EV-injected animals with respect to controls. In contrast, the E2-implanted animals exhibited beta-endorphin concentrations similar to controls. The present results confirm the increase in opioid receptor binding previously reported in the hypothalamus of EV-treated rats and further demonstrate that this increase is confined to the medial preoptic area and exclusively concerns mu-opioid receptors. The concomitant reduction in beta-endorphin levels observed in the same group of animals suggests that the observed increase in mu-opioid binding could reflect a chronic up-regulation of the receptor in response to compromised beta-endorphin input. Given the restriction of this effect to the site of origin of LHRH neurons and the demonstrated inhibitory role of opioids on LHRH release, it is tempting to postulate that such up-regulation could lead to the suppression of the plasma LH pattern that characterizes polycystic ovarian disease in the EV-treated rat

  11. Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus

    Directory of Open Access Journals (Sweden)

    Patak Eva

    2009-07-01

    Full Text Available Abstract Background In the mouse uterus, pregnancy is accompanied by changes in tachykinin and tachykinin receptor gene expression and in the uterotonic effects of endogenous tachykinins. In this study we have investigated whether changes in tachykinin expression and responses are a result of changes in ovarian steroid levels. Methods We quantified the mRNAs of tachykinins and tachykinin receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h and late (24 h responses to estrogen were evaluated and the participation of the estrogen receptors (ER, ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta. Results All genes encoding tachykinins (Tac1, Tac2 and Tac4 and tachykinin receptors (Tacr1, Tacr2 and Tacr3 were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and Tac4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2. Conclusion These results show that the expression of tachykinins and their receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus.

  12. Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus.

    Science.gov (United States)

    Pinto, Francisco M; Pintado, C Oscar; Pennefather, Jocelyn N; Patak, Eva; Candenas, Luz

    2009-07-23

    In the mouse uterus, pregnancy is accompanied by changes in tachykinin and tachykinin receptor gene expression and in the uterotonic effects of endogenous tachykinins. In this study we have investigated whether changes in tachykinin expression and responses are a result of changes in ovarian steroid levels. We quantified the mRNAs of tachykinins and tachykinin receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta. All genes encoding tachykinins (Tac1, Tac2 and Tac4) and tachykinin receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and Tac4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2. These results show that the expression of tachykinins and their receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus.

  13. The effect of catalase C262T gene polymorphism in susceptibility to ovarian cancer in Kermanshah province, Western Iran.

    Science.gov (United States)

    Moradi, Mohammad-Taher; Khazaei, Mansour; Khazaei, Mozafar

    2018-02-08

    Ovarian cancer has a heterogeneous biology and behaviour. Oxidative stress can initiate chronic inflammation, which can sequentially facilitate chronic diseases, including cancer. Oxidative stress may arise when there is extra reactive oxygen species (ROS) production and/or inadequate defence mechanisms. There are some antioxidant defences that can fight against oxidative damage, including catalase (CAT) enzyme. We sought to evaluate the association of CAT C262T gene polymorphism with increased risk of ovarian cancer. A total of 74 paraffin-embedded ovarian cancer blocks were taken from the archive of Imam-Reza Hospital, Kermanshah University of Medical Sciences, between 2010 and 2014. Also, 153 blood samples were harvested from healthy volunteers. For genotyping of CAT C262T, we designed allele-specific polymerase chain reaction (AS-PCR). 'T' allele of CAT C262T showed a protective effect against the risk of ovarian cancer [OR = 0.4 (95% CI 0.25-0.6), p value <.001]. Calculating adjusted odds ratio showed the distribution of alleles and genotypes was not affected by age. The present study reported a significant association between the distribution of CAT C262T gene polymorphism and ovarian cancer for the first time in a sample of the Iranian population. Impact Statement What is already known on this subject: Ovarian cancer has a heterogeneous biology and behaviour at the clinical, cellular and molecular aspects. Ovulation releases follicular fluid containing reactive oxygen species which is related to changes in the microenvironment, such as inflammation, that could be a factor in early ovarian carcinogenesis. There are some antioxidant defences that can protect cells against oxidative damage, including catalase (CAT). Different studies investigated the relationships between CAT C262T polymorphism and several diseases. Belotte et al. ( 2015 ), for the first time, indicated no significant association between CAT C262T and the risk of ovarian cancer, while they

  14. Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Claudia Figueroa-Romero

    Full Text Available Amyotrophic lateral sclerosis (ALS is a terminal disease involving the progressive degeneration of motor neurons within the motor cortex, brainstem and spinal cord. Most cases are sporadic (sALS with unknown causes suggesting that the etiology of sALS may not be limited to the genotype of patients, but may be influenced by exposure to environmental factors. Alterations in epigenetic modifications are likely to play a role in disease onset and progression in ALS, as aberrant epigenetic patterns may be acquired throughout life. The aim of this study was to identify epigenetic marks associated with sALS. We hypothesize that epigenetic modifications may alter the expression of pathogenesis-related genes leading to the onset and progression of sALS. Using ELISA assays, we observed alterations in global methylation (5 mC and hydroxymethylation (5 HmC in postmortem sALS spinal cord but not in whole blood. Loci-specific differentially methylated and expressed genes in sALS spinal cord were identified by genome-wide 5mC and expression profiling using high-throughput microarrays. Concordant direction, hyper- or hypo-5mC with parallel changes in gene expression (under- or over-expression, was observed in 112 genes highly associated with biological functions related to immune and inflammation response. Furthermore, literature-based analysis identified potential associations among the epigenes. Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.

  15. Canine Mammary Carcinomas: A Comparative Analysis of Altered Gene Expression

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    Farruk M. Lutful Kabir

    2015-12-01

    Full Text Available Breast cancer represents the second most frequent neoplasm in humans and sexually intact female dogs after lung and skin cancers, respectively. Many similar features in human and dog cancers including, spontaneous development, clinical presentation, tumor heterogeneity, disease progression and response to conventional therapies have supported development of this comparative model as an alternative to mice. The highly conserved similarities between canine and human genomes are also key to this comparative analysis, especially when compared to the murine genome. Studies with canine mammary tumor (CMT models have shown a strong genetic correlation with their human counterparts, particularly in terms of altered expression profiles of cell cycle regulatory genes, tumor suppressor and oncogenes and also a large group of non-coding RNAs or microRNAs (miRNAs. Because CMTs are considered predictive intermediate models for human breast cancer, similarities in genetic alterations and cancer predisposition between humans and dogs have raised further interest. Many cancer-associated genetic defects critical to mammary tumor development and oncogenic determinants of metastasis have been reported and appear to be similar in both species. Comparative analysis of deregulated gene sets or cancer signaling pathways has shown that a significant proportion of orthologous genes are comparably up- or down-regulated in both human and dog breast tumors. Particularly, a group of cell cycle regulators called cyclin-dependent kinase inhibitors (CKIs acting as potent tumor suppressors are frequently defective in CMTs. Interestingly, comparative analysis of coding sequences has also shown that these genes are highly conserved in mammals in terms of their evolutionary divergence from a common ancestor. Moreover, co-deletion and/or homozygous loss of the INK4A/ARF/INK4B (CDKN2A/B locus, encoding three members of the CKI tumor suppressor gene families (p16/INK4A, p14ARF and p15

  16. THE ABERRANT PROMOTER HYPERMETHYLATION PATTERN OF THE ANTI - ANGIOGENIC TSP1 GENE IN EPITHELIAL OVARIAN CARCINOMA: AN INDIAN STUDY

    Directory of Open Access Journals (Sweden)

    Ramesh

    2015-06-01

    Full Text Available PURPOSE: The promoter hypermethylation patterns of Thrombospodin - 1 gene in 50 EOC patients were studied and the methylation pattern was correlated with various clinic pathological parameters. METHODS: The promoter hypermethylation pattern of the TSP - 1 gene was assessed using nested PCR and Methylation specific PCR. STATISTICAL ANALYSIS: All the available data was statistically analyzed using the Chi square test or Fisher Exact Test on the SPSS software version 22.0 and a value <0.0 5 was considered statistically significant. RESULTS: Forty of the fifty ovarian carcinoma samples reported positive for methylation corresponding to a methylation frequency of 80%. A methylation frequency of 89.2%, 83.3% and 42.8% was observed in malignant , Low malignant potential (borderline and benign sample cohorts. CONCLUSION: From the results drawn from this study, it clearly shows that the anti angiogenic protein TSP - 1 is extensively hypermethylated in ovarian carcinoma and that it accumulates over t he progression of the disease from benign to malignant. As previous reports suggest that there is no evidence of mutation of this gene, promoter hypermethylation may be a crucial factor for the down regulation of the gene. Further by clubbing together the promoter hypermethylation pattern of TSP - 1 gene with hypermethylation patterns of other TSG may provide a better insight into the application of using methylation profiles of TSG as a biomarker in the detection of ovarian carcinoma.

  17. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    Directory of Open Access Journals (Sweden)

    Kuei-Fang Lee

    2014-01-01

    Full Text Available Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders.

  18. integIRTy: a method to identify genes altered in cancer by accounting for multiple mechanisms of regulation using item response theory.

    Science.gov (United States)

    Tong, Pan; Coombes, Kevin R

    2012-11-15

    Identifying genes altered in cancer plays a crucial role in both understanding the mechanism of carcinogenesis and developing novel therapeutics. It is known that there are various mechanisms of regulation that can lead to gene dysfunction, including copy number change, methylation, abnormal expression, mutation and so on. Nowadays, all these types of alterations can be simultaneously interrogated by different types of assays. Although many methods have been proposed to identify altered genes from a single assay, there is no method that can deal with multiple assays accounting for different alteration types systematically. In this article, we propose a novel method, integration using item response theory (integIRTy), to identify altered genes by using item response theory that allows integrated analysis of multiple high-throughput assays. When applied to a single assay, the proposed method is more robust and reliable than conventional methods such as Student's t-test or the Wilcoxon rank-sum test. When used to integrate multiple assays, integIRTy can identify novel-altered genes that cannot be found by looking at individual assay separately. We applied integIRTy to three public cancer datasets (ovarian carcinoma, breast cancer, glioblastoma) for cross-assay type integration which all show encouraging results. The R package integIRTy is available at the web site http://bioinformatics.mdanderson.org/main/OOMPA:Overview. kcoombes@mdanderson.org. Supplementary data are available at Bioinformatics online.

  19. PARK2, a Large Common Fragile Site Gene, is Part of a Stress Response Network in Normal Cells that is Disrupted During the Development of Ovarian Cancer

    National Research Council Canada - National Science Library

    Smith, David I

    2005-01-01

    .... The central two questions that we want to address with this work are what role does the inactivation of Parkin play in the development of ovarian cancer and whether this gene functions as part...

  20. Impact of obesity on 7,12-dimethylbenz[a]anthracene-induced altered ovarian connexin gap junction proteins in female mice

    Energy Technology Data Exchange (ETDEWEB)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Nteeba, Jackson, E-mail: nteeba@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2015-01-01

    The ovarian gap junction proteins alpha 4 (GJA4 or connexin 37; CX37), alpha 1 (GJA1 or connexin 43; CX43) and gamma 1 (GJC1 or connexin 45; CX45) are involved in cell communication and folliculogenesis. 7,12-dimethylbenz[a]anthracene (DMBA) alters Cx37 and Cx43 expression in cultured neonatal rat ovaries. Additionally, obesity has an additive effect on DMBA-induced ovarian cell death and follicle depletion, thus, we investigated in vivo impacts of obesity and DMBA on CX protein levels. Ovaries were collected from lean and obese mice aged 6, 12, 18, or 24 wks. A subset of 18 wk old mice (lean and obese) were dosed with sesame oil or DMBA (1 mg/kg; ip) for 14 days and ovaries collected 3 days thereafter. Cx43 and Cx45 mRNA and protein levels decreased (P < 0.05) after 18 wks while Cx37 mRNA and protein levels decreased (P < 0.05) after 24 wks in obese ovaries. Cx37 mRNA and antral follicle protein staining intensity were reduced (P < 0.05) by obesity while total CX37 protein was reduced (P < 0.05) in DMBA exposed obese ovaries. Cx43 mRNA and total protein levels were decreased (P < 0.05) by DMBA in both lean and obese ovaries while basal protein staining intensity was reduced (P < 0.05) in obese controls. Cx45 mRNA, total protein and protein staining intensity level were decreased (P < 0.05) by obesity. These data support that obesity temporally alters gap junction protein expression and that DMBA-induced ovotoxicity may involve reduced gap junction protein function. - Highlights: • Ovarian gap junction proteins are affected by ovarian aging and obesity. • DMBA exposure negatively impacts gap junction proteins. • Altered gap junction proteins may contribute to infertility.

  1. Impact of obesity on 7,12-dimethylbenz[a]anthracene-induced altered ovarian connexin gap junction proteins in female mice

    International Nuclear Information System (INIS)

    Ganesan, Shanthi; Nteeba, Jackson; Keating, Aileen F.

    2015-01-01

    The ovarian gap junction proteins alpha 4 (GJA4 or connexin 37; CX37), alpha 1 (GJA1 or connexin 43; CX43) and gamma 1 (GJC1 or connexin 45; CX45) are involved in cell communication and folliculogenesis. 7,12-dimethylbenz[a]anthracene (DMBA) alters Cx37 and Cx43 expression in cultured neonatal rat ovaries. Additionally, obesity has an additive effect on DMBA-induced ovarian cell death and follicle depletion, thus, we investigated in vivo impacts of obesity and DMBA on CX protein levels. Ovaries were collected from lean and obese mice aged 6, 12, 18, or 24 wks. A subset of 18 wk old mice (lean and obese) were dosed with sesame oil or DMBA (1 mg/kg; ip) for 14 days and ovaries collected 3 days thereafter. Cx43 and Cx45 mRNA and protein levels decreased (P < 0.05) after 18 wks while Cx37 mRNA and protein levels decreased (P < 0.05) after 24 wks in obese ovaries. Cx37 mRNA and antral follicle protein staining intensity were reduced (P < 0.05) by obesity while total CX37 protein was reduced (P < 0.05) in DMBA exposed obese ovaries. Cx43 mRNA and total protein levels were decreased (P < 0.05) by DMBA in both lean and obese ovaries while basal protein staining intensity was reduced (P < 0.05) in obese controls. Cx45 mRNA, total protein and protein staining intensity level were decreased (P < 0.05) by obesity. These data support that obesity temporally alters gap junction protein expression and that DMBA-induced ovotoxicity may involve reduced gap junction protein function. - Highlights: • Ovarian gap junction proteins are affected by ovarian aging and obesity. • DMBA exposure negatively impacts gap junction proteins. • Altered gap junction proteins may contribute to infertility

  2. DNA methylome and transcriptome sequencing in human ovarian granulosa cells links age-related changes in gene expression to gene body methylation and 3ʹ-end GC density

    Science.gov (United States)

    Yu, Bo; Russanova, Valya R.; Gravina, Silvia; Hartley, Stephen; Mullikin, James C.; Ignezweski, Alice; Graham, James; Segars, James H.; DeCherney, Alan H.; Howard, Bruce H.

    2015-01-01

    Diminished ovarian function occurs early and is a primary cause for age-related decline in female fertility; however, its underlying mechanism remains unclear. This study investigated the roles that genome and epigenome structure play in age-related changes in gene expression and ovarian function, using human ovarian granulosa cells as an experimental system. DNA methylomes were compared between two groups of women with distinct age-related differences in ovarian functions, using both Methylated DNA Capture followed by Next Generation Sequencing (MethylCap-seq) and Reduced Representation Bisulfite Sequencing (RRBS); their transcriptomes were investigated using mRNA-seq. Significant, non-random changes in transcriptome and DNA methylome features are observed in human ovarian granulosa cells as women age and their ovarian functions deteriorate. The strongest correlations between methylation and the age-related changes in gene expression are not confined to the promoter region; rather, high densities of hypomethylated CpG-rich regions spanning the gene body are preferentially associated with gene down-regulation. This association is further enhanced where CpG regions are localized near the 3ʹ-end of the gene. Such features characterize several genes crucial in age-related decline in ovarian function, most notably the AMH (Anti-Müllerian Hormone) gene. The genome-wide correlation between the density of hypomethylated intragenic and 3ʹ-end regions and gene expression suggests previously unexplored mechanisms linking epigenome structure to age-related physiology and pathology. PMID:25682867

  3. Sequence Variants of BRCA1 and BRCA2 Genes in Four Iranian Families with Breast and Ovarian Cancer.

    Science.gov (United States)

    Keshavarzi, F; Noughani, A Eskafi; Ayoubian, Mh; Zeinali, S

    2011-01-01

    BRCA1 and BRCA2 genes have been recognized to be responsible for 20-30% of hereditary breast cancers and approximately 50% of familial breast and ovarian cancers. Therefore, the demand for BRCA1 and BRCA2 mutation screening is rapidly increasing as their identification will affect medical management of people at increased risk. Because of high costs involved in analysis of BRCA1 and 2 genes, contribution of different mutation types in BRCA1 and 2 and not knowing who should be tested has hampered wide spread use of molecular testing of high -risk families. There is a need to identify the genes and types of mutations involved in breast or ovarian cancers at different age of onsets and polymorphism and polymorphic variations in our population. Twenty-seven patients with either early onset breast cancer (at age≤ 35 years) or a personal and/or family history of breast or ovarian cancer and 50 control subjects participated in this study. After collecting blood samples and extracting DNA, BRCA1 and BRCA2 genes were fully sequenced. Thirteen missense substitutions in BRCA1 and BRCA2 (9 and 4, respectively) were revealed. Two nucleotide substitutions were novel (Gly1140Ser in BRCA1 and Glu1391Gly in BRCA2). The Glu1038Pro and Gly1140Ser were found in large series of breast and ovarian cancer and matched controls. Some nucleotide substitutions were seen only in single families and other in several. In other cases, mutations were seen in both BRCA1 and BRCA2 genes. Clinical significance of these mutations was evaluated comparing with normal controls.

  4. Radiation Exposure Alters Expression of Metabolic Enzyme Genes In Mice

    Science.gov (United States)

    Wotring, Virginia E.; Mangala, L. S.; Zhang, Y.; Wu, H.

    2010-01-01

    Most pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. Because of the importance of the liver in drug metabolism it is important to understand the effects of spaceflight on the enzymes of the liver. Exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. This study is an effort to examine the effects of adaptive mechanisms that may be triggered by early exposure to low radiation doses. Using procedures approved by the JSC Animal Care & Use Committee, C57 male mice were exposed to Cs-137 in groups: controls, low dose (50 mGy), high dose (6Gy) and a fourth group that received both radiation doses separated by 24 hours. Animals were anesthetized and sacrificed 4 hours after their last radiation exposure. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted and purified (Absolutely RNA, Agilent). Quality of RNA samples was evaluated (Agilent Bioanalyzer 2100). Complementary DNA was prepared from high-quality RNA samples, and used to run RT-qPCR screening arrays for DNA Repair and Drug Metabolism (SuperArray, SABiosciences/Qiagen; BioRad Cfx96 qPCR System). Of 91 drug metabolism genes examined, expression of 7 was altered by at least one treatment condition. Genes that had elevated expression include those that metabolize promethazine and steroids (4-8-fold), many that reduce oxidation products, and one that reduces heavy metal exposure (greater than 200-fold). Of the 91 DNA repair and general metabolism genes examined, expression of 14 was altered by at least one treatment condition. These gene expression changes are likely homeostatic and could lead to development of new radioprotective countermeasures.

  5. Loss of heterozygosity in P53, BRCA1, and estrogen receptor genes and correlation to expression of p53 protein in ovarian epithelial tumors of different cell types and biological behavior.

    Science.gov (United States)

    Otis, C N; Krebs, P A; Quezado, M M; Albuquerque, A; Bryant, B; San Juan, X; Kleiner, D; Sobel, M E; Merino, M J

    2000-02-01

    Loss of heterozygosity (LOH) of tumor suppressor genes (TSGs) in ovarian epithelial tumors of differing cell types and biological behavior has not been thoroughly investigated. Moreover, there have been conflicting reports correlating LOH of the p53 gene to overexpression of p53 protein. This study evaluated 34 formalin-fixed, paraffin-embedded ovarian epithelial tumors for LOH by polymerase chain reaction (PCR) for the following microsatellite markers: TP53(17p13.1/p53 gene), D17S579(17q/BRCA1 gene), and ESR (6q24-27/estrogen receptor gene). LOH of the TP53 marker was detected in 4 (44%) of 9 informative serous cystadenocarcinomas (SCa) but in 0 of 4 informative clear cell carcinomas (CCa) and 0 of 5 informative serous tumors of low malignant potential (SLMP). LOH of the BRCA1 marker was detected in 5 (83%) of 6 informative SCa, but in 1 (13%) of 8 informative CCa and 1 (14%) of 7 informative SLMP. LOH of the ESR marker was detected in 4 (50%) of 8 informative SCa, but in 0 of 4 informative CCa and 1 (16%) of 6 informative SLMP. p53 protein overexpression was present in 8 of 12 SCa but did not correlate to TP53 LOH. LOH for TP53, D17S579/ BRCA1, and ESR is common in ovarian SCa, and is observed in primary tumors as well as metastases. In contrast, these genetic alterations are less common in CCa and in the biologically less aggressive SLMP tumors. These data suggest different mechanisms of oncogenesis in ovarian epithelial tumors of different cell types and biological behavior.

  6. Finding Combination of Features from Promoter Regions for Ovarian Cancer-related Gene Group Classification

    KAUST Repository

    Olayan, Rawan S.

    2012-12-01

    In classification problems, it is always important to use the suitable combination of features that will be employed by classifiers. Generating the right combination of features usually results in good classifiers. In the situation when the problem is not well understood, data items are usually described by many features in the hope that some of these may be the relevant or most relevant ones. In this study, we focus on one such problem related to genes implicated in ovarian cancer (OC). We try to recognize two important OC-related gene groups: oncogenes, which support the development and progression of OC, and oncosuppressors, which oppose such tendencies. For this, we use the properties of promoters of these genes. We identified potential “regulatory features” that characterize OC-related oncogenes and oncosuppressors promoters. In our study, we used 211 oncogenes and 39 oncosuppressors. For these, we identified 538 characteristic sequence motifs from their promoters. Promoters are annotated by these motifs and derived feature vectors used to develop classification models. We made a comparison of a number of classification models in their ability to distinguish oncogenes from oncosuppressors. Based on 10-fold cross-validation, the resultant model was able to separate the two classes with sensitivity of 96% and specificity of 100% with the complete set of features. Moreover, we developed another recognition model where we attempted to distinguish oncogenes and oncosuppressors as one group from other OC-related genes. That model achieved accuracy of 82%. We believe that the results of this study will help in discovering other OC-related oncogenes and oncosuppressors not identified as yet.

  7. [Effect of down-regulation of HE4 gene expression on biologic behavior of ovarian cancer cells].

    Science.gov (United States)

    Zhou, Lei; Xiao, Ran; Chen, Ying; Zhang, Jing; Lu, Ren-quan; Guo, Lin

    2013-10-01

    To investigate the effects of HE4 gene knockdown on the proliferation, adhesion and invasion of the ovarian cancer cells SKOV3. The knockdown of HE4 gene was performed by RNAi technology. The recombinant plasmids (pSUPER-HE4 shDNAs) were constructed and transfected into human ovarian cancer cells SKOV3. HE4 expression was then identified by real-time PCR and Western blot analysis. The invasion and adhesion ability of transduced cells were determined. In addition, cell proliferation and growth were analyzed by colonies formation assay. Knockdown of HE4 was achieved, and further confirmed by real-time PCR and Western blot. The proliferation of HE4-down-regulated cells was not affected, but the invasion ability of the transfected cells was reduced (P cells.

  8. Gene expression profile for predicting survival in advanced-stage serous ovarian cancer across two independent datasets.

    Directory of Open Access Journals (Sweden)

    Kosuke Yoshihara

    Full Text Available BACKGROUND: Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. METHODOLOGY/PRINCIPAL FINDINGS: Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01 and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR, 3.72; 95% confidence interval (CI, 2.66-5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20-1.98; p = 0.0008. Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008. CONCLUSIONS/SIGNIFICANCE: The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

  9. Risk of ovarian cancer and the NF-kappaB pathway: genetic association with IL1A and TNFSF10

    NARCIS (Netherlands)

    Charbonneau, B.; Block, M.S.; Bamlet, W.R.; Vierkant, R.A.; Kalli, K.R.; Fogarty, Z.; Rider, D.N.; Sellers, T.A.; Tworoger, S.S.; Poole, E.; Risch, H.A.; Salvesen, H.B.; Kiemeney, B.; Baglietto, L.; Giles, G.G.; Severi, G.; Trabert, B.; Wentzensen, N.; Chenevix-Trench, G.; Whittemore, A.S.; Sieh, W.; Chang-Claude, J.; Bandera, E.V.; Orlow, I.; Terry, K.; Goodman, M.T.; Thompson, P.J.; Cook, L.S.; Rossing, M.A.; Ness, R.B.; Narod, S.A.; Kupryjanczyk, J.; Lu, K.; Butzow, R.; Dork, T.; Pejovic, T.; Campbell, I.; Le, N.D.; Bunker, C.H.; Bogdanova, N.; Runnebaum, I.B.; Eccles, D.; Paul, J.; Wu, A.H.; Gayther, S.A.; Hogdall, E.; Heitz, F.; Kaye, S.B.; Karlan, B.Y.; Anton-Culver, H.; Gronwald, J.; Hogdall, C.K.; Lambrechts, D.; Fasching, P.A.; Menon, U.; Schildkraut, J.; Pearce, C.L.; Levine, D.A.; Kjaer, S.K.; Cramer, D.; Flanagan, J.M.; Phelan, C.M.; Brown, R.; Massuger, L.F.A.G.; Song, H.; Doherty, J.A.; Krakstad, C.; Liang, D.; Odunsi, K.; Berchuck, A.; Jensen, A.; Lubinski, J.; Nevanlinna, H.; Bean, Y.T.; Lurie, G.; Ziogas, A.; Walsh, C.; Despierre, E.; Brinton, L.; Hein, A.; Rudolph, A.; Dansonka-Mieszkowska, A.; Olson, S.H.; Harter, P.; Tyrer, J.; Vitonis, A.F.; Brooks-Wilson, A.; Aben, K.K.H.; Pike, M.C.; Ramus, S.J.; Wik, E.; Cybulski, C.; Lin, J.; Sucheston, L.; Edwards, R.; McGuire, V.; Lester, J.; Bois, A. du; Lundvall, L.; et al.,

    2014-01-01

    A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of

  10. Circadian Gene CLOCK Affects Drug-Resistant Gene Expression and Cell Proliferation in Ovarian Cancer SKOV3/DDP Cell Lines Through Autophagy.

    Science.gov (United States)

    Sun, Yang; Jin, Long; Sui, Yu-Xia; Han, Li-Li; Liu, Jia-Hua

    2017-05-01

    Abnormal autophagy regulation affects the chemoresistance of ovarian cancer, during which the circadian gene clock may play a major role. In this study, RNA interference plasmid pSUPER-Clock and overexpression plasmid pcDNA3.1-Clock of CLOCK were used to stably transfect the SKOV3/DDP cells by lipofection. Upon screening, the in vitro transfected cell lines with pSUPER-Clock, the autophagy level, and G 0 /G 1 phase cells were significantly reduced, and the expression levels of Clock, LC3, P-gp, and MRP2 were inhibited. In contrast, the autophagy level and G 0 /G 1 phase cells in cell lines transfected with pcDNA3.1-Clock were significantly increased, and the expressions of Clock, LC3, P-gp, and MRP2 were enhanced. In comparison with the untransfected control group showed the percentage of apoptotic cells in SKOV3/DDP cell lines of Clock interfering expression group after cisplatin treatment was significantly increased while the survival was substantially reduced. These results indicated that inhibiting the circadian gene Clock expression can reverse the cisplatin resistance of ovarian cancer SKOV3/DDP cell lines by affecting the protein expression of drug resistance genes during which autophagy plays an important role. The CLOCK gene may be designated as a novel candidate for targeted gene therapy in drug-resistant ovarian cancer.

  11. The role of p53 protein and MMP-2 tumor/stromal cells expression on progressive growth of ovarian neoplasms.

    Science.gov (United States)

    Grelewski, Piotr Grzegorz; Bar, Julia Krystyna

    2013-08-01

    The aim of our study was to evaluate p53 gene/protein status and MMP-2 expression in respect to ovarian tumors progress to define the role of these markers in the metastasis of ovarian carcinomas. MMP-2 and p53 alterations were evaluated on 80 malignant, 30 benign ovarian tumors, and 62 metastatic lesions by using HRM method for mutations in p53 gene and by using RT-PCR for mRNA MMP-2 level. Our data indicate that parallel expression of MMP-2 epithelial/stromal cells and p53 may enhance cells invasion and metastasis in ovarian carcinoma.

  12. Altered choroid plexus gene expression in major depressive disorder

    Directory of Open Access Journals (Sweden)

    Cortney Ann Turner

    2014-04-01

    Full Text Available Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus, the region that produces cerebrospinal fluid (CSF, in individuals with major depressive disorder (MDD. Genes that are expressed in the choroid plexus (CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the choroid plexus at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p< 0.05 between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFβ pathway. Quantitative real-time PCR (qRT-PCR confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the choroid plexus in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.

  13. Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes.

    Science.gov (United States)

    Earp, Madalene A; Raghavan, Rama; Li, Qian; Dai, Junqiang; Winham, Stacey J; Cunningham, Julie M; Natanzon, Yanina; Kalli, Kimberly R; Hou, Xiaonan; Weroha, S John; Haluska, Paul; Lawrenson, Kate; Gayther, Simon A; Wang, Chen; Goode, Ellen L; Fridley, Brooke L

    2017-07-18

    Gene fusions play a critical role in some cancers and can serve as important clinical targets. In epithelial ovarian cancer (EOC), the contribution of fusions, especially by histological type, is unclear. We therefore screened for recurrent fusions in a histologically diverse panel of 220 EOCs using RNA sequencing. The Pipeline for RNA-Sequencing Data Analysis (PRADA) was used to identify fusions and allow for comparison with The Cancer Genome Atlas (TCGA) tumors. Associations between fusions and clinical prognosis were evaluated using Cox proportional hazards regression models. Nine recurrent fusions, defined as occurring in two or more tumors, were observed. CRHR1-KANSL1 was the most frequently identified fusion, identified in 6 tumors (2.7% of all tumors). This fusion was not associated with survival; other recurrent fusions were too rare to warrant survival analyses. One recurrent in-frame fusion, UBAP1-TGM7, was unique to clear cell (CC) EOC tumors (in 10%, or 2 of 20 CC tumors). We found some evidence that CC tumors harbor more fusions on average than any other EOC histological type, including high-grade serous (HGS) tumors. CC tumors harbored a mean of 7.4 fusions (standard deviation [sd] = 7.4, N = 20), compared to HGS EOC tumors mean of 2.0 fusions (sd = 3.3, N = 141). Few fusion genes were detected in endometrioid tumors (mean = 0.24, sd = 0.74, N = 55) or mucinous tumors (mean = 0.25, sd = 0.5, N = 4) tumors. To conclude, we identify one fusion at 10% frequency in the CC EOC subtype, but find little evidence for common (> 5% frequency) recurrent fusion genes in EOC overall, or in HGS subtype-specific EOC tumors.

  14. WT1 gene expression as a prognostic marker in advanced serous epithelial ovarian carcinoma: an immunohistochemical study

    International Nuclear Information System (INIS)

    Netinatsunthorn, Wirote; Hanprasertpong, Jitti; Dechsukhum, Chavaboon; Leetanaporn, Roengsak; Geater, Alan

    2006-01-01

    WT1 is a tumor suppressor gene responsible for Wilms' tumor. WT1 reactivity is limited to ovarian serous carcinomas. Recent studies have shown that WT1 plays an important role in the progression of disease and indicates a poorer prognosis of human malignancies such as acute myeloid leukemia and breast cancer. The aims of this study were to determine the survival and recurrence-free survival of women with advanced serous epithelial ovarian carcinoma in relation to WT1 gene expression. The study accrued women over an 18-year period, from 1987–2004. During the study period, 163 patients were diagnosed with advanced serous epithelial ovarian carcinoma and had undergone complete post-operative chemotherapy, but the final study group comprised 99 patients. The records of these women were reviewed and the paraffin-embedded tissue of these women stained with WT1 immunostaining. Survival analysis was performed using Kaplan-Meier and Cox regression methods. Fifty patients showed WT1 staining and forty-nine did not. Five-year survival of non-staining and staining groups were 39.4% and 10.7% (p < 0.00005); five-year recurrence-free survival of these groups were 29.8% and ≤ 7.5% (p < 0.00005), respectively. For survival the HR of WT1 staining, adjusted for residual tumor and chemotherapy response, was 1.98 (95% CI 1.28–3.79), and for recurrence-free survival the HR was 3.36 (95% CI 1.60–7.03). The HR for recurrence-free survival was not confounded by any other variables. This study suggests that expression of WT1 gene may be indicative of an unfavorable prognosis in patients with advanced serous epithelial ovarian carcinoma

  15. Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    DEFF Research Database (Denmark)

    Kelemen, Linda E; Terry, Kathryn L; Goodman, Marc T

    2014-01-01

    SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds...... was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were...

  16. CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma.

    Directory of Open Access Journals (Sweden)

    Kalpana Kannan

    2014-03-01

    Full Text Available Ovarian cancer is the fifth leading cause of cancer death in women. Almost 70% of ovarian cancer deaths are due to the high-grade serous subtype, which is typically detected only after it has metastasized. Characterization of high-grade serous cancer is further complicated by the significant heterogeneity and genome instability displayed by this cancer. Other than mutations in TP53, which is common to many cancers, highly recurrent recombinant events specific to this cancer have yet to be identified. Using high-throughput transcriptome sequencing of seven patient samples combined with experimental validation at DNA, RNA and protein levels, we identified a cancer-specific and inter-chromosomal fusion gene CDKN2D-WDFY2 that occurs at a frequency of 20% among sixty high-grade serous cancer samples but is absent in non-cancerous ovary and fallopian tube samples. This is the most frequent recombinant event identified so far in high-grade serous cancer implying a major cellular lineage in this highly heterogeneous cancer. In addition, the same fusion transcript was also detected in OV-90, an established high-grade serous type cell line. The genomic breakpoint was identified in intron 1 of CDKN2D and intron 2 of WDFY2 in patient tumor, providing direct evidence that this is a fusion gene. The parental gene, CDKN2D, is a cell-cycle modulator that is also involved in DNA repair, while WDFY2 is known to modulate AKT interactions with its substrates. Transfection of cloned fusion construct led to loss of wildtype CDKN2D and wildtype WDFY2 protein expression, and a gain of a short WDFY2 protein isoform that is presumably under the control of the CDKN2D promoter. The expression of short WDFY2 protein in transfected cells appears to alter the PI3K/AKT pathway that is known to play a role in oncogenesis. CDKN2D-WDFY2 fusion could be an important molecular signature for understanding and classifying sub-lineages among heterogeneous high-grade serous ovarian

  17. Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

    Science.gov (United States)

    Charbonneau, Bridget; Moysich, Kirsten B; Kalli, Kimberly R; Oberg, Ann L; Vierkant, Robert A; Fogarty, Zachary C; Block, Matthew S; Maurer, Matthew J; Goergen, Krista M; Fridley, Brooke L; Cunningham, Julie M; Rider, David N; Preston, Claudia; Hartmann, Lynn C; Lawrenson, Kate; Wang, Chen; Tyrer, Jonathan; Song, Honglin; deFazio, Anna; Johnatty, Sharon E; Doherty, Jennifer A; Phelan, Catherine M; Sellers, Thomas A; Ramirez, Starr M; Vitonis, Allison F; Terry, Kathryn L; Van Den Berg, David; Pike, Malcolm C; Wu, Anna H; Berchuck, Andrew; Gentry-Maharaj, Aleksandra; Ramus, Susan J; Diergaarde, Brenda; Shen, Howard; Jensen, Allan; Menkiszak, Janusz; Cybulski, Cezary; Lubiłski, Jan; Ziogas, Argyrios; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Lester, Jenny; Walsh, Christine; Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn; Garcia-Closas, Montserrat; Yang, Hannah; Brinton, Louise A; Spiewankiewicz, Beata; Rzepecka, Iwona K; Dansonka-Mieszkowska, Agnieszka; Seibold, Petra; Rudolph, Anja; Paddock, Lisa E; Orlow, Irene; Lundvall, Lene; Olson, Sara H; Hogdall, Claus K; Schwaab, Ira; du Bois, Andreas; Harter, Philipp; Flanagan, James M; Brown, Robert; Paul, James; Ekici, Arif B; Beckmann, Matthias W; Hein, Alexander; Eccles, Diana; Lurie, Galina; Hays, Laura E; Bean, Yukie T; Pejovic, Tanja; Goodman, Marc T; Campbell, Ian; Fasching, Peter A; Konecny, Gottfried; Kaye, Stanley B; Heitz, Florian; Hogdall, Estrid; Bandera, Elisa V; Chang-Claude, Jenny; Kupryjanczyk, Jolanta; Wentzensen, Nicolas; Lambrechts, Diether; Karlan, Beth Y; Whittemore, Alice S; Culver, Hoda Anton; Gronwald, Jacek; Levine, Douglas A; Kjaer, Susanne K; Menon, Usha; Schildkraut, Joellen M; Pearce, Celeste Leigh; Cramer, Daniel W; Rossing, Mary Anne; Chenevix-Trench, Georgia; Pharoah, Paul D P; Gayther, Simon A; Ness, Roberta B; Odunsi, Kunle; Sucheston, Lara E; Knutson, Keith L; Goode, Ellen L

    2014-04-01

    The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.

  18. Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles.

    Science.gov (United States)

    Antoun, Stephanie; Atallah, David; Tahtouh, Roula; Alaaeddine, Nada; Moubarak, Malak; Khaddage, Abir; Ayoub, Eliane Nasr; Chahine, George; Hilal, George

    2018-01-01

    p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein's expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, apoptosis and transcription of p53 target genes. Mutations frequency and their effect on p53 expression were assessed by PCR-SSCP, sequencing and immunohistochemistry on 30 ovarian cancer biopsies. Six tumors were cultured, as well as SK-OV-3, OVCAR-3 and Igrov-1. SK-OV-3 cells were transfected with 2 TP53 mutants. p53 transcriptional activity was assayed by qPCR, apoptosis by flow cytometry and glycolysis by glucose and lactate measurements, with quantification of glycolytic enzymes expression. Our results showed a high frequency of the P72R mutant, associated with p53 overexpression in the ovarian biopsies. However, P72R mutant cells showed similar apoptosis and glycolysis as WT cells. DNA binding domain mutations decreased the transcriptional activity of the protein and increased glucose consumption and lactate production. Despite the overexpression of the P72R mutated protein in the biopsies, it showed a similar apoptotic activity and glucose regulation ability as WT p53. Knowing that p53 expression status is used for chemotherapeutic approaches and prognosis in ovarian cancer, the results obtained highlight the importance of locating TP53 mutations.

  19. Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Quaye, Lydia; Tyrer, Jonathan; Ramus, Susan J

    2009-01-01

    BACKGROUND: Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant...... control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide...... association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for...

  20. Analysis of the Mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer

    International Nuclear Information System (INIS)

    Davis, Sally J; Choong, David YH; Ramakrishna, Manasa; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L

    2011-01-01

    MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer. We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines. In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation. MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort

  1. Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation

    International Nuclear Information System (INIS)

    Pradhan, Manohar; Risberg, Björn Å; Tropé, Claes G; Rijn, Matt van de; Gilks, C Blake; Lee, Cheng-Han

    2010-01-01

    BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary. DNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status. Using image cytometry and oligonucleotide microarrays, we analyzed DNA ploidy, S-phase fraction and gene expression profile of 28 consecutive cases of ovarian high-grade serous adenocarcinomas, which included 8 tumor samples with BRCA1 somatic or germline mutation, 9 samples with promoter hypermethylation of BRCA1, and 11 samples with no BRCA1 loss. None had BRCA2 mutations. The prevalence of aneuploidy and tetraploidy was not statistically different in the three groups with different BRCA1 status. The gene expression profiles were also very similar between the groups, with only two genes showing significant differential expression when comparison was made between the group with BRCA1 mutation and the group with no demonstrable BRCA1 loss. There were no genes showing significant differences in expression when the group with BRCA1 loss through epigenetic silencing was compared to either of the other two groups. In this series of 28 high-grade serous carcinomas, gross genomic alteration characterized by aneuploidy did not correlate with BRCA1 status. In addition, the gene expression profiles of the tumors showed negligible differences between the three defined groups based on BRCA1 status. This suggests that all ovarian high-grade serous carcinomas arise through oncogenic mechanisms that result in chromosomal instability, irrespective of BRCA status; the molecular abnormalities underlying this in the BRCA

  2. Expression of Interactive Genes Associated with Apoptosis and Their Prognostic Value for Ovarian Serous Adenocarcinoma.

    Science.gov (United States)

    Shin, Kyusik; Kim, Ki Hyung; Yoon, Man Soo; Suh, Dong Soo; Lee, Ji Young; Kim, Ari; Eo, Wankyu

    2016-01-01

    Malignant ovarian tumor is one of the leading causes of worldwide cancer death. It is usually characterized by insidious onset and late diagnosis because of the absence of symptoms, allowing ovarian cancer cases to progress rapidly and become unresectable. The tumor suppressor, p53, plays an important role in regulating cell cycles and apoptosis. p53 is regulated by several molecules, and it interacts with other apoptotic proteins. To compare the prognosis of ovarian serous carcinoma and evaluate the expression of DNA-PKcs, Akt3, GSK-3β, and p53 in cancerous cells. DNA-PKcs, Akt3, GSK-3β, and p53 expression levels were scored using immunohistochemistry staining of tissue samples from 132 women with ovarian serous adenocarcinoma. Expression was confirmed by real-time RT-PCR. Analyses were stratified by age, tumor grades, cancer stages and serum CA 125 levels. Significant differences in DNA-PKcs, Akt3, and p53 expression were observed between participants with different stages and tumor grades of ovarian serous adenocarcinoma. DNA-PKcs and p53 expression increased along with increasing tumor grade. Meanwhile, DNA-PKcs, Akt3, and p53 expression increased along with increasing cancer stage, and with a decrease in 5-year overall survival rate. This study shows that elevated expression of DNA-PKcs, Akt3, and p53 in ovarian serous adenocarcinoma tissues are an indication of more advanced disease and worse prognosis.

  3. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    Science.gov (United States)

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bowtell, David; Webb, Penelope M.; deFazio, Anna; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kruger Kjaer, Susanne; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Sellers, Thomas A.; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D.; Gayther, Simon A.; Freedman, Matthew L.

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  4. The role of the REG4 gene and its encoding product in ovarian epithelial carcinoma

    International Nuclear Information System (INIS)

    Chen, Shuo; Gou, Wen-Feng; Zhao, Shuang; Niu, Zhe-Feng; Zhao, Yang; Takano, Yasuo; Zheng, Hua-Chuan

    2015-01-01

    Although its biological function remains poorly understood, REG4 is reported to be a potent activator of the EGFR/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis. SKOV3 cells were transfected with a REG4-expressing plasmid or treated with recombinant REG4. We then analyzed proliferation, cell cycle, apoptosis, invasion and metastasis or expression of related molecules. REG4 expression was examined in normal ovarian tissue, benign and borderline tumors, and cancers by immunohistochemistry or real-time PCR. REG4 overexpression and the recombinant protein inhibited cell apoptosis, enhanced G 2 /S progression, proliferation, migration and invasion. Furthermore, expression of Wnt5a, p70s6k, survivin and VEGF expression was increased, while Bax expression was decreased at both the mRNA and protein levels compared to control or mock cells (P < 0.05). REG4 mRNA levels were higher in benign tumors and primary cancer compared to those in normal ovarian tissue (P < 0.05) while, REG4 protein expression was higher in all three tumor types than that in normal ovarian tissue (P < 0.05). Higher REG4 mRNA expression was observed in mucinous carcinomas than serous carcinomas (P < 0.05), and in well- and moderately-differentiated carcinomas than poorly-differentiated carcinomas (P < 0.05). Survival analysis revealed an inverse relationship between REG4 expression and cumulative or relapse-free survival rates of the patients with ovarian cancer as an independent factor (P < 0.05). Our findings indicate that aberrant REG4 expression plays an essential role in early ovarian carcinogenesis and is closely linked to mucinous ovarian tumors, differentiation and adverse prognosis of ovarian cancer by modulating proliferation, apoptosis, migration and invasion. The online version of this article (doi:10.1186/s12885-015-1435-2) contains supplementary material, which is available to authorized users

  5. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

    NARCIS (Netherlands)

    Kar, S.P.; Tyrer, J.P.; Li, Q.; Lawrenson, K.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Chenevix-Trench, G.; Baker, H.; Bandera, E.V.; Bean, Y.T.; Beckmann, M.W.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.; Brooks-Wilson, A.; Butzow, R.; Campbell, I.; Carty, K.; Chang-Claude, J.; Chen, Y.A.; Chen, Z.; Cook, L.S.; Cramer, D.; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Eccles, D.; Easton, D.F.; Edwards, R.P.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Grownwald, J.; Harrington, P.; Harter, P.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hillemanns, P.; Hogdall, E.; Hogdall, C.K.; Hosono, S.; Iversen, E.S.; Jakubowska, A.; Paul, J.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kjaer, S.K.; Kelemen, L.E.; Kellar, M.; Kelley, J.; Kiemeney, L.A.L.M.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; McNeish, I.A.; Menon, U.; Modugno, F.; Moysich, K.B.; Narod, S.A.; Nedergaard, L.; Ness, R.B.; Nevanlinna, H.; Odunsi, K.; Olson, S.H.; Orlow, I.; Orsulic, S.; Weber, R.P.

    2015-01-01

    BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by

  6. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot"

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing

    2010-01-01

    We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes...

  7. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

    DEFF Research Database (Denmark)

    Kar, Siddhartha P; Tyrer, Jonathan P; Li, Qiyuan

    2015-01-01

    BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by...

  8. Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles

    OpenAIRE

    Antoun, Stephanie; Atallah, David; Tahtouh, Roula; Alaaeddine, Nada; Moubarak, Malak; Khaddage, Abir; Ayoub, Eliane Nasr; Chahine, George; Hilal, George

    2018-01-01

    Background p53 is a tumor suppressor and key regulator of glycolysis in cancer cells, however highly mutated in tumors. In ovarian cancer, studies concerning p53 mutations focus on the DNA binding domain since the majority of hotspot mutations affects this region. Yet, mutations in other regions such as the proline rich domain may also affect the protein’s expression and activity. The aim of this study is to investigate the effect of various positions of mutations in TP53 gene on glycolysis, ...

  9. Determination of BRAF V600E (VE1) protein expression and BRAF gene mutation status in codon 600 in borderline and low-grade ovarian cancers.

    Science.gov (United States)

    Sadlecki, Pawel; Walentowicz, Pawel; Bodnar, Magdalena; Marszalek, Andrzej; Grabiec, Marek; Walentowicz-Sadlecka, Malgorzata

    2017-05-01

    Epithelial ovarian tumors are a group of morphologically and genetically heterogeneous neoplasms. Based on differences in clinical phenotype and genetic background, ovarian neoplasms are classified as low-grade and high-grade tumor. Borderline ovarian tumors represent approximately 10%-20% of all epithelial ovarian masses. Various histological subtypes of ovarian malignancies differ in terms of their risk factor profiles, precursor lesions, clinical course, patterns of spread, molecular genetics, response to conventional chemotherapy, and prognosis. The most frequent genetic aberrations found in low-grade serous ovarian carcinomas and serous borderline tumors, as well as in mucinous cancers, are mutations in BRAF and KRAS genes. The most commonly observed BRAF mutation is substitution of glutamic acid for valine in codon 600 (V600E) in exon 15. The primary aim of this study was to determine whether fully integrated, real-time polymerase chain reaction-based Idylla™ system may be useful in determination of BRAF gene mutation status in codon 600 in patients with borderline ovarian tumors and low-grade ovarian carcinomas. The study included tissue specimens from 42 patients with histopathologically verified ovarian masses, who were operated on at the Department of Obstetrics and Gynecology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz (Poland). Based on histopathological examination of surgical specimens, 35 lesions were classified as low-grade ovarian carcinomas, and 7 as borderline ovarian tumors. Specimens with expression of BRAF V600E (VE1) protein were tested for mutations in codon 600 of the BRAF gene, using an automated molecular diagnostics platform Idylla™. Cytoplasmic immunoexpression of BRAF V600E (VE1) protein was found in three specimens: serous superficial papilloma, serous papillary cystadenoma of borderline malignancy, and partially proliferative serous cystadenoma. All specimens with the expression of BRAF V600E (VE1) protein were

  10. Interleukin-18 gene promoter and serum level in women with ovarian cancer.

    Science.gov (United States)

    Samsami Dehaghani, Alamtaj; Shahriary, Khatere; Kashef, Mohammad Amin; Naeimi, Sirous; Fattahi, Mohammad Javad; Mojtahedi, Zahra; Ghaderi, Abbas

    2009-11-01

    IL-18, initially defined as a potent inducer of IFN- gamma production, is a systemic, multifunctional cytokine with both pro-cancerous and anti-cancer activities. The contribution of the IL-18 promoter polymorphisms at positions -607 (C/A) and -137 (G/C) to cancer development has been reported. We sought to examine IL-18 serum level and its polymorphisms in Iranian women with ovarian cancer. Single nucleotide polymorphisms (SNPs) at positions -607 (C/A) and -137 (G/C) were analyzed by allele-specific polymerase chain reaction in 85 women with ovarian cancer and 158 healthy controls. IL-18 serum level was determined using ELISA method. No significant association was found between the allele, genotype, and haplotype distributions of the SNPs and ovarian cancer. Mean IL-18 serum level was significantly higher in patients than in controls (P = 0.008). Comparing IL-18 serum levels with genotypes at positions -607 and -137 revealed no significant difference. No association was also found between IL-18 levels and the disease stage. In conclusion, our results indicate that IL-18 promoter polymorphisms at positions -607 (C/A) and -137 (G/C) appear not to confer susceptibility to ovarian cancer in Iranian population; however, IL-18 serum level increases in ovarian cancer patients.

  11. Identification of epigenetically altered genes and potential gene targets in melanoma using bioinformatic methods

    Directory of Open Access Journals (Sweden)

    Duan HH

    2017-12-01

    Full Text Available Honghao Duan, Ke Jiang, Dengke Wei, Lijun Zhang, Deliang Cheng, Min Lv, Yuben Xu, Aimin He Department of Hand Surgery, Honghui Hospital, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of China Abstract: This study aimed to analyze epigenetically and genetically altered genes in melanoma to get a better understanding of the molecular circuitry of melanoma and identify potential gene targets for the treatment of melanoma. The microarray data of GSE31879, including mRNA expression profiles (seven melanoma and four melanocyte samples and DNA methylation profiles (seven melanoma and five melanocyte samples, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs and differentially methylated positions (DMPs were screened using the linear models for microarray data (limma package in melanoma compared with melanocyte samples. Gene ontology (GO and pathway enrichment analysis of the DEGs were carried out using the Database for Annotation, Visualization, and Integrated Discovery. Moreover, differentially methylated genes (DMGs were identified, and a transcriptional regulatory network was constructed using the University of California Santa Cruz genome browser database. A total of 1,215 DEGs (199 upregulated and 1,016 downregulated and 14,094 DMPs (10,450 upregulated and 3,644 downregulated were identified in melanoma compared with melanocyte samples. Additionally, the upregulated and downregulated DEGs were significantly associated with different GO terms and pathways, such as pigment cell differentiation, biosynthesis, and metabolism. Furthermore, the transcriptional regulatory network showed that DMGs such as Aristaless-related homeobox (ARX, damage-specific DNA binding protein 2 (DDB2, and myelin basic protein (MBP had higher node degrees. Our results showed that several methylated genes (ARX, DDB2, and MBP may be involved in melanoma progression. Keywords: melanoma, DNA

  12. Effects of introducing wild-type p53 gene on the radiosensitivity of SKOV-3 ovarian cancer cells

    International Nuclear Information System (INIS)

    Jin Zhen; Guan Ting; Li Shourou

    2002-01-01

    Objective: To study the effect of wild-type p53 gene on the radiosensitivity of SKOV-3 ovarian cancer cells. Methods: Recombinant eukaryotic expression vector pcDNA3 containing full-length human wild-type p53 cDNA was introduced by lipofectamine-mediated gene transfection into cultured SKOV-3 cells which had been irradiated with 2 and 4 Gy X-rays, respectively. The radiosensitivities of the tumor cells with different p53 status were studied. Results: The number of colonies in the SKOV-3, SKOV-3-vect, and SKOV-3-p53 groups decreased by 18.6%, 22.9% and 44.5%, respectively with 2 Gy irradiation, and decreased by 63.6%, 64.9% and 88.9%, respectively with 4 Gy irradiation. After introduction of p53 cDNA, the cell number in S phase and the ratio of G 2 /M phase of tumor cells decreased and the ratio of G 1 /G 0 phase increased. The introduction of p53 gene into cells led to cell cycle arrest in G 1 phase. Conclusion: Exogenous introduction of wild-type p53 cDNA into SKOV-3 ovarian cancer cells can increase their radiosensitivity

  13. A gene prenature ovarian failure associated with eyelid malformation maps to chromosomes 3q22-q23

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-05-01

    Premature ovarian failure and XX gonadal dysgenesis leading to female infertility have been reported in association with an autosomal dominantly inherited malformation of the eyelids: blepharophimosis-ptosis-epicanthus inversus syndrome (BPES; MIM 110100). This association distinguishes BPES type I from BPES type II, in which affected females are fertile and the transmission occurs through both sexes. Recently, a gene responsible for BPES type II has been mapped to chromosome 3q22-q23, and the critical region for the gene location has been reduced to the interval between loci D3S1615 and D3S1316. Hitherto, however, no information regarding the localization of the gene for BPES type I, in which female ovarian failure is associated with eyelid malformation, has been available. We have studied two independent families affected with BPES type I, including a total of 12 affected individuals (6 infertile women) and 6 healthy relatives. The diagnostic criteria for the ophthalmological anomaly included (1) reduced horizontal diameter of palpebral fissures, (2) drooping of the upper eyelids, and (3) an abnormal skinfold running from the lower lids. Telecanthus and a flat nasal bridge were present in most cases. In both families the disease was transmitted only by the male, and no affected woman of childbearing age was fertile. 12 refs., 2 figs., 1 tab.

  14. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Persani Luca

    2006-04-01

    Full Text Available Abstract Premature ovarian failure (POF is a primary ovarian defect characterized by absent menarche (primary amenorrhea or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea. It is a heterogeneous disorder affecting approximately 1% of women e.g. Turner syndrome represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation.

  15. The effects of MicroRNA transfections on global patterns of gene expression in ovarian cancer cells are functionally coordinated

    Directory of Open Access Journals (Sweden)

    Shahab Shubin W

    2012-08-01

    Full Text Available Abstract Background MicroRNAs (miRNAs are a class of small RNAs that have been linked to a number of diseases including cancer. The potential application of miRNAs in the diagnostics and therapeutics of ovarian and other cancers is an area of intense interest. A current challenge is the inability to accurately predict the functional consequences of exogenous modulations in the levels of potentially therapeutic miRNAs. Methods In an initial effort to systematically address this issue, we conducted miRNA transfection experiments using two miRNAs (miR-7, miR-128. We monitored the consequent changes in global patterns of gene expression by microarray and quantitative (real-time polymerase chain reaction. Network analysis of the expression data was used to predict the consequence of each transfection on cellular function and these predictions were experimentally tested. Results While ~20% of the changes in expression patterns of hundreds to thousands of genes could be attributed to direct miRNA-mRNA interactions, the majority of the changes are indirect, involving the downstream consequences of miRNA-mediated changes in regulatory gene expression. The changes in gene expression induced by individual miRNAs are functionally coordinated but distinct between the two miRNAs. MiR-7 transfection into ovarian cancer cells induces changes in cell adhesion and other developmental networks previously associated with epithelial-mesenchymal transitions (EMT and other processes linked with metastasis. In contrast, miR-128 transfection induces changes in cell cycle control and other processes commonly linked with cellular replication. Conclusions The functionally coordinated patterns of gene expression displayed by different families of miRNAs have the potential to provide clinicians with a strategy to treat cancers from a systems rather than a single gene perspective.

  16. Ovarian cancer treatment with a tumor-targeting and gene expression-controllable lipoplex

    OpenAIRE

    He, Zhi-Yao; Deng, Feng; Wei, Xia-Wei; Ma, Cui-Cui; Luo, Min; Zhang, Ping; Sang, Ya-Xiong; Liang, Xiao; Liu, Li; Qin, Han-Xiao; Shen, Ya-Li; Liu, Ting; Liu, Yan-Tong; Wang, Wei; Wen, Yan-Jun

    2016-01-01

    Overexpression of folate receptor alpha (FR?) and high telomerase activity are considered to be the characteristics of ovarian cancers. In this study, we developed FR?-targeted lipoplexes loaded with an hTERT promoter-regulated plasmid that encodes a matrix protein (MP) of the vesicular stomatitis virus, F-LP/pMP(2.5), for application in ovarian cancer treatment. We first characterized the pharmaceutical properties of F-LP/pMP(2.5). The efficient expression of the MP-driven hTERT promoter in ...

  17. Genome-wide methylation profiling of ovarian cancer patient-derived xenografts treated with the demethylating agent decitabine identifies novel epigenetically regulated genes and pathways

    Directory of Open Access Journals (Sweden)

    Tushar Tomar

    2016-10-01

    Full Text Available Abstract Background In high-grade serous ovarian cancer (HGSOC, intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far. Aims of this study were to explore how representative HGSOC PDXs are of their corresponding patient tumor methylome and to evaluate the effect of epigenetic therapy and cisplatin on putative epigenetically regulated genes and their related pathways in PDXs. Methods Genome-wide analysis of the DNA methylome of HGSOC patients with their corresponding PDXs, from different generations, was performed using Infinium 450 K methylation arrays. Furthermore, we analyzed global methylome changes after treatment of HGSOC PDXs with the FDA approved demethylating agent decitabine and cisplatin. Findings were validated by bisulfite pyrosequencing with subsequent pathway analysis. Publicly available datasets comprising HGSOC patients were used to analyze the prognostic value of the identified genes. Results Only 0.6–1.0 % of all analyzed CpGs (388,696 CpGs changed significantly (p < 0.01 during propagation, showing that HGSOC PDXs were epigenetically stable. Treatment of F3 PDXs with decitabine caused a significant reduction in methylation in 10.6 % of CpG sites in comparison to untreated PDXs (p < 0.01, false discovery rate <10 %. Cisplatin treatment had a marginal effect on the PDX methylome. Pathway analysis of decitabine-treated PDX tumors revealed several putative epigenetically regulated pathways (e.g., the Src family kinase

  18. Minimal alteration in muscle lipid genes following stabilized weight loss.

    Science.gov (United States)

    Coker, Robert H; Robinette, Leizleigh; Kern, Philip A

    2017-12-01

    Variations in skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), carntine palmitoyltransferase-1 (CPT-1), perilipin protein 2 (PLIN2), and adipose tissue triglyceride lipase (ATGL), and comparative gene identification-58 (CGI-58) have been described as playing important roles in the metabolic regulation of lipid oxidation, and may influence intramyocellular lipid (IMCL) and muscle lipid droplet size (LDS). While acute changes in caloric balance and/or aerobic capacity may affect lipid metabolism, the influence of sustained weight loss derived from caloric restriction with weight loss (CWL) compared with exercise training with weight loss (EWL) on the abovementioned parameters has not been fully elucidated. Using a combination of metabolic feeding and/or supervised exercise training, we evaluated the influence of stabilized weight loss elicited by CWL compared with EWL without the confounding influence of acute alterations in caloric balance on molecular markers of mitochondrial metabolism and lipid droplet size in middle-aged overweight individuals with impaired glucose tolerance. There were no significant changes in PGC-1α, CPT-1, PLIN2, ATGL and, CGI-58 messenger RNA (mRNA) in CWL and EWL. While there were no changes in ATGL mRNA in CWL, there was a strong trend (P = 0.05) for the ΔATGL mRNA in EWL with stabilized weight loss. There were no significant changes in IMCL or LDS within skeletal muscle in CWL or EWL, respectively. In conclusion, under the conditions of chronic caloric balance following dietary or exercise-based interventions, mediators of mitochondrial function, IMCL and LDS, were largely unaffected. Future studies should focus on intervention-based changes in protein expression and/or phosphorylation and the relationship to physiological endpoints.

  19. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

    NARCIS (Netherlands)

    Lawrenson, K.; Iversen, E.S.; Tyrer, J.; Weber, R.P.; Concannon, P.; Hazelett, D.J.; Li, Q.; Marks, J.R.; Berchuck, A.; Lee, J.M.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Bandera, E.V.; Bean, Y.; Beckmann, M.W.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A; Chen, Z.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Plisiecka-Halasa, J.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Eccles, D.; Easton, D.T.; Edwards, R.P.; Eilber, U.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Gronwald, J.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Jakubowska, A.; Paul, J.; Jensen, A.; Karlan, B.Y.; Kjaer, S.K.; Kelemen, L.E.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.; Krakstad, C.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Cannioto, R.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.; Moysich, K.B.; Narod, S.A.; Nedergaard, L.; Ness, R.B.; Azmi, M.A. Noor; Odunsi, K.; Olson, S.H.

    2015-01-01

    Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair

  20. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    DEFF Research Database (Denmark)

    Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P

    2016-01-01

    association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1...

  1. Effects of neonatal litter size and age on ovarian gene expression and follicular development in gilts

    Science.gov (United States)

    Gilts raised in small litters have greater ovulation rate, stay in the herd longer and produce more pigs. The objective was to understand how neonatal litter size affects gilt development. The hypothesis is that gilts reared in smaller litters have greater ovarian follicular development. Within 24 h...

  2. Histone Deacetylase Inhibitor Therapy in Epithelial Ovarian Cancer

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    Noriyuki Takai

    2010-01-01

    Full Text Available Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.

  3. Exome mutation burden predicts clinical outcome in ovarian cancer carrying mutated BRCA1 and BRCA2 genes

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria

    2013-01-01

    Reliable biomarkers predicting resistance or sensitivity to anti-cancer therapy are critical for oncologists to select proper therapeutic drugs in individual cancer patients. Ovarian and breast cancer patients carrying germline mutations in BRCA1 or BRCA2 genes are often sensitive to DNA damaging...... drugs and relative to non-mutation carriers present a favorable clinical outcome following therapy. Genome sequencing studies have shown a high number of mutations in the tumor genome in patients carrying BRCA1 or BRCA2 mutations (mBRCA). The present study used exome-sequencing and SNP 6 array data...... had either germlines or somatic mutations of BRCA1 or BRCA2 genes. The results revealed that the Nmut was significantly lower in the chemotherapy-resistant mBRCA HGSOC defined by progression within 6 months after completion of first line platinum-based chemotherapy. We found a significant association...

  4. Utility of gene promoter methylation in prediction of response to platinum-based chemotherapy in epithelial ovarian cancer (EOC).

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    Chaudhry, Parvesh; Srinivasan, Radhika; Patel, Firuza D

    2009-10-01

    The aim was to determine whether promoter methylation of BRCA1, MGMT, MLH1, RASSF1A, and p16 genes could predict response to platinum-based chemotherapy. Thirty-five subjects with epithelial ovarian cancer (EOC) treated by platinum-based chemotherapy were recruited. Methylation-specific polymerase chain reaction was carried out and the methylation index (MI) was also derived. Response to platinum-based chemotherapy was documented clinically, radiologically, and by serial CA125 levels. Methylated BRCA1 (p = .037) and a higher MI (p = .045) were associated with primary chemosensitivity. A better outcome was predicted by a higher MI (p = .032). In EOC, BRCA1 gene promoter methylation is useful in the prediction of response to chemotherapy.

  5. Insights into hepatopancreatic functions for nutrition metabolism and ovarian development in the crab Portunus trituberculatus: gene discovery in the comparative transcriptome of different hepatopancreas stages.

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    Wei Wang

    Full Text Available The crustacean hepatopancreas has different functions including absorption, storage of nutrients and vitellogenesis during growth, and ovarian development. However, genetic information on the biological functions of the crustacean hepatopancreas during such processes is limited. The swimming crab, Portunus trituberculatus, is a commercially important species for both aquaculture and fisheries in the Asia-Pacific region. This study compared the transcriptome in the hepatopancreas of female P. trituberculatus during the growth and ovarian maturation stages by 454 high-throughput pyrosequencing and bioinformatics. The goal was to discover genes in the hepatopancreas involved in food digestion, nutrition metabolism and ovarian development, and to identify patterns of gene expression during growth and ovarian maturation. Our transcriptome produced 303,450 reads with an average length of 351 bp, and the high quality reads were assembled into 21,635 contigs and 31,844 singlets. Based on BLASTP searches of the deduced protein sequences, there were 7,762 contigs and 4,098 singlets with functional annotation. Further analysis revealed 33,427 unigenes with ORFs, including 17,388 contigs and 16,039 singlets in the hepatopancreas, while only 7,954 unigenes (5,691 contigs and 2,263 singlets with the predicted protein sequences were annotated with biological functions. The deduced protein sequences were assigned to 3,734 GO terms, 25 COG categories and 294 specific pathways. Furthermore, there were 14, 534, and 22 identified unigenes involved in food digestion, nutrition metabolism and ovarian development, respectively. 212 differentially expressed genes (DEGs were found between the growth and endogenous stage of the hepatopancreas, while there were 382 DEGs between the endogenous and exogenous stage hepatopancreas. Our results not only enhance the understanding of crustacean hepatopancreatic functions during growth and ovarian development, but also represent

  6. Potential predictive markers of chemotherapy resistance in stage III ovarian serous carcinomas

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    Olsson Björn

    2009-10-01

    Full Text Available Abstract Background Chemotherapy resistance remains a major obstacle in the treatment of women with ovarian cancer. Establishing predictive markers of chemoresponse would help to individualize therapy and improve survival of ovarian cancer patients. Chemotherapy resistance in ovarian cancer has been studied thoroughly and several non-overlapping single genes, gene profiles and copy number alterations have been suggested as potential markers. The objective of this study was to explore genetic alterations behind chemotherapy resistance in ovarian cancer with the ultimate aim to find potential predictive markers. Methods To create the best opportunities for identifying genetic alterations of importance for resistance, we selected a homogenous tumor material concerning histology, stage and chemotherapy. Using high-resolution whole genome array comparative genomic hybridization (CGH, we analyzed the tumor genomes of 40 fresh-frozen stage III ovarian serous carcinomas, all uniformly treated with combination therapy paclitaxel/carboplatin. Fisher's exact test was used to identify significant differences. Subsequently, we examined four genes in the significant regions (EVI1, MDS1, SH3GL2, SH3KBP1 plus the ABCB1 gene with quantitative real-time polymerase chain reaction (QPCR to evaluate the impact of DNA alterations on the transcriptional level. Results We identified gain in 3q26.2, and losses in 6q11.2-12, 9p22.3, 9p22.2-22.1, 9p22.1-21.3, Xp22.2-22.12, Xp22.11-11.3, and Xp11.23-11.1 to be significantly associated with chemotherapy resistance. In the gene expression analysis, EVI1 expression differed between samples with gain versus without gain, exhibiting higher expression in the gain group. Conclusion In conclusion, we detected specific genetic alterations associated with resistance, of which some might be potential predictive markers of chemotherapy resistance in advanced ovarian serous carcinomas. Thus, further studies are required to validate

  7. In utero and lactational exposure to PCB 118 and PCB 153 alter ovarian follicular dynamics and GnRH-induced luteinizing hormone secretion in female lambs

    DEFF Research Database (Denmark)

    Kraugerud, Marianne; Aleksandersen, Mona; Nyengaard, Jens Randel

    2012-01-01

    The effects of in utero and lactational exposure to two structurally different polychlorinated biphenyl (PCB) congeners on follicular dynamics and the pituitary-gonadal axis in female lambs were investigated. Pregnant ewes received corn oil, PCB 118, or PCB 153, and offspring was maintained until...... 60 days postpartum. Ovarian follicles were quantified using stereology. Plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured using radioimmunoassay before and after administration of a gonadotropin releasing hormone (GnRH) analog. PCB 118 exposure increased numbers...... of transitional, secondary, and the sum of secondary, early antral, and antral (Σsecondary-antral) follicles, PCB 153 exposure only increased the number of primary follicles. GnRH-induced LH levels were significantly elevated in the PCB 153 exposure group. We conclude that PCB 153 and PCB 118 alter follicular...

  8. The frequency of cancer predisposition gene mutations in hereditary breast and ovarian cancer patients in Taiwan: From BRCA1/2 to multi-gene panels.

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    Pi-Lin Sung

    Full Text Available An important role of genetic factors in the development of breast cancer (BC or ovarian cancer (OC in Taiwanese (ethnic Chinese patients has been suggested. However, other than germline BRCA1 or BRCA2 mutations, which are related to hereditary breast-ovarian cancer (HBOC, cancer-predisposition genes have not been well studied in this population. The aim of the present study was to more accurately summarize the prevalence of genetic mutations in HBOC patients using various gene panels ranging in size from BRCA1/2 alone to multi-gene panels. Among 272 HBOC patients analyzed, the prevalence of BRCA1, BRCA2 and non-BRCA1/2 pathogenic mutations was 7.7% (21/272, 6.8% (16/236 and 8.2% (13/159, respectively. The total mutation rate was 18.4% (50/272. Although no founder mutations were identified in this study, two recurrent mutations, BRCA1 (c.3607C>T and BRCA2 (c.5164_5165 delAG, were found. The main pathogenic/likely pathogenic mutations in non-BRCA1/2 genes included ATM, BRIP1, FANCI, MSH2, MUYTH, RAD50, RAD51C and TP53. The prevalence rate of gene mutations in HBOC patients did not differ with respect to whether BC or OC was the first diagnosis or they presented a family history of the disease or their age at diagnosis. HBOC patients with both BC and OC exhibited a higher prevalence rate of mutations (50.0% than patients with OC (25.0% or BC (8.6% alone. In conclusion, evaluation of hereditary cancer risk in Taiwan HBOC patients, particularly individuals with double cancer, is strongly encouraged. Panel testing can yield additional genomic information, and widespread and well-designed panel testing will help in assessing more accurate mutational prevalence of risk genes.

  9. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

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    Sharon E Johnatty

    2010-07-01

    Full Text Available We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC. In the discovery stage, cases with epithelial ovarian cancer (n=675 and controls (n=1,162 were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5. However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03. Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24 p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

  10. [Effect of MTRR gene on apoptosis and autophagy pathways in multiresistant epithelial ovarian cancer].

    Science.gov (United States)

    Chen, J; Wang, Q; Zhang, W; Li, L

    2016-04-25

    To explore the effect of down-regulated methionine synthase reductase(MTRR)gene on the apoptosis and autophagy pathway, and offer a possible approach for the MTRR to reverse the multi-resistant ovarian cancer. (1)The experiment was divided into 3 groups, SKOV3/DDP-MTRRi(down-regulated MTRR group), SKOV3/DDP-NC(negative control group), and SKOV3/DDP(blank control group). Different concentration of cisplatin(0, 1, 2, and 4 μg/ml)treated on 3 groups cells. The apoptosis rate was measured by flow cytometry(FCM). Autophagy was detected by immunofluorescence. Autophagy microtubule associated protein light chain 3β(LC3B)and p62 were detected by western blot. The formation of autophagosome of cells was observed by transmission electron microscope.(2)Detection of autophagy and apoptosis of SKOV3/DDP-MTRRi induced by rapamycin. The experiment was divided into 4 groups included rapamycin group(5 nmol/L rapamycin), rapamycin+cisplatin group(5 nmol/L rapamycin+ 4 μg/ml cisplatin), cisplatin group(4 μg/ml cisplatin)and blank control group. LC3B and p62 protein were detected by western blot. The survival rate cells were detected by methyl thiazolyl tetrazolium(MTT)method. The apoptosis rate was measured by FCM.(3)The 3 groups cells(SKOV3/DDP, SKOV3/DDP-NC and SKOV3/DDP-MTRRi)induced by a certain concentration of cisplatin(4 μg/ml)after 48 hours, then detecting the protein expression of caspase, Bcl-2 family in apoptosis pathway and the key proteins in phosphatidylinositol-3 kinase(PI3K)/protein kinase B(Akt)autophagy pathways by western blot, getting the time when the proteins' expression changed. (1)The 3 groups cells(SKOV3/DDP, SKOV3/DDP-NC, and SKOV3/DDP-MTRRi)induced by a certain concentration of cisplatin(4 μg/ml)after 48 hours, apoptosis and autophagy of 3 groups of cells were gradually increased with the increased concentration of cisplatin. The apoptosis rate of SKOV3/DDP-MTRRi cells[(26.2 ± 1.4)%]were significantly increased compared with the SKOV3/DDP-NC cells or

  11. Elevated Serum Level of CA125 Is a Biomarker That Can Be Used to Alter Prognosis Determined by BRCA Mutation and Family History in Ovarian Cancer.

    Science.gov (United States)

    Liu, Weiling; Wang, Zhizhong; Ma, Jie; Hou, Yangyang; Zhao, Jiuzhou; Dong, Bing; Tu, Shichun; Wang, Li; Guo, Yongjun

    2017-09-01

    In this study, we determined whether serum tumor markers (STMs), including CA125, are associated with BRCA mutation status and if they can be used prognostically in sporadic ovarian cancer (SOC) and familial ovarian cancer (FOC). BRCA gene mutations were screened using next-generation sequencing (NGS) in 31 FOC and 66 SOC patients enrolled between 2013 and 2014. The serum levels of STM CEA, CA125, CA199, and HE4 were also measured in these patients to determine the prognostic potential of these markers and their association with BRCA mutations. Elevated levels of CA125, but not the other three STMs, were associated with FOC and BRCA mutations. Median progression-free survival (PFS) was significantly longer in patients with FOC, higher CA125 expression (>2000 U/mL), and BRCA mutation. Strikingly, the median PFS was not reached in either BRCA+/higher CA125 or FOC/higher CA125 patient groups and these patients had significantly longer PFS than those in other groups. As reported previously, we also detected more BRCA mutations in FOC than in SOC. No significant differences were observed in onset age, menopausal status, tumor stage, and distant metastasis between FOC and SOC patients or between BRCA+ and BRCA- patients. Elevated levels of serum CA125 are associated with FOC and BRCA mutations, which can be further exploited as a prognostic marker in OC.

  12. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions assoc...

  13. Selected Aspects of Molecular Diagnostics of Constitutional Alterations in BRCA1 and BRCA2 Genes Associated with Increased Risk of Breast Cancer in the Polish Population

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    Górski Bohdan

    2006-08-01

    Full Text Available Abstract Objectives This study was undertaken to determine: 1 Type and prevalence of founder mutations BRCA1 and BRCA2 genes in Polish families with strong aggregation of breast and/or ovarian cancer. 2 Risk of breast and/or ovarian cancer depending on type of BRCA1 gene mutation. 3 Prevalence of BRCA1 mutation and of other alleles presumably linked with predisposition to breast cancer in unselected Polish patients with breast cancer. 4 Risk of breast cancer in patients with 5972C/T polymorphism that alters the BRCA2 protein structure. Summary of the results 1. Among 66 families from several regions in Poland with a strong aggregation of breast/ovarian cancer, founder mutation of the BRCA1 gene were disclosed in 34 families and of the BRCA2 gene in on family. Altogether, seven different mutations were disclosed. Five mutations were found in at least two families in this group. The most frequent mutation was 5382insC (18 families, followed by C61G (7 families and 4153delA (4 families. 2. Among 200 families representative for Poland with strong aggregation of breast/ovarian cancer, mutation of the BRCA1 gene were found in 122 families (61% and of the BRCA2 gene in seven families (3,5%. 119 out of 122 mutations of the BRCA1 gene (97,5% were repeatable. Three recurrent mutations of the BRCA1 gene (5382insC, C61G, 4153delA characteristic for the Polish population were disclosed in 111 families representing 86% of all pathogenic sequences of this gene. 3. The risk of ovarian cancer in carriers of the three most frequent recurrent mutation of the BRCA1 gene in Poland is similar (OR 43.6 for 5382insC and 50 for 4153delA. The risk of breast cancer is significantly different for 4153delA (OR 1 and for other mutations (OR 10.9. 4. Among 2012 unselected breast cancers diagnosed in hospitals of nine Polish cities, mutations of the BRCA1 gene (5382insC, C61G, 4153delA were disclosed in 2.9% patients. CHEK2 alternation (1100delC, IVS2+1G>A, I157T was

  14. Candidate gene expression in Bos indicus ovarian tissues: pre-pubertal and post-pubertal heifers in diestrus

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    Mayara Morena Del Cambre Amaral Weller

    2016-10-01

    Full Text Available Growth factors such as bone morphogenetic proteins 6, 7, 15 and two isoforms of transforming growth factor-beta (BMP6, BMP7, BMP15, TGFB1 and TGFB2 and insulin-like growth factor system act as local regulators of ovarian follicular development. To elucidate if these factors as well as others candidate genes such as estrogen receptor 1 (ESR1, growth differentiation factor 9 (GDF9, follicle stimulating hormone receptor (FSHR, luteinizing hormone receptor (LHR, bone morphogenetic protein receptor, type 2 (BMPR2, type 1 insulin-like growth factor receptor (IGFR1, and key steroidogenic enzymes cytochrome P450 aromatase and 3-β-hydroxysteroid dehydrogenase (CYP19A1 and HSD3B1 could modulate or influence diestrus on the onset of puberty in Brahman heifers, their ovarian mRNA expression was measured before and after puberty (luteal phase. Six post-pubertal (POST heifers were euthanized on the luteal phase of their second cycle, confirmed by corpus luteum observation, and six pre-pubertal (PRE heifers were euthanized in the same day. Quantitative real-time PCR analysis showed that the expression of FSHR, BMP7, CYP19A1, IGF1 and IGFR1 mRNA was greater in PRE heifers, when contrasted to POST heifers. The expression of LHR and HSD3B1 was lower in PRE heifers. Differential expression of ovarian genes could be associated with changes in follicular dynamics and different cell populations that have emerged as consequence of puberty and the luteal phase. The emerging hypothesis is that BMP7 and IGF1 are co-expressed and may modulate the expression of FSHR, LHR and IGFR1 and CYP19A1. BMP7 could influence the down-regulation of LHR and up-regulation of FSHR and CYP19A1, which mediates the follicular dynamics in heifer ovaries. Up-regulation of IGF1 expression pre-puberty, compared to post-puberty diestrus, correlates with increased levels FSHR and CYP19A1. Thus, BMP7 and IGF1 may play synergic roles and were predicted to interact, from the expression data (P = 0

  15. The use of laser microdissection in the identification of suitable reference genes for normalization of quantitative real-time PCR in human FFPE epithelial ovarian tissue samples.

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    Jing Cai

    Full Text Available Quantitative real-time PCR (qPCR is a powerful and reproducible method of gene expression analysis in which expression levels are quantified by normalization against reference genes. Therefore, to investigate the potential biomarkers and therapeutic targets for epithelial ovarian cancer by qPCR, it is critical to identify stable reference genes. In this study, twelve housekeeping genes (ACTB, GAPDH, 18S rRNA, GUSB, PPIA, PBGD, PUM1, TBP, HRPT1, RPLP0, RPL13A, and B2M were analyzed in 50 ovarian samples from normal, benign, borderline, and malignant tissues. For reliable results, laser microdissection (LMD, an effective technique used to prepare homogeneous starting material, was utilized to precisely excise target tissues or cells. One-way analysis of variance (ANOVA and nonparametric (Kruskal-Wallis tests were used to compare the expression differences. NormFinder and geNorm software were employed to further validate the suitability and stability of the candidate genes. Results showed that epithelial cells occupied a small percentage of the normal ovary indeed. The expression of ACTB, PPIA, RPL13A, RPLP0, and TBP were stable independent of the disease progression. In addition, NormFinder and geNorm identified the most stable combination (ACTB, PPIA, RPLP0, and TBP and the relatively unstable reference gene GAPDH from the twelve commonly used housekeeping genes. Our results highlight the use of homogeneous ovarian tissues and multiple-reference normalization strategy, e.g. the combination of ACTB, PPIA, RPLP0, and TBP, for qPCR in epithelial ovarian tissues, whereas GAPDH, the most commonly used reference gene, is not recommended, especially as a single reference gene.

  16. The use of laser microdissection in the identification of suitable reference genes for normalization of quantitative real-time PCR in human FFPE epithelial ovarian tissue samples.

    Science.gov (United States)

    Cai, Jing; Li, Tao; Huang, Bangxing; Cheng, Henghui; Ding, Hui; Dong, Weihong; Xiao, Man; Liu, Ling; Wang, Zehua

    2014-01-01

    Quantitative real-time PCR (qPCR) is a powerful and reproducible method of gene expression analysis in which expression levels are quantified by normalization against reference genes. Therefore, to investigate the potential biomarkers and therapeutic targets for epithelial ovarian cancer by qPCR, it is critical to identify stable reference genes. In this study, twelve housekeeping genes (ACTB, GAPDH, 18S rRNA, GUSB, PPIA, PBGD, PUM1, TBP, HRPT1, RPLP0, RPL13A, and B2M) were analyzed in 50 ovarian samples from normal, benign, borderline, and malignant tissues. For reliable results, laser microdissection (LMD), an effective technique used to prepare homogeneous starting material, was utilized to precisely excise target tissues or cells. One-way analysis of variance (ANOVA) and nonparametric (Kruskal-Wallis) tests were used to compare the expression differences. NormFinder and geNorm software were employed to further validate the suitability and stability of the candidate genes. Results showed that epithelial cells occupied a small percentage of the normal ovary indeed. The expression of ACTB, PPIA, RPL13A, RPLP0, and TBP were stable independent of the disease progression. In addition, NormFinder and geNorm identified the most stable combination (ACTB, PPIA, RPLP0, and TBP) and the relatively unstable reference gene GAPDH from the twelve commonly used housekeeping genes. Our results highlight the use of homogeneous ovarian tissues and multiple-reference normalization strategy, e.g. the combination of ACTB, PPIA, RPLP0, and TBP, for qPCR in epithelial ovarian tissues, whereas GAPDH, the most commonly used reference gene, is not recommended, especially as a single reference gene.

  17. Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

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    Carmen J. Zamora-Sánchez

    2018-03-01

    Full Text Available Glioblastomas (GBM are the most frequent and aggressive brain tumors. In these malignancies, progesterone (P4 promotes proliferation, migration, and invasion. The P4 metabolite allopregnanolone (3α-THP similarly promotes cell proliferation in the U87 human GBM cell line. Here, we evaluated global changes in gene expression of U87 cells treated with 3α-THP, P4, and the 5α-reductase inhibitor, finasteride (F. 3α-THP modified the expression of 137 genes, while F changed 90. Besides, both steroids regulated the expression of 69 genes. After performing an over-representation analysis of gene ontology terms, we selected 10 genes whose products are cytoskeleton components, transcription factors, and proteins involved in the maintenance of DNA stability and replication to validate their expression changes by RT-qPCR. 3α-THP up-regulated six genes, two of them were also up-regulated by F. Two genes were up-regulated by P4 alone, however, such an effect was blocked by F when cells were treated with both steroids. The remaining genes were regulated by the combined treatments of 3α-THP + F or P4 + F. An in-silico analysis revealed that promoters of the six up-regulated genes by 3α-THP possess cyclic adenosine monophosphate (cAMP responsive elements along with CCAAT/Enhancer binding protein alpha (CEBPα binding sites. These findings suggest that P4 and 3α-THP regulate different sets of genes that participate in the growth of GBMs.

  18. Continuous soy isoflavones exposure from weaning to maturity induces downregulation of ovarian steroidogenic factor 1 gene expression and corresponding changes in DNA methylation pattern.

    Science.gov (United States)

    Wang, Wenxiang; Sun, Yan; Guo, Yiwei; Cai, Ping; Li, Yuchen; Liu, Jin; Cai, Guoxi; Kiyoshi, Aoyagi; Zhang, Wenchang

    2017-11-05

    Female Wistar rats were treated with orally administered soy isoflavones at concentrations of 0, 25, 50, or 100mg/kg body weight from weaning until sexual maturity (3 mo.), and ovarian steroidogenesis was evaluated. After soy isoflavones were administered, a significant (Psoy isoflavones can significantly (Psoy isoflavone administration from weaning until sexual maturity could inhibit ovarian steroidogenesis, suggesting that SF-1 might play an important role in this effect. In addition, DNA methylation might play a role in the downregulation of SF-1 gene expression induced by soy isoflavones. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Polyploidization altered gene functions in cotton (Gossypium spp.).

    Science.gov (United States)

    Xu, Zhanyou; Yu, John Z; Cho, Jaemin; Yu, Jing; Kohel, Russell J; Percy, Richard G

    2010-12-16

    Cotton (Gossypium spp.) is an important crop plant that is widely grown to produce both natural textile fibers and cottonseed oil. Cotton fibers, the economically more important product of the cotton plant, are seed trichomes derived from individual cells of the epidermal layer of the seed coat. It has been known for a long time that large numbers of genes determine the development of cotton fiber, and more recently it has been determined that these genes are distributed across At and Dt subgenomes of tetraploid AD cottons. In the present study, the organization and evolution of the fiber development genes were investigated through the construction of an integrated genetic and physical map of fiber development genes whose functions have been verified and confirmed. A total of 535 cotton fiber development genes, including 103 fiber transcription factors, 259 fiber development genes, and 173 SSR-contained fiber ESTs, were analyzed at the subgenome level. A total of 499 fiber related contigs were selected and assembled. Together these contigs covered about 151 Mb in physical length, or about 6.7% of the tetraploid cotton genome. Among the 499 contigs, 397 were anchored onto individual chromosomes. Results from our studies on the distribution patterns of the fiber development genes and transcription factors between the At and Dt subgenomes showed that more transcription factors were from Dt subgenome than At, whereas more fiber development genes were from At subgenome than Dt. Combining our mapping results with previous reports that more fiber QTLs were mapped in Dt subgenome than At subgenome, the results suggested a new functional hypothesis for tetraploid cotton. After the merging of the two diploid Gossypium genomes, the At subgenome has provided most of the genes for fiber development, because it continues to function similar to its fiber producing diploid A genome ancestor. On the other hand, the Dt subgenome, with its non-fiber producing D genome ancestor

  20. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

    DEFF Research Database (Denmark)

    Song, Honglin; Dicks, Ed; Ramus, Susan J

    2015-01-01

    PURPOSE: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. PATIENTS AND METHODS: The coding s...

  1. Identification of differentially expressed ovarian genes during primary and early secondary oocyte growth in coho salmon, Oncorhynchus kisutch

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    Iliev Dimitar B

    2008-01-01

    Full Text Available Abstract Background The aim of this study was to identify differentially expressed ovarian genes during primary and early secondary oocyte growth in coho salmon, a semelparous teleost that exhibits synchronous follicle development. Methods Reciprocal suppression subtractive hybridization (SSH libraries were generated from ovaries with perinucleolus (P or cortical alveolus (CA stage follicles and selected genes were assessed with quantitative PCR (qPCR. An assessment of changes in RNA composition during oocyte growth and its relationship to transcript levels was also conducted. Results SSH revealed several differentially expressed genes during early oogenesis, some which will not likely be utilized until 1–3 years later in salmon. Zona pellucida glycoprotein (zp genes, vitellogenin receptor (vldlr isoforms, cathepsin B (ctsba, cyclin E (ccne, a DnaJ transcript (dnaja2, and a ferritin subunit (fth3 were significantly elevated at the P stage, while a C-type lectin, retinol dehydrogenase (rdh1, and a coatomer protein subunit (cope were upregulated at the CA stage. Putative follicle cell transcripts such as anti-Müllerian hormone (amh, lipoprotein lipase (lpl, apolipoprotein E (apoe, gonadal soma-derived growth factor (gsdf and follicle-stimulating hormone receptor (fshr also increased significantly at the CA stage. The analysis of RNA composition during oocyte growth showed that the total RNA yield and proportion of messenger RNA relative to non-polyadenylated RNAs declined as oogenesis progressed. This influenced apparent transcript levels depending on the type of RNA template used and normalization method. Conclusion In coho salmon, which exhibit a dramatic change in oocyte size and RNA composition during oogenesis, use of messenger RNA as template and normalization of qPCR data to a housekeeping gene, ef1a, yielded results that best reflected transcript abundance within the ovarian follicle. Synthesis of zp transcripts and proteins involved in

  2. Metabolic Effects of FecB Gene on Follicular Fluid and Ovarian Vein Serum in Sheep (Ovis aries

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    Xiaofei Guo

    2018-02-01

    Full Text Available The FecB gene has been discovered as an important gene in sheep for its high relationship with the ovulation rate, but its regulatory mechanism remains unknown. In the present study, liquid chromatography-mass spectrometry (LC-MS and gas chromatography-mass spectrometry (GC-MS techniques were adopted to detect the metabolic effects of FecB gene in follicular fluid (FF and ovarian vein serum (OVS in Small Tail Han (STH sheep. ANOVA and random forest statistical methods were employed for the identification of important metabolic pathways and biomarkers. Changes in amino acid metabolism, redox environment, and energy metabolism were observed in FF from the three FecB genotype STH ewes. Principal component analysis (PCA and hierarchical clustering analysis (HCA showed that metabolic effects of FecB gene are more pronounced in FF than in OVS. Therefore, the difference of the metabolic profile in FF is also affected by the FecB genotypes. In Spearman correlation analysis, key metabolites (e.g., glucose 6-phosphate, glucose 1-phosphate, aspartate, asparagine, glutathione oxidized (GSSG, cysteine-glutathione disulfide, γ-glutamylglutamine, and 2-hydrosybutyrate in ovine FF samples showed a significant correlation with the ovulation rate. Our findings will help to explain the metabolic mechanism of high prolificacy ewes and benefit fertility identification.

  3. Association of Exon 10A and 10B inactivating mutation of follicle stimulating hormone receptor gene (FSHR) and Polycystic Ovarian Syndrome in Vellore cohort

    Science.gov (United States)

    Sekar, Nishu; Kulkarni, Rucha; Ozalkar, Sharvari; Prabhu, Yogamaya D.; Renu, Kaviyarasi; Ramgir, Shalaka S.; Abilash, V. G.

    2017-11-01

    Polycystic ovarian syndrome is the most common heterogenous endocrine disorder in women. Follicle stimulating hormone receptor is associated with normal development as well as maturation of follicles and triggers estrogen production in granulosa cells of the ovary. Inactivating mutation in FSHR gene correlated with reduction of ovarian function in women is due to damage to receptor function. This study aims to investigate whether inactivating mutations, in follicle stimulating hormone receptor gene is related to polycystic ovarian morphology in women with PCOS. Genomic DNA isolated from 15 subjects from Sandhya Hospital, Vellore (10 patients with PCOS and 5 healthy controls) was taken for this study. Patient data included a clinical report, hormonal levels, and ovarian morphological details. DNA isolation was followed by DNA amplification by polymerase chain reaction using Exon 10 A and Exon 10 B primers. The PCR-RFLP analysis was performed using Dde1 restriction enzyme. Here we discuss inactivating mutation found in Exon 10 of FSHR gene in patients with PCOS.The absence of inactivating mutation was observed through PCR-RFLP study on Exon 10A and Exon 10B.

  4. The gene copy number of c-MET has a significant impact on progression-free survival in Korean patients with ovarian carcinoma.

    Science.gov (United States)

    Kim, Wook Youn; Shim, Seung-Hyuk; Jung, Ho Young; Dong, Meari; Kim, Soo-Nyung; Lee, Sun Joo

    2017-06-01

    The aim of this study was to compare the protein overexpression and gene copy number (GCN) of c-MET in ovarian carcinoma and to assess their prognostic roles in Korean women. MET protein expression and GCN status were determined using immunohistochemistry (IHC) and silver in situ hybridization, respectively, in 105 ovarian carcinomas comprising 63 serous, 12 mucinous, 20 clear cell, and 10 endometrioid carcinomas. All cases had been treated and followed up at a single institute in Seoul, Korea. MET protein overexpression was observed in 35 of 105 (33.3%) ovarian carcinomas, with IHC 2+ in 27 and IHC 3+ in 8. The overexpression rates of serous, mucinous, clear cell, and endometrioid carcinomas were 14.3%, 83.3%, 65.0%, and 30.0%, respectively. MET protein overexpression was significant in mucinous carcinoma (P ovarian carcinomas, respectively. Eleven of 12 cases were high-grade serous carcinomas. The remaining case was clear cell carcinoma. HP and GA were associated with a poor PFS (P = .001). There was no significant correlation between a high level of protein expression and increased GCN of MET (r = -0.127, P = .197). In Korean women, HP and GA of MET were significantly correlated with a poor PFS. MET GCN may serve as a biomarker for poor prognosis in patients with ovarian carcinoma. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. TP53 gene status and human papilloma virus infection in response to platinum plus taxane-based chemotherapy of epithelial ovarian carcinomas.

    Science.gov (United States)

    Malisic, E; Jankovic, R; Jakovljevic, K; Radulovic, S

    2011-01-01

    Lack of symptoms in early stages of disease and resistance to chemotherapy make epithelial ovarian carcinomas one of the most lethal neoplasms among gynaecological malignancies. The aim of this study was to analyse the impact of TP53 mutations, codon 72 polymorphism and human papillomavirus (HPV) infection on the response to platinum-taxane combination chemotherapy in patients with epithelial ovarian carcinomas. The study was conducted on 26 ovarian carcinoma patients who received carboplatin plus paclitaxel combination chemotherapy. DNA was isolated by salting-out procedure. Mutations in exons 4-8 of TP53 gene were detected by PCR-SSCP and confirmed by automatic DNA sequencing. Codon 72 polymorphism was assessed by the RFLP method. HPV infection was detected through amplification of one part of L1 viral gene. Genotyping was performed by DNA sequencing. Fisher's exact and log-rank tests were used for statistical analysis. TP53 mutations were present in 5/26 (19.2%) ovarian carcinomas. The distribution of codon 72 TP53 genotypes was: Arg/Arg 38.5%, Arg/Pro 50.0%, Pro/Pro 11.5%. HPV was present in 4/26 (15.4%) ovarian carcinomas. All HPV-positive tumors were HPV16 type. Patients with mutations in TP53 gene, Arg/Arg genotype of codon 72 and absence of HPV infection experienced the highest tumor response rate to platinum-taxane chemotherapy. However, no significant correlation between progression free interval (PFI) and the examined biomarkers was observed. Our results indicate that, based on the TP53 gene status and the presence/absence of HPV infection, the subgroups of patients having better initial response to platinum-taxane therapy could be distinguished. This might contribute to more adequate treatment and individual therapeutic approach.

  6. Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome.

    Science.gov (United States)

    Bellver, José; Martínez-Conejero, José Antonio; Labarta, Elena; Alamá, Pilar; Melo, Marco Antonio Barreto; Remohí, José; Pellicer, Antonio; Horcajadas, José Antonio

    2011-06-01

    To determine whether luteal phase endometrial transcriptome is altered in obese women during the window of implantation (WOI), considering the presence of infertility, fat distribution and association with polycystic ovary syndrome (PCOS). Prospective study. University-affiliated infertility clinic, between May 2007 and March 2009. One control group of women with normal weight (n=4), and four study groups of obese women (n=6 each one) according to the association with infertility, PCOS, and ovarian stimulation. The endometrium was biopsied 7 days after LH surge or hCG administration in 28 women. Endometrial gene expression during the WOI. One hundred and fifty-one genes were dysregulated in obese groups compared with controls. This dysregulation was more pronounced when infertility was associated. The biologic processes of these genes belonged mainly to development and regulation of different biological functions such as transcription and biosynthesis. The molecular functions overrepresented were transcription and peptide receptor activity. The endometrium of obese women with PCOS showed dysregulated genes related to biologic processes such as development, morphogenesis, and the immune system, as well as different molecular functions such as protein binding, binding, growth factor activity, and carboxylic acid transmembrane transporter activity. Some of these genes have been previously related to implantation and unexplained infertility. Obese women present a different endometrial gene expression than controls during the WOI, which is more pronounced when infertility or polycystic ovary syndrome are associated. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  7. Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging

    Science.gov (United States)

    Cacciatore, Chiara; Busnelli, Marta; Rossetti, Raffaella; Bonetti, Silvia; Paffoni, Alessio; Mari, Daniela; Ragni, Guido; Persani, Luca; Arosio, M.; Beck-Peccoz, P.; Biondi, M.; Bione, S.; Bruni, V.; Brigante, C.; Cannavo`, S.; Cavallo, L.; Cisternino, M.; Colombo, I.; Corbetta, S.; Crosignani, P.G.; D'Avanzo, M.G.; Dalpra, L.; Danesino, C.; Di Battista, E.; Di Prospero, F.; Donti, E.; Einaudi, S.; Falorni, A.; Foresta, C.; Fusi, F.; Garofalo, N.; Giotti, I.; Lanzi, R.; Larizza, D.; Locatelli, N.; Loli, P.; Madaschi, S.; Maghnie, M.; Maiore, S.; Mantero, F.; Marozzi, A.; Marzotti, S.; Migone, N.; Nappi, R.; Palli, D.; Patricelli, M.G.; Pisani, C.; Prontera, P.; Petraglia, F.; Radetti, G.; Renieri, A.; Ricca, I.; Ripamonti, A.; Rossetti, R.; Russo, G.; Russo, S.; Tonacchera, M.; Toniolo, D.; Torricelli, F.; Vegetti, W.; Villa, N.; Vineis, P.; Wasniewsk, M.; Zuffardi, O.

    2012-01-01

    Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. PMID:22879975

  8. Mismatch repair and treatment resistance in ovarian cancer

    Directory of Open Access Journals (Sweden)

    van der Burg Maria EL

    2006-07-01

    Full Text Available Abstract Background The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. Methods We determined, microsatellite instability (MSI as a marker for MMR inactivation (analysis of BAT25 and BAT26, MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR in 75 ovarian carcinomas and eight ovarian cancer cell lines Results MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation, SKOV3 (no MLH1 mRNA expression and 2774 (no altered expression of MMR genes. Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response. The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. Conclusion No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation.

  9. Mismatch repair and treatment resistance in ovarian cancer

    International Nuclear Information System (INIS)

    Helleman, Jozien; Staveren, Iris L van; Dinjens, Winand NM; Kuijk, Patricia F van; Ritstier, Kirsten; Ewing, Patricia C; Burg, Maria EL van der; Stoter, Gerrit; Berns, Els MJJ

    2006-01-01

    The treatment of ovarian cancer is hindered by intrinsic or acquired resistance to platinum-based chemotherapy. The aim of this study is to determine the frequency of mismatch repair (MMR) inactivation in ovarian cancer and its association with resistance to platinum-based chemotherapy. We determined, microsatellite instability (MSI) as a marker for MMR inactivation (analysis of BAT25 and BAT26), MLH1 promoter methylation status (methylation specific PCR on bisulfite treated DNA) and mRNA expression of MLH1, MSH2, MSH3, MSH6 and PMS2 (quantitative RT-PCR) in 75 ovarian carcinomas and eight ovarian cancer cell lines MSI was detected in three of the eight cell lines i.e. A2780 (no MLH1 mRNA expression due to promoter methylation), SKOV3 (no MLH1 mRNA expression) and 2774 (no altered expression of MMR genes). Overall, there was no association between cisplatin response and MMR status in these eight cell lines. Seven of the 75 ovarian carcinomas showed MLH1 promoter methylation, however, none of these showed MSI. Forty-six of these patients received platinum-based chemotherapy (11 non-responders, 34 responders, one unknown response). The resistance seen in the eleven non-responders was not related to MSI and therefore also not to MMR inactivation. No MMR inactivation was detected in 75 ovarian carcinoma specimens and no association was seen between MMR inactivation and resistance in the ovarian cancer cell lines as well as the ovarian carcinomas. In the discussion, the results were compared to that of twenty similar studies in the literature including in total 1315 ovarian cancer patients. Although no association between response and MMR status was seen in the primary tumor the possible role of MMR inactivation in acquired resistance deserves further investigation

  10. The association between inflammation-related genes and serum androgen levels in men: The Prostate, Lung, Colorectal, and Ovarian Study

    Science.gov (United States)

    Meyer, Tamra E.; Chu, Lisa W.; Li, Qizhai; Yu, Kai; Rosenberg, Philip S.; Menashe, Idan; Chokkalingam, Anand P.; Quraishi, Sabah M.; Huang, Wen-Yi; Weiss, Jocelyn M.; Kaaks, Rudolf; Hayes, Richard B.; Chanock, Stephen J.; Hsing, Ann W.

    2011-01-01

    BACKGROUND Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes. METHODS In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method. RESULTS Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-valueT in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione. CONCLUSIONS These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk. PMID:21520164

  11. Fluoride Exposure, Follicle Stimulating Hormone Receptor Gene Polymorphism and Hypothalamus-pituitary-ovarian Axis Hormones in Chinese Women.

    Science.gov (United States)

    Zhao, Ming Xu; Zhou, Guo Yu; Zhu, Jing Yuan; Gong, Biao; Hou, Jia Xiang; Zhou, Tong; Duan, Li Ju; Ding, Zhong; Cui, Liu Xin; Ba, Yue

    2015-09-01

    The effects of fluoride exposure on the functions of reproductive and endocrine systems have attracted widespread attention in academic circle nowadays. However, it is unclear whether the gene-environment interaction may modify the secretion and activity of hypothalamus-pituitary- ovarian (HPO) axis hormones. Thus, the aim of this study was to explore the influence of fluoride exposure and follicle stimulating hormone receptor (FSHR) gene polymorphism on reproductive hormones in Chinese women. A cross sectional study was conducted in seven villages of Henan Province, China during 2010-2011. A total of 679 women aged 18-48 years were recruited through cluster sampling and divided into three groups, i.e. endemic fluorosis group (EFG), defluoridation project group (DFPG), and control group (CG) based on the local fluoride concentration in drinking water. The serum levels of gonadotropin releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were determined respectively and the FSHR polymorphism was detected by real time PCR assay. The results provided the preliminary evidence indicating the gene-environment interaction on HPO axis hormones in women. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  12. PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer

    NARCIS (Netherlands)

    Ling, G.; Ahmadian, A.; Persson, A.; Undén, A. B.; Afink, G.; Williams, C.; Uhlén, M.; Toftgård, R.; Lundeberg, J.; Pontén, F.

    2001-01-01

    It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer. We determined loss of heterozygosity in the patched and p53 loci as well as

  13. Nursing frequency alters circadian patterns of mammary gene expression in lactating mice

    Science.gov (United States)

    Milking frequency impacts lactation in dairy cattle and in rodent models of lactation. The role of circadian gene expression in this process is unknown. The hypothesis tested was that changing nursing frequency alters the circadian patterns of mammary gene expression. Mid-lactation CD1 mice were stu...

  14. Alterations in tumour suppressor gene p53 in human gliomas from ...

    Indian Academy of Sciences (India)

    Unknown

    Alterations in the tumour suppressor p53 gene are among the most common defects seen in a variety of human cancers. In order ... from Indian patients, we checked 44 untreated primary gliomas for mutations in exons 5–9 of the p53 gene by. PCR-SSCP ... function of p53 is critical to the efficiency of many cancer treatment ...

  15. Altered gene-expression profile in rat plasma and promoted body ...

    African Journals Online (AJOL)

    ... among which five GO annotations and four KEGG pathways were annotated. Findings indicate that EE during pregnancy could positively promote the body and nervous system development of offspring, involving the evidence for altered gene expression profile. Keywords: Environmental enrichment, rats, gene expression ...

  16. Alterations in tumour suppressor gene p53 in human gliomas from ...

    Indian Academy of Sciences (India)

    Alterations in the tumour suppressor p53 gene are among the most common defects seen in a variety of human cancers. In order to study the significance of the p53 gene in the genesis and development of human glioma from Indian patients, we checked 44 untreated primary gliomas for mutations in exons 5–9 of the p53 ...

  17. Specitic gene alterations in radiation-induced tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Joo Mee; Kang, Chang Mo; Lee, Seung Sook; Cho, Chul Koo; Bae, Sang Woo; Lee, Su Jae; Lee, Yun Sil [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2004-07-01

    To identify a set of genes involved in the development of radiation-induced tumorigenesis, we used DNA microarrays consisting of 1,176 mouse genes and compared expression profiles of radioresistant cells, designated NIH3T3-R1 and -R4. These cells were tumorigenic in a nude mouse grafting system, as compared to the parental NIH3T3 cells. Expressions of MDM2, CDK6 and CDC25B were found to increase more than 3-fold. Entactin protein levels were downregulated in NIH3T3-R1 and -R4 cells. Changes in expression genes were confirmed by reverse transcription-PCR or western blotting. When these genes were transfected to NIH3T3 cells, the CDC25B and MDM2 overexpressing NIH3T3 cells showed radioresistance, while 2 CDK6 overexpressing cells did not. In the case of entactin overexpressing NIH3T3-R1 or R-4 cells were still radioresistant. Furthermore, the CDC25B and MDM2 overexpressing cells grafted to nude mice, were tumorigenic. NIH3T3-R1 and R4 cells showed increased radiation-induced apoptosis, accompanied by faster growth rate, rather than and earlier radiation-induced G2/M phase arrest, suggesting that the radioresistance of NIH3T3-R1 and R4 cells was due to faster growth rate, rather than induction of apoptosis. In the case of MDM2 and CDC25B overexpressing cells, similar phenomena, such as increased apoptosis and faster growth rate, were shown. The above results, therefore, demonstrate involvement of CDC25B and MDM2 overexpression in radiation-induced tumorigenesis and provide novel targets for detection of radiation-induced carcinogenesis.

  18. Molecular characterization of 103 ovarian serous and mucinous tumors.

    Science.gov (United States)

    Vereczkey, Ildikó; Serester, Orsolya; Dobos, Judit; Gallai, Mónika; Szakács, Orsolya; Szentirmay, Zoltán; Tóth, Erika

    2011-09-01

    The pathogenesis of ovarian carcinomas is heterogeneous, with even the same entities showing great variance. In our study we investigated the mutations of the BRAF, KRAS, and p53 genes in serous and mucinous borderline tumors and in low grade and high grade serous and mucinous tumors. The mutations of BRAF and KRAS genes have been shown in 60% of borderline and low grade (well differentiated) serous and mucinous tumors, but very rarely in high grade (moderately and poorly differentiated) carcinomas. However mutations of p53 are very common in high grade tumors and this indicates a "dualistic" model of ovarian tumorigenesis. A total of 80 serous tumors, including serous borderline, low grade and high grade tumors, and 23 mucinous tumors, including borderline and invasive tumors were analysed for BRAF and KRAS mutations using real time PCR method followed by melting point analysis. P53 mutation was investigated by immunohistochemistry. We assumed mutation of the p53 gene when 100% of tumor cells showed strong nuclear positivity. We observed differences in genetic alterations in the development of the low grade tumors and between low and high grade tumors too. In some bilateral or stage II-III cases we observed differences between the mutation status of the left and right ovarian tumors and between the primary tumor and its implants. In one case in a tumor with micropapillary pattern showing high grade nuclear atypia we could detect mutations in both KRAS and p53 genes. The majority of our mucinous ovarian tumor cases showed a KRAS mutation. We have not found mutations of the BRAF and p53 genes in these cases. We have found as have others, that there is a dualistic pathway of ovarian carcinogenesis. In the majority of cases, low grade epithelial tumors develop in a stepwise manner due to genetic alterations of the members of MAP-kinase pathway; however mutation of the p53 gene is the key event in the development of high grade tumors.

  19. Rapid Evolution of Ovarian-Biased Genes in the Yellow Fever Mosquito (Aedes aegypti).

    Science.gov (United States)

    Whittle, Carrie A; Extavour, Cassandra G

    2017-08-01

    Males and females exhibit highly dimorphic phenotypes, particularly in their gonads, which is believed to be driven largely by differential gene expression. Typically, the protein sequences of genes upregulated in males, or male-biased genes, evolve rapidly as compared to female-biased and unbiased genes. To date, the specific study of gonad-biased genes remains uncommon in metazoans. Here, we identified and studied a total of 2927, 2013, and 4449 coding sequences (CDS) with ovary-biased, testis-biased, and unbiased expression, respectively, in the yellow fever mosquito Aedes aegypti The results showed that ovary-biased and unbiased CDS had higher nonsynonymous to synonymous substitution rates (dN/dS) and lower optimal codon usage (those codons that promote efficient translation) than testis-biased genes. Further, we observed higher dN/dS in ovary-biased genes than in testis-biased genes, even for genes coexpressed in nonsexual (embryo) tissues. Ovary-specific genes evolved exceptionally fast, as compared to testis- or embryo-specific genes, and exhibited higher frequency of positive selection. Genes with ovary expression were preferentially involved in olfactory binding and reception. We hypothesize that at least two potential mechanisms could explain rapid evolution of ovary-biased genes in this mosquito: (1) the evolutionary rate of ovary-biased genes may be accelerated by sexual selection (including female-female competition or male-mate choice) affecting olfactory genes during female swarming by males, and/or by adaptive evolution of olfactory signaling within the female reproductive system ( e.g. , sperm-ovary signaling); and/or (2) testis-biased genes may exhibit decelerated evolutionary rates due to the formation of mating plugs in the female after copulation, which limits male-male sperm competition. Copyright © 2017 by the Genetics Society of America.

  20. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Iversen, Edwin S; Tyrer, Jonathan

    2015-01-01

    genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association...

  1. The altered promoter methylation of oxytocin receptor gene in autism.

    Science.gov (United States)

    Elagoz Yuksel, Mine; Yuceturk, Betul; Karatas, Omer Faruk; Ozen, Mustafa; Dogangun, Burak

    Autism spectrum disorder (ASD) is one of the lifelong existing disorders. Abnormal methylation status of gene promoters of oxytonergic system has been implicated as among the etiologic factors of ASDs. We, therefore, investigated the methylation frequency of oxytocin receptor gene (OXTR) promoter from peripheral blood samples of children with autistic features. Our sample includes 66 children in total (22-94 months); 27 children with ASDs according to the DSM-IV-TR and the Childhood Autism Rating Scale (CARS) and 39 children who do not have any autistic like symptoms as the healthy control group. We investigated the DNA methylation status of OXTR promoter by methylation specific enzymatic digestion of genomic DNA and polymerase chain reaction. A significant relationship has been found between ASDs and healthy controls for the reduction of methylation frequency of the regions MT1 and MT3 of OXTR. We could not find any association in the methylation frequency of MT2 and MT4 regions of OXTR. Although our findings indicate high frequency of OXTR promoter hypomethylation in ASDs, there is need for independent replication of the results for a bigger sample set. We expect that future studies with the inclusion of larger, more homogeneous samples will attempt to disentangle the causes of ASDs.

  2. Novel functional MAR elements of double minute chromosomes in human ovarian cells capable of enhancing gene expression.

    Directory of Open Access Journals (Sweden)

    Yan Jin

    Full Text Available Double minute chromosomes or double minutes (DMs are cytogenetic hallmarks of extrachromosomal genomic amplification and play a critical role in tumorigenesis. Amplified copies of oncogenes in DMs have been associated with increased growth and survival of cancer cells but DNA sequences in DMs which are mostly non-coding remain to be characterized. Following sequencing and bioinformatics analyses, we have found 5 novel matrix attachment regions (MARs in a 682 kb DM in the human ovarian cancer cell line, UACC-1598. By electrophoretic mobility shift assay (EMSA, we determined that all 5 MARs interact with the nuclear matrix in vitro. Furthermore, qPCR analysis revealed that these MARs associate with the nuclear matrix in vivo, indicating that they are functional. Transfection of MARs constructs into human embryonic kidney 293T cells showed significant enhancement of gene expression as measured by luciferase assay, suggesting that the identified MARS, particularly MARs 1 to 4, regulate their target genes in vivo and are potentially involved in DM-mediated oncogene activation.

  3. Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients.

    Science.gov (United States)

    Manguoğlu, Esra; Güran, Sefik; Yamaç, Deniz; Colak, Taner; Simşek, Mehmet; Baykara, Mehmet; Akaydın, Mustafa; Lüleci, Güven

    2010-12-01

    Distribution and prevalence of germline mutations in BRCA1 and BRCA2 differ among different populations. For the Turkish population, several studies have addressed high-risk breast cancer and ovarian cancer (BC-OC) patients. In most studies, both genes were analyzed in part, and a quite heterogeneous mutation spectrum was observed. For high-risk Turkish prostate cancer (PCa) patients, however, there are no data available about mutations of germline BRCA genes. To accurately determine the contribution of germline mutations in BRCA1 and BRCA2 in Turkish BC, OC, and PCa high-risk patients, 106 high-risk BC-OC patients, 50 high-risk PCa patients, and 50 control subjects were recruited. The study represents the only full screening, to date, of a large series of Turkish high-risk BC-OC patients and the only study in Turkish high-risk PCa patients. Mutation screenings were performed on coding exons of both genes with either denaturing gradient gel electrophoresis or denaturing high performance liquid chromatography, or with both techniques. Three deleterious mutations in BRCA1 and three deleterious mutations in BRCA2 were detected in different BC-OC patients, and one truncating mutation was detected in a high-risk PCa patient. In addition, 28 different unclassified and mostly novel variants were detected in both genes, as well as several silent polymorphisms. These findings reflect the genetic heterogeneity of the Turkish population and are relevant to genetic counseling and clinical management. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Methoxychlor induces atresia by altering Bcl2 factors and inducing caspase activity in mouse ovarian antral follicles in vitro

    Science.gov (United States)

    Basavarajappa, Mallikarjuna S.; Karman, Bethany N.; Wang, Wei; Gupta, Rupesh K.; Flaws, Jodi A.

    2012-01-01

    Methoxychlor (MXC) is an organochlorine pesticide widely used in many countries against various species of insects that attack crops and domestic animals. MXC reduces fertility by increasing atresia (death) of antral follicles in vivo. MXC also induces atresia of antral follicles after 96 h in vitro. The current work tested the hypothesis that MXC induces morphological atresia at early time points (24 and 48 h) by altering pro-apoptotic (Bax, Bok, Casp3, and caspase activity) and anti-apoptotic (Bcl2 and Bcl-xL) factors in the follicles. The results indicate that at 24 h, MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax/Bcl2. At 48–96 h, MXC induced morphological atresia. At 24–96 h, MXC increased caspase activities. These data suggest that MXC may induce atresia by altering Bcl2 factors and inducing caspase activities in antral follicles. PMID:23000595

  5. Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”

    Science.gov (United States)

    Chen, Xiaoqing; Macgregor, Stuart; Duffy, David L.; Spurdle, Amanda B.; deFazio, Anna; Gava, Natalie; Webb, Penelope M.; Rossing, Mary Anne; Doherty, Jennifer Anne; Goodman, Marc T.; Lurie, Galina; Thompson, Pamela J.; Wilkens, Lynne R.; Ness, Roberta B.; Moysich, Kirsten B.; Chang-Claude, Jenny; Wang-Gohrke, Shan; Cramer, Daniel W.; Terry, Kathryn L.; Hankinson, Susan E.; Tworoger, Shelley S.; Garcia-Closas, Montserrat; Yang, Hannah; Lissowska, Jolanta; Chanock, Stephen J.; Pharoah, Paul D.; Song, Honglin; Whitemore, Alice S.; Pearce, Celeste L.; Stram, Daniel O.; Wu, Anna H.; Pike, Malcolm C.; Gayther, Simon A.; Ramus, Susan J.; Menon, Usha; Gentry-Maharaj, Aleksandra; Anton-Culver, Hoda; Ziogas, Argyrios; Hogdall, Estrid; Kjaer, Susanne K.; Hogdall, Claus; Berchuck, Andrew; Schildkraut, Joellen M.; Iversen, Edwin S.; Moorman, Patricia G.; Phelan, Catherine M.; Sellers, Thomas A.; Cunningham, Julie M.; Vierkant, Robert A.; Rider, David N.; Goode, Ellen L.; Haviv, Izhak; Chenevix-Trench, Georgia

    2010-01-01

    We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with P per-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. P per-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (P per-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus. PMID:20628624

  6. Altered phenotypes in plants transformed with chimeric tobacco peroxidase genes

    Energy Technology Data Exchange (ETDEWEB)

    Lagrimini, L.M.

    1990-12-31

    Peroxidases have been implicated in a variety of secondary metabolic reactions including lignification, cross-linking of cell wall polysaccharides, oxidation of indole-3-acetic acid, regulation of cell elongation, wound-healing, phenol oxidation, and pathogen defense. However, due to the many different isoenzymes and even more potential substrates, it has proven difficult to verify actual physiological roles for peroxidase. We are studying the molecular biology of the tobacco peroxidase genes, and have utilized genetic engineering techniques to produce transgenic plants which differ only in their expression of an individual peroxidase isoenzyme. Many of the in planta functions for any individual isoenzyme may be predicted through the morphological and physiological analysis of transformed plants.

  7. Altered phenotypes in plants transformed with chimeric tobacco peroxidase genes

    Energy Technology Data Exchange (ETDEWEB)

    Lagrimini, L.M.

    1990-01-01

    Peroxidases have been implicated in a variety of secondary metabolic reactions including lignification, cross-linking of cell wall polysaccharides, oxidation of indole-3-acetic acid, regulation of cell elongation, wound-healing, phenol oxidation, and pathogen defense. However, due to the many different isoenzymes and even more potential substrates, it has proven difficult to verify actual physiological roles for peroxidase. We are studying the molecular biology of the tobacco peroxidase genes, and have utilized genetic engineering techniques to produce transgenic plants which differ only in their expression of an individual peroxidase isoenzyme. Many of the in planta functions for any individual isoenzyme may be predicted through the morphological and physiological analysis of transformed plants.

  8. Alterations in the hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-adrenal axes in athletic women.

    Science.gov (United States)

    Loucks, A B; Mortola, J F; Girton, L; Yen, S S

    1989-02-01

    The functional integrity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes was assessed by determining pulsatile LH, ACTH, and cortisol secretion during the early follicular phase in athletic women with regular menstrual cycles (CA; n = 9), athletic women with amenorrhea (AA; n = 9), and regularly cyclic sedentary women (CS; n = 8). The CA and AA women were not significantly different in body composition, exercise training, psychometric tests, or dietary consumption. The CA women had shorter luteal phases (P less than 0.05) and lower urinary excretion of pregnanediol glucuronide than the CS women. In the AA women, urinary estrone glucuronide, pregnanediol glucuronide, and LH excretion were low throughout a 30-day period. The CA women had a 24-h pattern of pulsatile LH secretion characterized by reduced frequency (P less than 0.05) and increased amplitude (P less than 0.05), yielding an overall increased 24-h mean level (P less than 0.05), but interpulse intervals similar to those in the CS women. During sleep, LH pulse frequency slowed in the CS and CA women, while pulse amplitude increased and the mean serum LH level decreased in both groups. The AA women had even fewer pulses (P less than 0.05) of normal amplitude occurring at much more variable (P less than 0.01) interpulse intervals. Sleep-associated changes in LH pulsatility were absent. Responses to a 10-microgram bolus GnRH dose revealed blunted (P less than 0.05) FSH release in CA and augmented (P less than 0.05) LH release in AA women. The groups did not differ in any 24-h ACTH pulse pattern parameter or in cortisol pulse frequencies. Yet, early morning (0200-0800 h) serum cortisol levels were higher (P less than 0.05) in both groups of athletes, and this elevation was extended through the day (0800-2000 h; P less than 0.001) and evening (2000-0200 h; P less than 0.05) in the AA women. The plasma ACTH and serum cortisol responses to bolus human CRH administration were blunted in

  9. Long non-coding RNA TUG1 regulates ovarian cancer proliferation and metastasis via affecting epithelial-mesenchymal transition.

    Science.gov (United States)

    Kuang, Defeng; Zhang, Xiaoping; Hua, Shaofang; Dong, Wei; Li, Zhiguo

    2016-10-01

    Ovarian cancer is the fifth leading cause of cancer-related death in women worldwide, and recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in cancer development. However, the role of lncRNAs in ovarian cancer is largely unclear. In this study, we focused on the taurine up-regulated gene 1 (TUG1) and examined its molecular mechanism in ovarian cancer. Here, we reported that TUG1 was up-regulated in ovarian cancer tissues and ovarian cancer cells, and TUG1 expression was positively correlated with tumor grade and FIGO stage. In vitro functional assays (CCK-8 assay, colony formation assay, and cell invasion assay) revealed that knock-down of TUG1 by small RNA inference significantly inhibited cell proliferation, colony formation and cell invasion in ovarian cancer cells. Further experiment showed that knock-down of TUG1 induced cell apoptosis and altered the protein expression levels of apoptosis-related mediators in ovarian cancer cells. More importantly, knock-down of TUG1 also reversed epithelial-mesenchymal transition in ovarian cancer. In summary, our results suggest that knock-down of TUG1 may represent a novel therapeutic strategy for the treatment of ovarian cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Cisplatin-induced apoptosis and p53 gene status in a cisplatin-resistant human ovarian carcinoma cell line.

    Science.gov (United States)

    Fajac, A; Da Silva, J; Ahomadegbe, J C; Rateau, J G; Bernaudin, J F; Riou, G; Bénard, J

    1996-09-27

    Cisplatin-induced apoptosis and p53 gene status were analyzed in human ovarian carcinoma using a parental IGR-OV1 line and a derived cisplatin-resistant IGR-OV1/DDP subline. Compared with parental cells, cisplatin-resistant cells exhibited a 5-fold higher resistance index and a 2-fold longer doubling time. Cisplatin induced apoptosis in both cell lines, as assessed by cell morphology and the presence of a DNA ladder. However, high concentrations were necessary to induce apoptosis in resistant cells. These cells elicited a 5-fold decrease in the number of platinum atoms bound per nucleotide. IGR-OV1/DDP cells also exhibited enhanced drug efflux and a higher glutathione content. Our data suggest that the levels of cisplatin-DNA lesions are critical for drug sensitivity and apoptosis induction in this in vitro ovarian carcinoma model. Comparative analysis of the p53 gene in sensitive and resistant cells revealed the presence of the same heterozygous mutation in exon 5. A 2-fold increase in p53 mRNA and protein amounts was observed in resistant cells as assessed by Northern and Western blots, respectively. Immunocytochemical staining revealed a higher percentage of p53 stained nuclei in resistant cells. RT-PCR analysis of p53 transcripts showed that both wild-type and mutated alleles were transcribed in sensitive as well as in resistant cells. However, mutated transcripts were 1.5-fold more abundant than wild-type transcripts in sensitive cells, whereas they were 2-fold higher in resistant cells. In addition, mdm-2 protein was over-expressed in resistant cells. Our results address the question of the functionality of p53 protein and its possible role in apoptosis induction in this model. In resistant cells, p53 protein might be inactivated by 2 mechanisms: mutation and complexation with mdm-2 protein. Therefore, the presence of non-functional p53 in resistant cells might be involved in the relative failure of cisplatin-induced apoptosis in these cells.

  11. BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.

    Directory of Open Access Journals (Sweden)

    Harriet E Feilotter

    Full Text Available The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.

  12. Alterations in radioresistance of eucaryotic cells after the transfer of genomic wildtype DNA and metallothionein genes

    International Nuclear Information System (INIS)

    Lohrer, H.

    1987-01-01

    The presented paper describes experiments concerning the alteration of radiosensitivity of eucaryotic cells after gene transfer. Ionizing radiation (γ- or X-ray) induces DNA single- or double strand breaks, which are religated by an unknown repair system. Repair deficient cells are highly sensitive to ionizing radiation. In the experiments described, cells from a patient with the heritable disease Ataxia telangiectasia were used as well as two X-ray sensitive CHO mutant cell lines. After gene transfer of an intact human DNA repair gene or a metallothionein gene the cells should regain radioresistance. (orig.) [de

  13. Cumulus cells gene expression profiling in terms of oocyte maturity in controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist.

    Science.gov (United States)

    Devjak, Rok; Fon Tacer, Klementina; Juvan, Peter; Virant Klun, Irma; Rozman, Damjana; Vrtačnik Bokal, Eda

    2012-01-01

    In in vitro fertilization (IVF) cycles controlled ovarian hyperstimulation (COH) is established by gonadotropins in combination with gonadotropin-releasing hormone (GnRH) agonists or antagonists, to prevent premature luteinizing hormone (LH) surge. The aim of our study was to improve the understanding of gene expression profile of cumulus cells (CC) in terms of ovarian stimulation protocol and oocyte maturity. We applied Affymetrix gene expression profiling in CC of oocytes at different maturation stages using either GnRH agonists or GnRH antagonists. Two analyses were performed: the first involved CC of immature metaphase I (MI) and mature metaphase II (MII) oocytes where 359 genes were differentially expressed, and the second involved the two GnRH analogues where no differentially expressed genes were observed at the entire transcriptome level. A further analysis of 359 differentially genes was performed, focusing on anti-Müllerian hormone receptor 2 (AMHR2), follicle stimulating hormone receptor (FSHR), vascular endothelial growth factor C (VEGFC) and serine protease inhibitor E2 (SERPINE2). Among other differentially expressed genes we observed a marked number of new genes connected to cell adhesion and neurotransmitters such as dopamine, glycine and γ-Aminobutyric acid (GABA). No differential expression in CC between the two GnRH analogues supports the findings of clinical studies where no significant difference in live birth rates between both GnRH analogues has been proven.

  14. Endocrine modulation, inhibition of ovarian development and hepatic alterations in rainbow trout exposed to polluted river water

    Energy Technology Data Exchange (ETDEWEB)

    Vigano, Luigi, E-mail: vigano@irsa.cnr.i [Water Research Institute, National Council of Research, Brugherio, Milan (Italy); Benfenati, Emilio [Mario Negri Institute, Laboratory of Environmental Chemistry and Toxicology, Milan (Italy); Bottero, Sergio; Cevasco, Alessandra; Monteverde, Martino; Mandich, Alberta [Department of Environmental, Experimental and Applied Biology, University of Genoa, Genoa (Italy)

    2010-12-15

    Under laboratory conditions, female rainbow trout were exposed to graded concentrations of water from the River Lambro, a polluted tributary of the River Po, and to the effluent of a large wastewater treatment plant which flows into the River Lambro. In field exposures, trout were held in cages in the River Po upstream and downstream from the confluence of the River Lambro. After 10-day (laboratory) and 30-day (laboratory and field) exposures, trout were examined for several chemical, biochemical and histological endpoints. The results indicated that exposure to complex mixtures of chemicals, including estrogen receptor agonists, aryl-hydrocarbon receptor agonists, and probably antiandrogens, had occurred. Exposure altered the plasma levels of 17{beta}-estradiol and testosterone, and some treatments also enhanced the activity of hepatic ethoxyresorufin O-deethylase. Gonadal histology showed varying levels of degenerative processes characterised by oocyte atresia, haemorrhages, melano-macrophage centres (MMCs), and oogonia proliferation. Liver histology showed less severe effects. - This study examined the progression of hormonal and gonadal alterations in female trout exposed to river water from an area known to affect resident fish species.

  15. Altered global gene expression profiles in human gastrointestinal epithelial Caco2 cells exposed to nanosilver

    Directory of Open Access Journals (Sweden)

    Saura C. Sahu

    Full Text Available Extensive consumer exposure to food- and cosmetics-related consumer products containing nanosilver is of public safety concern. Therefore, there is a need for suitable in vitro models and sensitive predictive rapid screening methods to assess their toxicity. Toxicogenomic profile showing subtle changes in gene expressions following nanosilver exposure is a sensitive toxicological endpoint for this purpose. We evaluated the Caco2 cells and global gene expression profiles as tools for predictive rapid toxicity screening of nanosilver. We evaluated and compared the gene expression profiles of Caco-2 cells exposed to 20 nm and 50 nm nanosilver at a concentration 2.5 μg/ml. The global gene expression analysis of Caco2 cells exposed to 20 nm nanosilver showed that a total of 93 genes were altered at 4 h exposure, out of which 90 genes were up-regulated and 3 genes were down-regulated. The 24 h exposure of 20 nm silver altered 15 genes in Caco2 cells, out of which 14 were up-regulated and one was down-regulated. The most pronounced changes in gene expression were detected at 4 h. The greater size (50 nm nanosilver at 4 h exposure altered more genes by more different pathways than the smaller (20 nm one. Metallothioneins and heat shock proteins were highly up-regulated as a result of exposure to both the nanosilvers. The cellular pathways affected by the nanosilver exposure is likely to lead to increased toxicity. The results of our study presented here suggest that the toxicogenomic characterization of Caco2 cells is a valuable in vitro tool for assessing toxicity of nanomaterials such as nanosilver. Keywords: Nanosilver, Silver nanoparticles, Nanoparticles, Toxicogenomics, DNA microarray, Global gene expression profiles, Caco2 cells

  16. Differential Regulation of Gene and Protein Expression by Zinc Oxide Nanoparticles in Hen's Ovarian Granulosa Cells: Specific Roles of Nanoparticles.

    Directory of Open Access Journals (Sweden)

    Yong Zhao

    Full Text Available Annually, tons and tons of zinc oxide nanoparticles (ZnO NPs are produced in the world. And they are applied in almost all aspects of our life. Their release from the products into environment may pose issue for human health. Although many studies have reported the adverse effects of ZnO NPs on organisms, little is known about the effects on female reproductive systems or the related mechanisms. Quantitative proteomics have not been applied although quantitative transcriptomics have been used in zinc oxide nanoparticles (ZnO NPs research. Genes are very important players however proteins are the real actors in the biological systems. By using hen's ovarian granulosa cells, it was found that ZnO-NP-5μg/ml and ZnSO4-10μg/ml treatments produced the same amount of intracellular Zn and resulted in similar cell growth inhibition. And NPs were found in the treated cells. However, ZnO-NP-5μg/ml specifically regulated the expression of genes and proteins compared with that in ZnSO4-10μg/ml treatment. For the first time, this investigation reports that intact NPs produce different impacts on the expression of genes and proteins involved in specific pathways compared to that by Zn2+. The findings enrich our knowledge for the molecular insights of zinc oxide nanoparticles effects on the female reproductive systems. This also may raise the health concern that ZnO NPs may adversely affect the female reproductive systems through regulation of specific signaling pathways.

  17. De novo transcriptome sequencing and comparative analysis to discover genes involved in ovarian maturity in Strongylocentrotus nudus.

    Science.gov (United States)

    Jia, Zhiying; Wang, Qiai; Wu, Kaikai; Wei, Zhenlin; Zhou, Zunchun; Liu, Xiaolin

    2017-09-01

    Strongylocentrotus nudus is an edible sea urchin, mainly harvested in China. Correlation studies indicated that S. nudus with larger diameter have a prolonged marketing time and better palatability owing to their precocious gonads and extended maturation process. However, the molecular mechanism underlying this phenomenon is still unknown. Here, transcriptome sequencing was applied to study the ovaries of adult S. nudus with different shell diameters to explore the possible mechanism. In this study, four independent cDNA libraries were constructed, including two from the big size urchins and two from the small ones using a HiSeq™2500 platform. A total of 88,581 unigenes were acquired with a mean length of 1354bp, of which 66,331 (74.88%) unigenes could be annotated using six major publicly available databases. Comparative analysis revealed that 353 unigenes were differentially expressed (with log2(ratio)≥1, FDR≤0.001) between the two groups. Of these, 20 differentially expressed genes (DEGs) were selected to confirm the accuracy of RNA-seq data by quantitative real-time RT-PCR. Furthermore, gene ontology and KEGG pathway enrichment analyses were performed to find the putative genes and pathways related to ovarian maturity. Eight unigenes were identified as significant DEGs involved in reproduction related pathways; these included Mos, Cdc20, Rec8, YP30, cytochrome P450 2U1, ovoperoxidase, proteoliaisin, and rendezvin. Our research fills the gap in the studies on the S. nudus ovaries using transcriptome analysis. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

    DEFF Research Database (Denmark)

    Jim, Heather S L; Lin, Hui-Yi; Tyrer, Jonathan P

    2015-01-01

    Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovari...

  19. Altered Clock and Lipid Metabolism-Related Genes in Atherosclerotic Mice Kept with Abnormal Lighting Condition

    Directory of Open Access Journals (Sweden)

    Zhu Zhu

    2016-01-01

    Full Text Available Background. The risk of atherosclerosis is elevated in abnormal lipid metabolism and circadian rhythm disorder. We investigated whether abnormal lighting condition would have influenced the circadian expression of clock genes and clock-controlled lipid metabolism-related genes in ApoE-KO mice. Methods. A mouse model of atherosclerosis with circadian clock genes expression disorder was established using ApoE-KO mice (ApoE-KO LD/DL mice by altering exposure to light. C57 BL/6J mice (C57 mice and ApoE-KO mice (ApoE-KO mice exposed to normal day and night and normal diet served as control mice. According to zeitgeber time samples were acquired, to test atheromatous plaque formation, serum lipids levels and rhythmicity, clock genes, and lipid metabolism-related genes along with Sirtuin 1 (Sirt1 levels and rhythmicity. Results. Atherosclerosis plaques were formed in the aortic arch of ApoE-KO LD/DL mice. The serum lipids levels and oscillations in ApoE-KO LD/DL mice were altered, along with the levels and diurnal oscillations of circadian genes, lipid metabolism-associated genes, and Sirt1 compared with the control mice. Conclusions. Abnormal exposure to light aggravated plaque formation and exacerbated disorders of serum lipids and clock genes, lipid metabolism genes and Sirt1 levels, and circadian oscillation.

  20. Alteration of the retinoblastoma gene locus in radium-exposed individuals

    International Nuclear Information System (INIS)

    Hardwick, J.P.; Schlenker, R.; Huberman, E.

    1991-01-01

    This study was performed to determine if the retinoblastoma suppressor gene was altered in individuals exposed to radium. We analyzed the Rb gene in 30 individuals, 17 of whom were exposed to radium either occupationally or iatrogenically. In the kidney DNA from four of nine radium-exposed individuals, the Rb gene was deleted. Three of these alterations in the Rb gene were internal deletions, which resulted in the absence of Rb mRNA accumulation. These results imply that the Rb gene is susceptible to radium-induced damage and confirm previous showing that radiation preferentially causes genomic deletions. The pronounced alterations in the non-tumorigenic femurs from radium-exposed individuals suggests that in the many years of exposure there was a selection of cells with alterations, presumably because of their growth advantage. Also it implies that deletions of one of the Rb alleles can be one of the events (perhaps an initial one) in the progression of radium-induced sarcomas. 11 refs., 2 figs

  1. Premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Vujović Svetlana

    2012-01-01

    Full Text Available Premature ovarian failure (POF is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc. The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone, karyotype (<30 years of age, ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc.

  2. Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer.

    Science.gov (United States)

    Trujillano, Daniel; Weiss, Maximilian E R; Schneider, Juliane; Köster, Julia; Papachristos, Efstathios B; Saviouk, Viatcheslav; Zakharkina, Tetyana; Nahavandi, Nahid; Kovacevic, Lejla; Rolfs, Arndt

    2015-03-01

    Genetic testing for hereditary breast and/or ovarian cancer mostly relies on laborious molecular tools that use Sanger sequencing to scan for mutations in the BRCA1 and BRCA2 genes. We explored a more efficient genetic screening strategy based on next-generation sequencing of the BRCA1 and BRCA2 genes in 210 hereditary breast and/or ovarian cancer patients. We first validated this approach in a cohort of 115 samples with previously known BRCA1 and BRCA2 mutations and polymorphisms. Genomic DNA was amplified using the Ion AmpliSeq BRCA1 and BRCA2 panel. The DNA Libraries were pooled, barcoded, and sequenced using an Ion Torrent Personal Genome Machine sequencer. The combination of different robust bioinformatics tools allowed detection of all previously known pathogenic mutations and polymorphisms in the 115 samples, without detecting spurious pathogenic calls. We then used the same assay in a discovery cohort of 95 uncharacterized hereditary breast and/or ovarian cancer patients for BRCA1 and BRCA2. In addition, we describe the allelic frequencies across 210 hereditary breast and/or ovarian cancer patients of 74 unique definitely and likely pathogenic and uncertain BRCA1 and BRCA2 variants, some of which have not been previously annotated in the public databases. Targeted next-generation sequencing is ready to substitute classic molecular methods to perform genetic testing on the BRCA1 and BRCA2 genes and provides a greater opportunity for more comprehensive testing of at-risk patients. Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  3. Increased COX-2 expression in patients with ovarian cancer | Lin ...

    African Journals Online (AJOL)

    The pathogenesis of ovarian cancer remains poorly understood. Genome-wide gene expression profiling can provide novel genetic data involved in the pathogenesis of disease. In this study, using normal ovarian surface epithelium and abnormal ovarian surface epithelium of patients with ovarian cancer as models for ...

  4. Global differential gene expression in response to growth temperature alteration in group A Streptococcus.

    Science.gov (United States)

    Smoot, L M; Smoot, J C; Graham, M R; Somerville, G A; Sturdevant, D E; Migliaccio, C A; Sylva, G L; Musser, J M

    2001-08-28

    Pathogens are exposed to different temperatures during an infection cycle and must regulate gene expression accordingly. However, the extent to which virulent bacteria alter gene expression in response to temperatures encountered in the host is unknown. Group A Streptococcus (GAS) is a human-specific pathogen that is responsible for illnesses ranging from superficial skin infections and pharyngitis to severe invasive infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. GAS survives and multiplies at different temperatures during human infection. DNA microarray analysis was used to investigate the influence of temperature on global gene expression in a serotype M1 strain grown to exponential phase at 29 degrees C and 37 degrees C. Approximately 9% of genes were differentially expressed by at least 1.5-fold at 29 degrees C relative to 37 degrees C, including genes encoding transporter proteins, proteins involved in iron homeostasis, transcriptional regulators, phage-associated proteins, and proteins with no known homologue. Relatively few known virulence genes were differentially expressed at this threshold. However, transcription of 28 genes encoding proteins with predicted secretion signal sequences was altered, indicating that growth temperature substantially influences the extracellular proteome. TaqMan real-time reverse transcription-PCR assays confirmed the microarray data. We also discovered that transcription of genes encoding hemolysins, and proteins with inferred roles in iron regulation, transport, and homeostasis, was influenced by growth at 40 degrees C. Thus, GAS profoundly alters gene expression in response to temperature. The data delineate the spectrum of temperature-regulated gene expression in an important human pathogen and provide many unforeseen lines of pathogenesis investigation.

  5. mRNA detection of tumor-rejection genes BAGE, GAGE, and MAGE in peritoneal fluid from patients with ovarian carcinoma as a potential diagnostic tool.

    Science.gov (United States)

    Hofmann, Manfred; Ruschenburg, Ilka

    2002-06-25

    It has been found that the members of the BAGE, MAGE, and GAGE gene families are expressed almost exclusively in neoplastic tissues. Normal tissues, except testis and placenta, are negative. Therefore, the expression of these genes may serve as a useful diagnostic marker in detecting malignant disease. The involvement of the serous cavities by malignant neoplasms has important therapeutic and prognostic implications. Accordingly, the diagnosis of peritoneal spread of ovarian carcinoma plays an important role for both initial and second-look staging procedures. In some patients, however, a definite diagnosis cannot be established by morphologic or immunocytologic examination alone. Detection of tumor specific gene expression may be a sensitive additional tool in these settings. The authors studied the gene expression observed in 44 ascites specimens. Gene expression was evaluated by reverse transcription-polymerase chain reaction analysis and sequencing. Of 44 ascites specimens, the expression of BAGE, MAGE-1, MAGE-3, and GAGE-1/2 was recognized in 17 specimens (63%), 2 specimens (7%), 8 specimens (30%), and 8 specimens (30%) with histologically proven ovarian carcinoma, respectively. Expression of the MAGE and GAGE genes was not observed in patients with nonneoplastic disease, whereas BAGE expression was seen in one patient with cirrhosis. These findings show that testing for BAGE, GAGE-1/2, MAGE-1, and MAGE-3 transcriptional activity in ascites specimens results in high sensitivity in diagnosing malignant ascites. Copyright 2002 American Cancer Society.

  6. CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine.

    Science.gov (United States)

    Ecke, Laurel E; Cleck, Jessica N; White, Peter; Schug, Jonathan; Mifflin, Lauren; Blendy, Julie A

    2011-09-01

    The neuronal circuitry underlying stress- and drug-induced reinstatement of cocaine-seeking has been relatively well characterized; however, less is known regarding the long-term molecular changes following cocaine administration that may promote future reinstatement. The transcription factor cAMP response element-binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned reward, suggesting that different molecular mechanisms may underlie these two types of reinstatement. To explore the relationship between this transcription factor and reinstatement, we utilized the place-conditioning paradigm to examine alterations in gene expression in the amygdala, a neural substrate critically involved in stress-induced reinstatement, following the development of cocaine reward and subsequent extinction. Our findings demonstrate that the amygdala transcriptome was altered by CREB deficiency more than by previous cocaine experience, with an over-representation of genes involved in the immune response. However, a subset of genes involved in stress and immune response demonstrated a drug×genotype interaction, indicating that cocaine produces different long-term alterations in gene expression depending on the presence or absence of CREB. This profile of gene expression in the context of addiction enhances our understanding of the long-term molecular changes that occur throughout the addiction cycle and identifies novel genes and pathways that might lead to the creation of better therapeutic agents.

  7. NF-Y activates genes of metabolic pathways altered in cancer cells.

    Science.gov (United States)

    Benatti, Paolo; Chiaramonte, Maria Luisa; Lorenzo, Mariangela; Hartley, John A; Hochhauser, Daniel; Gnesutta, Nerina; Mantovani, Roberto; Imbriano, Carol; Dolfini, Diletta

    2016-01-12

    The trimeric transcription factor NF-Y binds to the CCAAT box, an element enriched in promoters of genes overexpressed in tumors. Previous studies on the NF-Y regulome identified the general term metabolism as significantly enriched. We dissect here in detail the targeting of metabolic genes by integrating analysis of NF-Y genomic binding and profilings after inactivation of NF-Y subunits in different cell types. NF-Y controls de novo biosynthetic pathways of lipids, teaming up with the master SREBPs regulators. It activates glycolytic genes, but, surprisingly, is neutral or represses mitochondrial respiratory genes. NF-Y targets the SOCG (Serine, One Carbon, Glycine) and Glutamine pathways, as well as genes involved in the biosynthesis of polyamines and purines. Specific cancer-driving nodes are generally under NF-Y control. Altogether, these data delineate a coherent strategy to promote expression of metabolic genes fuelling anaerobic energy production and other anabolic pathways commonly altered in cancer cells.

  8. Altered gene expression in highly purified enterocytes from patients with active coeliac disease

    Directory of Open Access Journals (Sweden)

    Jackson John

    2008-08-01

    Full Text Available Abstract Background Coeliac disease is a multifactorial inflammatory disorder of the intestine caused by ingestion of gluten in genetically susceptible individuals. Genes within the HLA-DQ locus are considered to contribute some 40% of the genetic influence on this disease. However, information on other disease causing genes is sparse. Since enterocytes are considered to play a central role in coeliac pathology, the aim of this study was to examine gene expression in a highly purified isolate of these cells taken from patients with active disease. Epithelial cells were isolated from duodenal biopsies taken from five coeliac patients with active disease and five non-coeliac control subjects. Contaminating T cells were removed by magnetic sorting. The gene expression profile of the cells was examined using microarray analysis. Validation of significantly altered genes was performed by real-time RT-PCR and immunohistochemistry. Results Enterocyte suspensions of high purity (98–99% were isolated from intestinal biopsies. Of the 3,800 genes investigated, 102 genes were found to have significantly altered expression between coeliac disease patients and controls (p Conclusion This study provides a profile of the molecular changes that occur in the intestinal epithelium of coeliac patients with active disease. Novel candidate genes were revealed which highlight the contribution of the epithelial cell to the pathogenesis of coeliac disease.

  9. Copy Number Alterations in Enzyme-Coding and Cancer-Causing Genes Reprogram Tumor Metabolism.

    Science.gov (United States)

    Sharma, Ashwini Kumar; Eils, Roland; König, Rainer

    2016-07-15

    Somatic copy number alterations frequently occur in the cancer genome affecting not only oncogenic or tumor suppressive genes, but also passenger and potential codriver genes. An intrinsic feature resulting from such genomic perturbations is the deregulation in the metabolism of tumor cells. In this study, we have shown that metabolic and cancer-causing genes are unexpectedly often proximally positioned in the chromosome and share loci with coaltered copy numbers across multiple cancers (19 cancer types from The Cancer Genome Atlas). We have developed an analysis pipeline, Identification of Metabolic Cancer Genes (iMetCG), to infer the functional impact on metabolic remodeling from such coamplifications and codeletions and delineate genes driving cancer metabolism from those that are neutral. Using our identified metabolic genes, we were able to classify tumors based on their tissue and developmental origins. These metabolic genes were similar to known cancer genes in terms of their network connectivity, isoform frequency, and evolutionary features. We further validated these identified metabolic genes by (i) using gene essentiality data from several tumor cell lines, (ii) showing that these identified metabolic genes are strong indicators for patient survival, and (iii) observing a significant overlap between our identified metabolic genes and known cancer-metabolic genes. Our analyses revealed a hitherto unknown generic mechanism for large-scale metabolic reprogramming in cancer cells based on linear gene proximities between cancer-causing and -metabolic genes. We have identified 119 new metabolic cancer genes likely to be involved in rewiring cancer cell metabolism. Cancer Res; 76(14); 4058-67. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. Microarray profiling for differential gene expression in PMSG-hCG stimulated preovulatory ovarian follicles of Chinese Taihu and Large White sows

    Directory of Open Access Journals (Sweden)

    Xiong Yuanzhu

    2011-02-01

    Full Text Available Abstract Background The Chinese Taihu is one of the most prolific pig breeds in the world, which farrows at least five more piglets per litter than Western pig breeds partly due to a greater ovulation rate. Variation of ovulation rate maybe associated with the differences in the transcriptome of Chinese Taihu and Large White ovaries. In order to understand the molecular basis of the greater ovulation rate of Chinese Taihu sows, expression profiling experiments were conducted to identify differentially expressed genes in ovarian follicles at the preovulatory stage of a PMSG-hCG stimulated estrous cycle from 3 Chinese Taihu and 3 Large White cycling sows by using the Affymetrix Porcine Genechip™. Results One hundred and thirty-three differentially expressed genes were identified between Chinese Taihu and Large White sows by using Affymetrix porcine GeneChip (p ≤ 0.05, Fold change ≥ 2 or ≤ 0.5. Gene Ontology (GO analysis revealed that these genes belonged to the class of genes that participated in regulation of cellular process, regulation of biological process, biological regulation, developmental process, cell communication and signal transduction and so on. Significant differential expression of 6 genes including WNT10B and DKK2 in the WNT signaling pathway was detected. Real-time RT-PCR confirmed the expression pattern in seven of eight selected genes. A search of chromosomal location revealed that 92 differentially expressed transcripts located to the intervals of quantitative trait loci (QTLs for reproduction traits. Furthermore, SNPs of two differentially expressed genes- BAX and BMPR1B were showed to be associated with litter size traits in Large White pigs and Chinese DIV line pigs (p ≤ 0.1 or p ≤ 0.05. Conclusions Our study detected many genes that showed differential expression between ovary follicles of two divergent breeds of pigs. Genes involved with regulation of cellular process, regulation of biological process, in

  11. Impact of hormonal modulation at proestrus on ovarian responses and uterine gene expression of suckled anestrous beef cows

    Directory of Open Access Journals (Sweden)

    Manoel Francisco de Sá Filho

    2017-11-01

    Full Text Available Abstract Background This study evaluated the impact of hormonal modulation at the onset of proestrus on ovarian response and uterine gene expression of beef cows. Methods A total of 172 anestrous beef cows were assigned to one of four groups according to the treatment with estradiol cypionate (ECP and/or equine chorionic gonadotropin (eCG [CON (n = 43, ECP (n = 43, eCG (n = 44 and ECP + eCG (n = 42]. Results ECP-treated cows (ECP and ECP + eCG groups presented greater occurrence of estrus (44.6% vs. 65.4%; P = 0.01 and pregnancy per AI [47.1% vs. 33.3%; P = 0.07], but similar progesterone (P4 concentration at subsequent diestrus than cows not treated with ECP (CON and eCG groups. Nonetheless, eCG-treated cows (eCG and ECP + eCG groups presented larger follicle at timed AI (12.6 ± 0.3 vs. 13.5 ± 0.3 mm; P = 0.03, greater ovulation rate (96.5% vs. 82.6%; P = 0.008 and greater P4 concentration at d 6 (3.9 ± 0.2 vs. 4.8 ± 0.2 ng/mL; P = 0.001 than cows not treated with eCG (CON and ECP groups. Next, cows with a new corpus luteum 6 d after TAI were submitted to uterine biopsy procedure. Uterine fragments [CON (n = 6, ECP (n = 6] were analyzed by RNA-Seq and a total of 135 transcripts were differentially expressed between groups (73 genes up-regulated by ECP treatment. Subsequently, uterine samples were analyzed by qPCR (genes associated with cell proliferation. ECP treatment induced greater abundance of PTCH2 (P = 0.07 and COL4A1 (P = 0.02, whereas suppressed EGFR (P = 0.09 expression. Conversely, eCG treatment increased abundance of HB-EGF (P = 0.06, ESR2 (P = 0.09, and ITGB3 (P = 0.05, whereas it reduced transcription of ESR1 (P = 0.05. Collectively, supplementation with ECP or eCG at the onset of proestrous of anestrous beef cows influenced ovarian responses, global and specific endometrial gene expression. Conclusion Proestrus estradiol regulate the endometrial transcriptome, particularly

  12. Expressing yeast SAMdc gene confers broad changes in gene expression and alters fatty acid composition in tomato fruit.

    Science.gov (United States)

    Kolotilin, Igor; Koltai, Hinanit; Bar-Or, Carmiya; Chen, Lea; Nahon, Sahadia; Shlomo, Haviva; Levin, Ilan; Reuveni, Moshe

    2011-07-01

    Tomato (Solanum lycopersicum) fruits expressing a yeast S-adenosyl methionine decarboxylase (ySAMdc) gene under control of a ripening-induced promoter show altered phytonutrient content and broad changes in gene expression. Genome-wide transcriptional alterations in pericarp tissues of the ySAMdc-expressing fruits are shown. Consistent with the ySAMdc expression pattern from the ripening-induced promoter, very minor transcriptional alterations were detected at the mature green developmental stage. At the breaker and red stages, altered levels of numerous transcripts were observed with a general tendency toward upregulation in the transgenic fruits. Ontological analysis of up- and downregulated transcript groups revealed various affected metabolic processes, mainly carbohydrate and amino acid metabolism, and protein synthesis, which appeared to be intensified in the ripening transgenic fruits. Other functional ontological categories of altered transcripts represented signal transduction, transcription regulation, RNA processing, molecular transport and stress response, as well as metabolism of lipids, glycans, xenobiotics, energy, cofactors and vitamins. In addition, transcript levels of genes encoding structural enzymes for several biosynthetic pathways showed strong correlations to levels of specific metabolites that displayed altered levels in transgenic fruits. Increased transcript levels of fatty acid biosynthesis enzymes were accompanied by a change in the fatty acid profile of transgenic fruits, most notably increasing ω-3 fatty acids at the expense of other lipids. Thus, SAMdc is a prime target in manipulating the nutritional value of tomato fruits. Combined with analyses of selected metabolites in the overripe fruits, a model of enhanced homeostasis of the pericarp tissue in the polyamine-accumulating tomatoes is proposed. Copyright © Physiologia Plantarum 2011.

  13. Acceptance of, inclination for, and barriers in genetic testing for gene mutations that increase the risk of breast and ovarian cancers among female residents of Warsaw

    Directory of Open Access Journals (Sweden)

    Dominik Olejniczak

    2016-03-01

    Full Text Available Aim of the study : To check the degree of acceptance of, inclination for, and barriers in genetic testing for gene mutations that increase the risk of breast and ovarian cancers among female residents of Warsaw Material and methods : This study involved 562 women between 20 and 77 years of age, all of whom were patients visiting gynaecologists practising in clinics in the City of Warsaw. The studied population was divided into six age categories. The study method was a diagnostic poll conducted with the use of an original questionnaire containing 10 multiple-choice questions. Results: Nearly 70% of the women showed an interest in taking a test to detect predispositions to develop breast and ovarian cancer. More than 10% did not want to take such a test, while every fifth women was undecided. No statistically significant differences between the respondents’ willingness to pay and education were found (p = 0.05. The most frequent answer given by women in all groups was that the amount to pay was too high. Such an answer was given by 52.17% of women with primary education, 65.22% of women with vocational education, 58.61% of women with secondary education, and 41.62% of women with higher education. Conclusions : Women with a confirmed increased risk of developing breast and/or ovarian cancer due to inter alia the presence of BRCA1 and BRCA2 gene mutations should pay particular attention to 1 st and 2 nd level prophylaxis.

  14. Alterations in tumour suppressor gene p53 in human gliomas from ...

    Indian Academy of Sciences (India)

    Unknown

    [Phatak P, Selvi S K, Divya T, Hegde A S, Hegde S and Somasundaram K 2002 Alterations in tumour suppressor gene p53 in human gliomas from Indian patients; J. Biosci. 27 673–678]. 1. Introduction. Glioma, a neoplasm of neuroglial cells, is the most common type of brain tumour, constituting more than 50% of all.

  15. Influence of ovarian hormones on development of ingestive responding to alterations in fatty acid oxidation in female rats

    Science.gov (United States)

    Swithers, Susan E.; McCurley, Melissa; Hamilton, Erica; Doerflinger, Alicia

    2008-01-01

    Adult male rats have been demonstrated to increase food intake in response to administration of drugs that interfere with oxidation of fatty acids (e.g. methyl palmoxirate and mercaptoacetate [MA]), effects that are larger in animals maintained on a high-fat diet. In contrast, while administration of MA has been reported to stimulate food intake in pre-pubertal female rats, food intake is not stimulated by MA in adult female rats. Instead, administration of MA to adult females results in changes in reproductive behavior and physiology. The present experiments were designed to examine the effects of administration of MA on food intake in adult female rats. The results demonstrated that, as previously reported, food intake was stimulated by MA in adult male rats on low-fat and high-fat diets, but food intake in was not stimulated by MA in gonadally-intact adult female rats on either low-fat or high-fat diet. Further, MA did not stimulate food intake in female rats ovariectomized as adults. However, when females were ovariectomized prior to the onset of puberty (postnatal day 25 – 28), food intake was stimulated by administration of MA in adulthood. Finally, cyclic injections of 17-β-estradiol benzoate given to females ovariectomized prior to the onset of puberty abolished the stimulatory effects of MA on food intake in adult females. Taken together, the data suggest that exposure to estrogens during the time of puberty in female rats can persistently alter adult ingestive responding to signals related to changes in energy utilization. PMID:18586247

  16. Risk of Ovarian Cancer and the NF-κB Pathway

    DEFF Research Database (Denmark)

    Charbonneau, Bridget; Block, Matthew S; Bamlet, William R

    2014-01-01

    participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P ovarian cancer (low malignant potential tumors OR, 0.......85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.......A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk...

  17. Alterations in the p53 pathway and prognosis in advanced ovarian cancer: a multi-factorial analysis of the EORTC Gynaecological Cancer group (study 55865)

    NARCIS (Netherlands)

    Green, J. A.; Berns, E. M. J. J.; Coens, C.; van Luijk, I.; Thompson-Hehir, J.; van Diest, P.; Verheijen, R. H. M.; van de Vijver, M.; van Dam, P.; Kenter, G. G.; Tjalma, W.; Ewing, P. C.; Teodorovic, I.; Vergote, I.; van der Burg, M. E. L.

    2006-01-01

    PURPOSE: The study was designed to determine independent prognostic variables in suboptimally debulked advanced ovarian cancer patients entered in the randomised phase III study EORTC 55865. EXPERIMENTAL DESIGN: Retrospectively collected paraffin blocks from 169 patients with stages IIb-IV

  18. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    DEFF Research Database (Denmark)

    Chornokur, Ganna; Lin, Hui-Yi; Tyrer, Jonathan P

    2015-01-01

    BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. ...... imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes....

  19. Screening for common mutations in BRCA1 and BRCA2 genes: interest in genetic testing of Tunisian families with breast and/or ovarian cancer.

    Science.gov (United States)

    Fourati, Asma; Louchez, Marie-Michèle; Fournier, Joelle; Gamoudi, Amor; Rahal, Khaled; El May, Michèle-Véronique; El May, Ahmed; Revillion, Françoise; Peyrat, Jean-Philippe

    2014-11-01

    In the Tunisian population, as yet a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer. These mutations are located in a few exons of BRCA1/2. The aim of the present study was to search for these mutations in 66 unrelated patients with hereditary breast and/or ovarian cancer in order to assess the interest in such a targeted approach for genetic testing in Tunisia. Blood specimens from the 66 Tunisian patients, with family history of breast and/or ovarian cancer, were collected at the Salah Azaiz Cancer Institute of Tunis. The exons 5, 20 and part of exon 11 of BRCA1 as well as part of exons 10 and 11 of BRCA2 were analyzed by Sanger sequencing. 12 patients had deleterious mutations in the BRCA1 or BRCA2 genes (18%), including a novel frame-shift mutation of BRCA1 (c.3751dup; 3780insT). Four distinct BRCA1 mutations were detected eight patients: c.5266dup (5382insC) and c.211dup (330insA) each in three patients, c.3751dup (3870insT) and c.4041_4042del (4160delAG) each in one patient. The four remaining cases all carried the same BRCA2 mutation, c.1310_1313del (1538delAAGA). Besides these deleterious mutations, eight polymorphisms and unclassified variants were detected, one of them being never reported (BRCA1c.3030T>G, p.Pro1010Pro). In this study, we show that targeting relevant exons in BRCA1 and BRCA2 genes allows detection of a substantial percentage of mutations in the Tunisian population. Therefore such an approach may be of interest in genetic testing of high-risk breast and ovarian cancer families in Tunisia.

  20. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

    NARCIS (Netherlands)

    Chornokur, G.; Lin, H.Y.; Tyrer, J.P.; Lawrenson, K.; Dennis, J.; Amankwah, E.K.; Qu, X.; Tsai, Y.Y.; Jim, H.S.; Chen, Z.; Chen, A.Y.; Permuth-Wey, J.; Aben, K.; Anton-Culver, H.; Antonenkova, N.; Bruinsma, F.; Bandera, E.V.; Bean, Y.T.; Beckmann, M.W.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bunker, C.H.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Bois, A. du; Despierre, E.; Dicks, E.; Doherty, J.A.; Dork, T.; Durst, M.; Easton, D.F.; Eccles, D.M.; Edwards, R.P.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goodman, M.T.; Gronwald, J.; Harrington, P.; Harter, P.; Hein, A.; Heitz, F.; Hildebrandt, M.A.T.; Hillemanns, P.; Hogdall, C.K.; Hogdall, E.; Hosono, S.; Jakubowska, A.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kelemen, L.E.; Kellar, M.; Kiemeney, L.A.L.M.; Krakstad, C.; Kjaer, S.K.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lim, B.K.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.A.G.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; McNeish, I.; Menon, U.; Milne, R.L.; Modugno, F.; Moysich, K.B.; Ness, R.B.; Nevanlinna, H.; Eilber, U.; Odunsi, K.; Olson, S.H.; Orlow, I., et al.

    2015-01-01

    BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As

  1. Infectivity enhanced adenoviral-mediated mda-7/IL-24 gene therapy for ovarian carcinoma

    NARCIS (Netherlands)

    Leath, CA; Kataram, M; Bhagavatula, P; Gopalkrishnan, RV; Dent, P; Fisher, PB; Pereboev, A; Carey, D; Lebedeva, [No Value; Haisma, HJ; Alvarez, RD; Curiel, DT; Mahasreshti, PJ

    Objective. Melanoma differentiation associated gene-7 [mda-7/interleukin (IL)-24] has been identified as a novel anti-cancer agent, which specifically induces apoptosis in cancer cells but not in normal epithelial, endothelial and fibroblast cells. The objective of this study was to evaluate the

  2. Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.

    Directory of Open Access Journals (Sweden)

    Heidi Marjonen

    Full Text Available The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v ethanol for the first 8 days of gestation (GD 0.5-8.5. Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60: we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in

  3. Genetic profiles distinguish different types of hereditary ovarian cancer

    DEFF Research Database (Denmark)

    Domanska, Katarina; Malander, Susanne; Staaf, Johan

    2010-01-01

    Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian canc...... that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer.......Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer...... (HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers...

  4. Mutation or Loss of p53 Differentially Modifies TGFβ Action in Ovarian Cancer

    Science.gov (United States)

    Ó hAinmhire, Eoghainín; Quartuccio, Suzanne M.; Cheng, Whay; Ahmed, Roshan A.; King, Shelby M.; Burdette, Joanna E.

    2014-01-01

    Ovarian cancer is the most lethal gynecological disease affecting women in the US. The Cancer Genome Atlas Network identified p53 mutations in 96% of high-grade serous ovarian carcinomas, demonstrating its critical role. Additionally, the Transforming Growth Factor Beta (TGFβ) pathway is dysfunctional in various malignancies, including ovarian cancer. This study investigated how expression of wild-type, mutant, or the absence of p53 alters ovarian cancer cell response to TGFβ signaling, as well as the response of the ovarian surface epithelium and the fallopian tube epithelium to TGFβ. Only ovarian cancer cells expressing wild-type p53 were growth inhibited by TGFβ, while ovarian cancer cells that were mutant or null p53 were not. TGFβ induced migration in p53 null SKOV3 cells, which was not observed in SKOV3 cells with stable expression of mutant p53 R273H. Knockdown of wild-type p53 in the OVCA 420 ovarian cancer cells enhanced cell migration in response to TGFβ. Increased protein expression of DKK1 and TMEPAI, two pro-invasive genes with enhanced expression in late stage metastatic ovarian cancer, was observed in p53 knockdown and null cells, while cells stably expressing mutant p53 demonstrated lower DKK1 and TMEPAI induction. Expression of mutant p53 or loss of p53 permit continued proliferation of ovarian cancer cell lines in the presence of TGFβ; however, cells expressing mutant p53 exhibit reduced migration and decreased protein levels of DKK1 and TMEPAI. PMID:24586866

  5. Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells

    International Nuclear Information System (INIS)

    Kalayda, Ganna V; Wagner, Christina H; Buß, Irina; Reedijk, Jan; Jaehde, Ulrich

    2008-01-01

    Copper homeostasis proteins ATP7A and ATP7B are assumed to be involved in the intracellular transport of cisplatin. The aim of the present study was to assess the relevance of sub cellular localisation of these transporters for acquired cisplatin resistance in vitro. For this purpose, localisation of ATP7A and ATP7B in A2780 human ovarian carcinoma cells and their cisplatin-resistant variant, A2780cis, was investigated. Sub cellular localisation of ATP7A and ATP7B in sensitive and resistant cells was investigated using confocal fluorescence microscopy after immunohistochemical staining. Co-localisation experiments with a cisplatin analogue modified with a carboxyfluorescein-diacetate residue were performed. Cytotoxicity of the fluorescent cisplatin analogue in A2780 and A2780cis cells was determined using an MTT-based assay. The significance of differences was analysed using Student's t test or Mann-Whitney test as appropriate, p values of < 0.05 were considered significant. In the sensitive cells, both transporters are mainly localised in the trans-Golgi network, whereas they are sequestrated in more peripherally located vesicles in the resistant cells. Altered localisation of ATP7A and ATP7B in A2780cis cells is likely to be a consequence of major abnormalities in intracellular protein trafficking related to a reduced lysosomal compartment in this cell line. Changes in sub cellular localisation of ATP7A and ATP7B may facilitate sequestration of cisplatin in the vesicular structures of A2780cis cells, which may prevent drug binding to genomic DNA and thereby contribute to cisplatin resistance. Our results indicate that alterations in sub cellular localisation of transport proteins may contribute to cisplatin resistance in vitro. Investigation of intracellular protein localisation in primary tumour cell cultures and tumour tissues may help to develop markers of clinically relevant cisplatin resistance. Detection of resistant tumours in patients may in turn

  6. Genetics Home Reference: ovarian cancer

    Science.gov (United States)

    ... single protein building blocks (amino acids) in the p53 protein, which reduces or eliminates the protein's tumor ... of the ovary malignant tumor of the ovary ovarian carcinoma Related Information How are genetic conditions and genes ...

  7. Cancer Risks Associated With Inherited Mutations in Ovarian Cancer Susceptibility Genes Beyond BRCA1 and BRCA2

    Science.gov (United States)

    2017-05-01

    5 5. Changes /Problems 6 6. Products 6 7. Participants & Other Collaborating Organizations 7 8. Appendices NA 1. INTRODUCTION Ovarian, peritoneal...TERMS Ovarian cancer, drug resistance , rucaparib, phase 2, DNA repair, homologous recombination, nonhomologous end-joining (NHEJ), poly(ADP-ribose...who were eager to send us AA patients at the time we proposed this study, the change in clinical testing has hampered our enrollment. Please see

  8. Altered expression of immune-related genes in children with Down syndrome.

    Directory of Open Access Journals (Sweden)

    Bruna Lancia Zampieri

    Full Text Available Individuals with Down syndrome (DS have a high incidence of immunological alterations with increased susceptibility to bacterial and viral infections and high frequency of different types of hematologic malignancies and autoimmune disorders. In the current study, we profiled the expression pattern of 92 immune-related genes in peripheral blood mononuclear cells (PBMCs of two different groups, children with DS and control children, to identify differentially expressed genes that might be of pathogenetic importance for the development and phenotype of the immunological alterations observed in individuals with DS. PBMCs samples were obtained from six DS individuals with karyotypically confirmed full trisomy 21 and six healthy control individuals (ages 2-6 years. Gene expression was profiled in duplicate according to the manufacturer's instructions provided by commercially available TaqMan Human Immune Array representing 92 immune function genes and four reference genes on a 96-plex gene card. A set of 17 differentially expressed genes, not located on chromosome 21 (HSA21, involved in immune and inflammatory pathways was identified including 13 genes (BCL2, CCL3, CCR7, CD19, CD28, CD40, CD40LG, CD80, EDN1, IKBKB, IL6, NOS2 and SKI significantly down-regulated and four genes (BCL2L1, CCR2, CCR5 and IL10 significantly up-regulated in children with DS. These findings highlight a list of candidate genes for further investigation into the molecular mechanism underlying DS pathology and reinforce the secondary effects of the presence of a third copy of HSA21.

  9. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility

    DEFF Research Database (Denmark)

    Permuth, Jennifer B; Reid, Brett; Earp, Madalene

    2016-01-01

    RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleo......, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing....

  10. Regulatory region of the vitellogenin receptor gene sufficient for high-level, germ line cell-specific ovarian expression in transgenic Aedes aegypti mosquitoes.

    Science.gov (United States)

    Cho, Kook-Ho; Cheon, Hyang-Mi; Kokoza, Vladimir; Raikhel, Alexander S

    2006-04-01

    Vitellogenin receptor (VgR) is responsible for the receptor-mediated endocytosis of vitellogenin (Vg) in the egg formation of an oviparous animal, including insects. Little is known about regulation of VgR gene expression. We analyzed the upstream region of the VgR gene from Aedes aegypti (AaVgR) to identify regulatory elements responsible for its expression in germ cell-specific ovarian expression. Experiments with genetic transformation using the transgene containing the 1.5-Kb upstream portion of the AaVgR gene fused with DsRed and the piggyBac vector showed that this regulatory region is sufficient for correct female and ovary-specific expression of the transgene. This 1.5-Kb upstream region contained binding sites for the ecdysone regulatory hierarchy early gene products E74 and BR-C, as well as transcription factors determining correct tissue- and stage-specific expression of GATA and HNF3/fkh. In situ hybridization demonstrated that in the ovaries of transgenic females DsRed mRNA was present in ovarian germ cells and nurse cells of mature ovarian follicles, together with VgR mRNA. In contrast, DsRed mRNA was absent in the oocyte that had a high level of endogenous VgR mRNA. Although the 1.5-Kb upstream region was sufficient to drive a high-level germ line cell-specific expression of the reporter, additional signals were required for translocation of exogenous mRNA from nurse cells into the oocyte.

  11. Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk

    Science.gov (United States)

    Amankwah, Ernest K.; Lin, Hui-Yi; Tyrer, Jonathan P.; Lawrenson, Kate; Dennis, Joe; Chornokur, Ganna; Aben, Katja KH.; Anton-Culver, Hoda; Antonenkova, Natalia; Bruinsma, Fiona; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bunker, Clareann H.; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chen, Zhihua; Chen, Y. Ann; Chang-Claude, Jenny; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; du Bois, Andreas; Despierre, Evelyn; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; Dürst, Matthias; Easton, Douglas F.; Eccles, Diana M.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goodman, Marc T.; Gronwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis N.; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Claus K.; Hogdall, Estrid; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Jim, Heather; Kellar, Melissa; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lim, Boon Kiong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Ian; Menon, Usha; Milne, Roger L.; Modugno, Francesmary; Moysich, Kirsten B.; Ness, Roberta B.; Nevanlinna, Heli; Eilber, Ursula; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schernhammer, Eva; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Spiewankiewicz, Beata; Sucheston-Campbell, Lara; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Lotte; Tangen, Ingvild L.; Tworoger, Shelley S.; van Altena, Anne M.; Vierkant, Robert A.; Vergote, Ignace; Walsh, Christine S.; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wu, Anna H.; Wu, Xifeng; Woo, Yin-Ling; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Kelemen, Linda E.; Berchuck, Andrew; Schildkraut, Joellen M.; Ramus, Susan J.; Goode, Ellen L.; Monteiro, Alvaro N.A.; Gayther, Simon A.; Narod, Steven A.; Pharoah, Paul D. P.; Sellers, Thomas A.; Phelan, Catherine M.

    2016-01-01

    Introduction Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population. Methods We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant. Results In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. Conclusion These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC. PMID:26399219

  12. Di-(2 ethylhexyl phthalate and flutamide alter gene expression in the testis of immature male rats

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    Yu Frank H

    2009-09-01

    Full Text Available Abstract We previously demonstrated that the androgenic and anti-androgenic effects of endocrine disruptors (EDs alter reproductive function and exert distinct effects on developing male reproductive organs. To further investigate these effects, we used an immature rat model to examine the effects of di-(2 ethylhexyl phthalate (DEHP and flutamide (Flu on the male reproductive system. Immature male SD rats were treated daily with DEHP and Flu on postnatal days (PNDs 21 to 35, in a dose-dependent manner. As results, the weights of the testes, prostate, and seminal vesicle and anogenital distances (AGD decreased significantly in response to high doses of DEHP or Flu. Testosterone (T levels significantly decreased in all DEHP- treated groups, whereas luteinizing hormone (LH plasma levels were not altered by any of the two treatments at PND 36. However, treatment with DEHP or Flu induced histopathological changes in the testes, wherein degeneration and disorders of Leydig cells, germ cells and dilatation of tubular lumen were observed in a dose-dependent manner. Conversely, hyperplasia and denseness of Leydig, Sertoli and germ cells were observed in rats given with high doses of Flu. The results by cDNA microarray analysis indicated that 1,272 genes were up-regulated by more than two-fold, and 1,969 genes were down-regulated in response to DEHP, Flu or both EDs. These genes were selected based on their markedly increased or decreased expression levels. These genes have been also classified on the basis of gene ontology (e.g., steroid hormone biosynthetic process, regulation of transcription, signal transduction, metabolic process, biosynthetic process.... Significant decreases in gene expression were observed in steroidogenic genes (i.e., Star, Cyp11a1 and Hsd3b. In addition, the expression of a common set of target genes, including CaBP1, Vav2, Plcd1, Lhx1 and Isoc1, was altered following exposure to EDs, suggesting that they may be marker genes to

  13. Immunosenescence Is Associated With Altered Gene Expression And Epigenetic Regulation In Primary And Secondary Immune Organs

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    Corinne eSidler

    2013-10-01

    Full Text Available Deterioration of the immune system (immunosenescence with age is associated with an increased susceptibility to infection, autoimmune disease and cancer, and reduced responsiveness to vaccination. Immunosenescence entails a reduced supply of naïve T cells from the thymus and increased specialization of peripheral T cell clones. Both thymic involution and peripheral T cell homeostasis are thought to involve cellular senescence. In order to analyze this at the molecular level, we studied gene expression profiles, epigenetic status and genome stability in the thymus and spleen of 1-month, 4-month and 18-month-old Long Evans rats. In the thymus, altered gene expression, DNA and histone hypomethylation, increased genome instability and apoptosis were observed in 18-month-old animals compared to 1- and 4-month-old animals. In the spleen, alterations in gene expression and epigenetic regulation occurred already by the age of 4 months compared to 1 month and persisted in 18-month-old compared to 1-month-old rats. In both organs, these changes were accompanied by the altered composition of resident T cell populations. Our study suggests that both senescence and apoptosis may be involved in altered organ function.

  14. Transcription factors and stress response gene alterations in human keratinocytes following Solar Simulated Ultra Violet Radiation.

    Science.gov (United States)

    Marais, Thomas L Des; Kluz, Thomas; Xu, Dazhong; Zhang, Xiaoru; Gesumaria, Lisa; Matsui, Mary S; Costa, Max; Sun, Hong

    2017-10-19

    Ultraviolet radiation (UVR) from sunlight is the major effector for skin aging and carcinogenesis. However, genes and pathways altered by solar-simulated UVR (ssUVR), a mixture of UVA and UVB, are not well characterized. Here we report global changes in gene expression as well as associated pathways and upstream transcription factors in human keratinocytes exposed to ssUVR. Human HaCaT keratinocytes were exposed to either a single dose or 5 repetitive doses of ssUVR. Comprehensive analyses of gene expression profiles as well as functional annotation were performed at 24 hours post irradiation. Our results revealed that ssUVR modulated genes with diverse cellular functions changed in a dose-dependent manner. Gene expression in cells exposed to a single dose of ssUVR differed significantly from those that underwent repetitive exposures. While single ssUVR caused a significant inhibition in genes involved in cell cycle progression, especially G2/M checkpoint and mitotic regulation, repetitive ssUVR led to extensive changes in genes related to cell signaling and metabolism. We have also identified a panel of ssUVR target genes that exhibited persistent changes in gene expression even at 1 week after irradiation. These results revealed a complex network of transcriptional regulators and pathways that orchestrate the cellular response to ssUVR.

  15. Duration of chronic inflammation alters gene expression in muscle from untreated girls with juvenile dermatomyositis

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    Gordish-Dressman Heather

    2008-07-01

    Full Text Available Abstract Background To evaluate the impact of the duration of chronic inflammation on gene expression in skeletal muscle biopsies (MBx from untreated children with juvenile dermatomyositis (JDM and identify genes and biological processes associated with the disease progression, expression profiling data from 16 girls with active symptoms of JDM greater than or equal to 2 months were compared with 3 girls with active symptoms less than 2 months. Results Seventy-nine genes were differentially expressed between the groups with long or short duration of untreated disease. Genes involved in immune responses and vasculature remodelling were expressed at a higher level in muscle biopsies from children with greater or equal to 2 months of symptoms, while genes involved in stress responses and protein turnover were expressed at a lower level. Among the 79 genes, expression of 9 genes showed a significant linear regression relationship with the duration of untreated disease. Five differentially expressed genes – HLA-DQA1, smooth muscle myosin heavy chain, clusterin, plexin D1 and tenomodulin – were verified by quantitative RT-PCR. The chronic inflammation of longer disease duration was also associated with increased DC-LAMP+ and BDCA2+ mature dendritic cells, identified by immunohistochemistry. Conclusion We conclude that chronic inflammation alters the gene expression patterns in muscle of untreated children with JDM. Symptoms lasting greater or equal to 2 months were associated with dendritic cell maturation and anti-angiogenic vascular remodelling, directly contributing to disease pathophysiology.

  16. Genome wide transcriptome analysis of dendritic cells identifies genes with altered expression in psoriasis.

    Science.gov (United States)

    Filkor, Kata; Hegedűs, Zoltán; Szász, András; Tubak, Vilmos; Kemény, Lajos; Kondorosi, Éva; Nagy, István

    2013-01-01

    Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGE-Seq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with

  17. Comparison of gene expression profiles altered by comfrey and riddelliine in rat liver.

    Science.gov (United States)

    Guo, Lei; Mei, Nan; Dial, Stacey; Fuscoe, James; Chen, Tao

    2007-11-01

    Comfrey (Symphytum officinale) is a perennial plant and has been consumed by humans as a vegetable, a tea and an herbal medicine for more than 2000 years. It, however, is hepatotoxic and carcinogenic in experimental animals and hepatotoxic in humans. Pyrrolizidine alkaloids (PAs) exist in many plants and many of them cause liver toxicity and/or cancer in humans and experimental animals. In our previous study, we found that the mutagenicity of comfrey was associated with the PAs contained in the plant. Therefore, we suggest that carcinogenicity of comfrey result from those PAs. To confirm our hypothesis, we compared the expression of genes and processes of biological functions that were altered by comfrey (mixture of the plant with PAs) and riddelliine (a prototype of carcinogenic PA) in rat liver for carcinogenesis in this study. Groups of 6 Big Blue Fisher 344 rats were treated with riddelliine at 1 mg/kg body weight by gavage five times a week for 12 weeks or fed a diet containing 8% comfrey root for 12 weeks. Animals were sacrificed one day after the last treatment and the livers were isolated for gene expression analysis. The gene expressions were investigated using Applied Biosystems Rat Whole Genome Survey Microarrays and the biological functions were analyzed with Ingenuity Analysis Pathway software. Although there were large differences between the significant genes and between the biological processes that were altered by comfrey and riddelliine, there were a number of common genes and function processes that were related to carcinogenesis. There was a strong correlation between the two treatments for fold-change alterations in expression of drug metabolizing and cancer-related genes. Our results suggest that the carcinogenesis-related gene expression patterns resulting from the treatments of comfrey and riddelliine are very similar, and PAs contained in comfrey are the main active components responsible for carcinogenicity of the plant.

  18. Altered circadian rhythm and metabolic gene profile in rats subjected to advanced light phase shifts.

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    Laura Herrero

    Full Text Available The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT, brown adipose tissue (BAT and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level.

  19. Transfection of Sertoli cells with androgen receptor alters gene expression without androgen stimulation.

    Science.gov (United States)

    Fietz, D; Markmann, M; Lang, D; Konrad, L; Geyer, J; Kliesch, S; Chakraborty, T; Hossain, H; Bergmann, M

    2015-12-29

    Androgens play an important role for the development of male fertility and gained interest as growth and survival factors for certain types of cancer. Androgens act via the androgen receptor (AR/Ar), which is involved in various cell biological processes such as sex differentiation. To study the functional mechanisms of androgen action, cell culture systems and AR-transfected cell lines are needed. Transfection of AR into cell lines and subsequent gene expression analysis after androgen treatment is well established to investigate the molecular biology of target cells. However, it remains unclear how the transfection with AR itself can modulate the gene expression even without androgen stimulation. Therefore, we transfected Ar-deficient rat Sertoli cells 93RS2 by electroporation using a full length human AR. Transfection success was confirmed by Western Blotting, immunofluorescence and RT-PCR. AR transfection-related gene expression alterations were detected with microarray-based genome-wide expression profiling of transfected and non-transfected 93RS2 cells without androgen stimulation. Microarray analysis revealed 672 differentially regulated genes with 200 up- and 472 down-regulated genes. These genes could be assigned to four major biological categories (development, hormone response, immune response and metabolism). Microarray results were confirmed by quantitative RT-PCR analysis for 22 candidate genes. We conclude from our data, that the transfection of Ar-deficient Sertoli cells with AR has a measurable effect on gene expression even without androgen stimulation and cause Sertoli cell damage. Studies using AR-transfected cells, subsequently stimulated, should consider alterations in AR-dependent gene expression as off-target effects of the AR transfection itself.

  20. Shared Gene Expression Alterations in Nasal and Bronchial Epithelium for Lung Cancer Detection.

    Science.gov (United States)

    2017-07-01

    We previously derived and validated a bronchial epithelial gene expression biomarker to detect lung cancer in current and former smokers. Given that bronchial and nasal epithelial gene expression are similarly altered by cigarette smoke exposure, we sought to determine if cancer-associated gene expression might also be detectable in the more readily accessible nasal epithelium. Nasal epithelial brushings were prospectively collected from current and former smokers undergoing diagnostic evaluation for pulmonary lesions suspicious for lung cancer in the AEGIS-1 (n = 375) and AEGIS-2 (n = 130) clinical trials and gene expression profiled using microarrays. All statistical tests were two-sided. We identified 535 genes that were differentially expressed in the nasal epithelium of AEGIS-1 patients diagnosed with lung cancer vs those with benign disease after one year of follow-up ( P  cancer-associated gene expression alterations between the two airway sites ( P  lung cancer classifier derived in the AEGIS-1 cohort that combined clinical factors (age, smoking status, time since quit, mass size) and nasal gene expression (30 genes) had statistically significantly higher area under the curve (0.81; 95% confidence interval [CI] = 0.74 to 0.89, P  = .01) and sensitivity (0.91; 95% CI = 0.81 to 0.97, P  = .03) than a clinical-factor only model in independent samples from the AEGIS-2 cohort. These results support that the airway epithelial field of lung cancer-associated injury in ever smokers extends to the nose and demonstrates the potential of using nasal gene expression as a noninvasive biomarker for lung cancer detection. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Altered gene expression in early postnatal monoamine oxidase A knockout mice.

    Science.gov (United States)

    Chen, Kevin; Kardys, Abbey; Chen, Yibu; Flink, Stephen; Tabakoff, Boris; Shih, Jean C

    2017-08-15

    We reported previously that monoamine oxidase (MAO) A knockout (KO) mice show increased serotonin (5-hydroxytryptamine, 5-HT) levels and autistic-like behaviors characterized by repetitive behaviors, and anti-social behaviors. We showed that administration of the serotonin synthesis inhibitor para-chlorophenylalanine (pCPA) from post-natal day 1 (P1) through 7 (P7) in MAO A KO mice reduced the serotonin level to normal and reverses the repetitive behavior. These results suggested that the altered gene expression at P1 and P7 may be important for the autistic-like behaviors seen in MAO A KO mice and was studied here. In this study, Affymetrix mRNA array data for P1 and P7 MAO A KO mice were analyzed using Partek Genomics Suite and Ingenuity Pathways Analysis to identify genes differentially expressed versus wild-type and assess their functions and relationships. The number of significant differentially expressed genes (DEGs) varied with age: P1 (664) and P7 (3307) [false discovery rate (FDR) 1.5 for autism-linked genes and >2.0 for functionally categorized genes]. Eight autism-linked genes were differentially expressed in P1 (upregulated: NLGN3, SLC6A2; down-regulated: HTR2C, MET, ADSL, MECP2, ALDH5A1, GRIN3B) while four autism-linked genes were differentially expressed at P7 (upregulated: HTR2B; downregulated: GRIN2D, GRIN2B, CHRNA4). Many other genes involved in neurodevelopment, apoptosis, neurotransmission, and cognitive function were differentially expressed at P7 in MAO A KO mice. This result suggests that modulation of these genes by the increased serotonin may lead to neurodevelopmental alteration in MAO A KO mice and results in autistic-like behaviors. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Desert hedgehog is a mammal-specific gene expressed during testicular and ovarian development in a marsupial

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    O'Hara William A

    2011-12-01

    Full Text Available Abstract Background Desert hedgehog (DHH belongs to the hedgehog gene family that act as secreted intercellular signal transducers. DHH is an essential morphogen for normal testicular development and function in both mice and humans but is not present in the avian lineage. Like other hedgehog proteins, DHH signals through the patched (PTCH receptors 1 and 2. Here we examine the expression and protein distribution of DHH, PTCH1 and PTCH2 in the developing testes of a marsupial mammal (the tammar wallaby to determine whether DHH signalling is a conserved factor in gonadal development in all therian mammals. Results DHH, PTCH1 and PTCH2 were present in the marsupial genome and highly conserved with their eutherian orthologues. Phylogenetic analyses indicate that DHH has recently evolved and is a mammal-specific hedgehog orthologue. The marsupial PTCH2 receptor had an additional exon (exon 21a not annotated in eutherian PTCH2 proteins. Interestingly we found evidence of this exon in humans and show that its translation would result in a truncated protein with functions similar to PTCH1. We also show that DHH expression was not restricted to the testes during gonadal development (as in mice, but was also expressed in the developing ovary. Expression of DHH, PTCH1 and PTCH2 in the adult tammar testis and ovary was consistent with findings in the adult mouse. Conclusions These data suggest that there is a highly conserved role for DHH signalling in the differentiation and function of the mammalian testis and that DHH may be necessary for marsupial ovarian development. The receptors PTCH1 and PTCH2 are highly conserved mediators of hedgehog signalling in both the developing and adult marsupial gonads. Together these findings indicate DHH is an essential therian mammal-specific morphogen in gonadal development and gametogenesis.

  3. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    International Nuclear Information System (INIS)

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-01-01

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C → A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C → T, two C → A, one C → G, and one A → T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab

  4. ELF5 in epithelial ovarian carcinoma tissues and biological behavior in ovarian carcinoma cells.

    Science.gov (United States)

    Yan, Hongchao; Qiu, Linglin; Xie, Xiaolei; Yang, He; Liu, Yongli; Lin, Xiaoman; Huang, Hongxiang

    2017-03-01

    The expression of E74-like factor 5 (ELF5) in epithelial ovarian carcinoma tissues and its effects on biological behavior in ovarian carcinoma cells were assessed in search for a new approach for gene treatment of epithelial ovarian carcinoma. RT-PCR technology was applied to detect the expression of ELF5 mRNA in epithelial ovarian carcinoma (n=49), borderline ovarian epithelial tumor (n=19), benign ovarian epithelial tumor (n=31) and normal ovarian tissues (n=40). Then, we transfected recombinant plasmid pcDNA3.1‑ELF5+EGFP into human ovarian carcinoma SKOV3 cells (recombinant plasmid group) in vitro and screened out stably transfected cells to conduct multiplication culture. Western blot analysis was performed to detect the expression of ELF5 protein in the different groups. Flow cytometry was employed to detect cell apoptosis and cycles. ELF5 mRNA in epithelial ovarian carcinoma and borderline ovarian epithelial tumor tissues were significantly lower (Povarian epithelial tumor and normal ovarian tissues. ELF5 protein expression in the cells of recombinant plasmid group was significantly higher compared with empty plasmid and blank control groups. The capacity of cell reproductive recombinant plasmid group at each time point decreased (Povarian carcinoma SKOV3 cells and promoted apoptosis of human ovarian carcinoma SKOV3 cells inhibiting their growth and invasive capacity; and thus providing a new approach to gene treatment of ovarian carcinoma.

  5. Inner ear tissue remodeling and ion homeostasis gene alteration in murine chronic otitis media.

    Science.gov (United States)

    MacArthur, Carol J; Hausman, Fran; Kempton, J Beth; Sautter, Nathan; Trune, Dennis R

    2013-02-01

    Studies were designed to ascertain the impact of chronic middle ear infection on the numerous ion and water channels, transporters, and tissue remodeling genes in the inner and middle ear. Permanent sensorineural hearing loss is a significant problem resulting from chronic middle ear disease, although the inner ear processes involved are poorly defined. Maintaining a balanced ionic composition of endolymph in the inner ear is crucial for hearing; thus, it was hypothesized that this may be at risk with inflammation. Inner and middle ear RNA collected separately from 6-month-old C3H/HeJ mice with prolonged middle ear disease were subjected to qRT-PCR for 8 common inflammatory cytokine genes, 24 genes for channels controlling ion (sodium, potassium, and chloride) and water (aquaporin) transport, tight junction claudins, and gap junction connexins, and 32 tissue remodeling genes. Uninfected Balb/c mice were used as controls. Significant increase in inner ear inflammatory and ion homeostasis (claudin, aquaporin, and gap junction) gene expression, and both upregulation and downregulation of tissue remodeling gene expression occurred. Alteration in middle ear ion homeostasis and tissue remodeling gene expression was noted in the setting of uniform upregulation of cytokine genes. Chronic inflammatory middle ear disease can impact inner ear ion and water transport functions and induce tissue remodeling. Recognizing these inner ear mechanisms at risk may identify potential therapeutic targets to maintain hearing during prolonged otitis media.

  6. Altered gene expression in blood and sputum in COPD frequent exacerbators in the ECLIPSE cohort.

    Directory of Open Access Journals (Sweden)

    Dave Singh

    Full Text Available Patients with chronic obstructive pulmonary disease (COPD who are defined as frequent exacerbators suffer with 2 or more exacerbations every year. The molecular mechanisms responsible for this phenotype are poorly understood. We investigated gene expression profile patterns associated with frequent exacerbations in sputum and blood cells in a well-characterised cohort. Samples from subjects from the ECLIPSE COPD cohort were used; sputum and blood samples from 138 subjects were used for microarray gene expression analysis, while blood samples from 438 subjects were used for polymerase chain reaction (PCR testing. Using microarray, 150 genes were differentially expressed in blood (>±1.5 fold change, p≤0.01 between frequent compared to non-exacerbators. In sputum cells, only 6 genes were differentially expressed. The differentially regulated genes in blood included downregulation of those involved in lymphocyte signalling and upregulation of pro-apoptotic signalling genes. Multivariate analysis of the microarray data followed by confirmatory PCR analysis identified 3 genes that predicted frequent exacerbations; B3GNT, LAF4 and ARHGEF10. The sensitivity and specificity of these 3 genes to predict the frequent exacerbator phenotype was 88% and 33% respectively. There are alterations in systemic immune function associated with frequent exacerbations; down-regulation of lymphocyte function and a shift towards pro-apoptosis mechanisms are apparent in patients with frequent exacerbations.

  7. Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases.

    Directory of Open Access Journals (Sweden)

    Ana Blanco

    Full Text Available BACKGROUND: The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3-4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer. METHODS: 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification. RESULTS: Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop previously reported, and c.3362del (p.Gly1121ValfsX3 which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%. CONCLUSIONS: The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s involved in the development of breast/pancreatic cancer families is required.

  8. Ovarian Cancer Pathogenesis: A Model in Evolution

    Directory of Open Access Journals (Sweden)

    Alison M. Karst

    2010-01-01

    Full Text Available Ovarian cancer is a deadly disease for which there is no effective means of early detection. Ovarian carcinomas comprise a diverse group of neoplasms, exhibiting a wide range of morphological characteristics, clinical manifestations, genetic alterations, and tumor behaviors. This high degree of heterogeneity presents a major clinical challenge in both diagnosing and treating ovarian cancer. Furthermore, the early events leading to ovarian carcinoma development are poorly understood, thus complicating efforts to develop screening modalities for this disease. Here, we provide an overview of the current models of ovarian cancer pathogenesis, highlighting recent findings implicating the fallopian tube fimbria as a possible site of origin of ovarian carcinomas. The ovarian cancer model will continue to evolve as we learn more about the genetics and etiology of this disease.

  9. Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis

    DEFF Research Database (Denmark)

    Vestergaard, Anna Lindeløv; Thorup, Katrine; Knudsen, Ulla Breth

    2011-01-01

    Endometriosis displays some features that resemble malignant processes, including invasive growth, resistance to apoptosis, and distant implantation. The objective of this study was to investigate whether gene alterations that are frequent in endometrial and/or ovarian cancers contribute to the p......Endometriosis displays some features that resemble malignant processes, including invasive growth, resistance to apoptosis, and distant implantation. The objective of this study was to investigate whether gene alterations that are frequent in endometrial and/or ovarian cancers contribute...... to the pathogenesis of endometriosis. Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score (rAFS) stage 1 (N=1), 2 (N=10), 3 (N=11), or 4 (N=1) endometriosis. Six genes (APC, CDKN2A, PYCARD, RARB, RASSF1, and ESR1) were analyzed for promoter hypermethylation...... in a single lesion. No gene alterations were found in the remaining samples. Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis. However, other proto-oncogenes and tumor suppressor genes should be tested for alterations in order...

  10. A combined blood based gene expression and plasma protein abundance signature for diagnosis of epithelial ovarian cancer - a study of the OVCAD consortium

    International Nuclear Information System (INIS)

    Pils, Dietmar; Sehouli, Jalid; Braicu, Ioana; Vergote, Ignace; Van Gorp, Toon; Mahner, Sven; Concin, Nicole; Speiser, Paul; Zeillinger, Robert; Tong, Dan; Hager, Gudrun; Obermayr, Eva; Aust, Stefanie; Heinze, Georg; Kohl, Maria; Schuster, Eva; Wolf, Andrea

    2013-01-01

    The immune system is a key player in fighting cancer. Thus, we sought to identify a molecular ‘immune response signature’ indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC. Comparing the expression of 32,000 genes in a leukocytes fraction from 44 EOC patients and 19 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes (AP2A1, B4GALT1, C1orf63, CCR2, CFP, DIS3, NEAT1, NOXA1, OSM, PAPOLG, PRIC285, ZNF419, and BC037918) which were finally used in 343 samples (90 healthy, six cystadenoma, eight low malignant potential tumor, 19 FIGO I/II, and 220 FIGO III/IV EOC patients). Using new 65 controls and 224 EOC patients (thereof 14 FIGO I/II) the abundances of six plasma proteins (MIF, prolactin, CA125, leptin, osteopondin, and IGF2) was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC. Combined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%. The combination of gene expression and plasma protein based blood derived biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer

  11. Bacillus amyloliquefaciens alters gene expression, ROS production, and lignin synthesis in cotton seedling roots.

    Science.gov (United States)

    Irizarry, Ivelisse; White, James F

    2018-02-23

    Previous research demonstrated that applying Bacillus amyloliquefaciens to cotton seeds promotes growth, alters root architecture, and alleviates salt stress of cotton seedlings. This research was undertaken to further study the genetic responses elicited in cotton seedlings by this growth promoting bacterium. GeneChip microarrays and RT-qPCR were used to detect changes in gene expression in seedling roots inoculated with B. amyloliquefaciens. Roots were stained with 3'3-diaminobenzidine and phloroglucinol-HCl to determine whether treated seedlings had a greater accumulation of reactive oxygen species and lignin. 252 transcripts were differentially expressed in inoculated cotton seedling roots. 139 transcripts were up-regulated and 113 were down-regulated. Some up-regulated transcripts were related to nitrate assimilation, cell growth, hormones, transport, transcription factors, and antioxidants. Five genes identified to be up-regulated using microarrays were determined to be up-regulated using RT-qPCR. Inoculated cotton seedling roots had a greater accumulation of reactive oxygen species and lignin. The differential expression of genes associated with diverse functions supports that B. amyloliquefaciens elicits a complex genetic response in seedling roots. This study demonstrated that beneficial bacteria can alter gene expression of cotton that leads to growth promotion. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  12. Ovarian Cancers: Genetic Abnormalities, Tumor Heterogeneity and Progression, Clonal Evolution and Cancer Stem Cells

    Science.gov (United States)

    Castelli, Germana; Pelosi, Elvira

    2018-01-01

    Four main histological subtypes of ovarian cancer exist: serous (the most frequent), endometrioid, mucinous and clear cell; in each subtype, low and high grade. The large majority of ovarian cancers are diagnosed as high-grade serous ovarian cancers (HGS-OvCas). TP53 is the most frequently mutated gene in HGS-OvCas; about 50% of these tumors displayed defective homologous recombination due to germline and somatic BRCA mutations, epigenetic inactivation of BRCA and abnormalities of DNA repair genes; somatic copy number alterations are frequent in these tumors and some of them are associated with prognosis; defective NOTCH, RAS/MEK, PI3K and FOXM1 pathway signaling is frequent. Other histological subtypes were characterized by a different mutational spectrum: LGS-OvCas have increased frequency of BRAF and RAS mutations; mucinous cancers have mutation in ARID1A, PIK3CA, PTEN, CTNNB1 and RAS. Intensive research was focused to characterize ovarian cancer stem cells, based on positivity for some markers, including CD133, CD44, CD117, CD24, EpCAM, LY6A, ALDH1. Ovarian cancer cells have an intrinsic plasticity, thus explaining that in a single tumor more than one cell subpopulation, may exhibit tumor-initiating capacity. The improvements in our understanding of the molecular and cellular basis of ovarian cancers should lead to more efficacious treatments. PMID:29389895

  13. Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk

    DEFF Research Database (Denmark)

    Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A

    2009-01-01

    , CDK4, RB1, CDKN2D, and CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium...... and National Institute of Environmental Health Sciences SNPs Program. Logistic regression assuming a log-additive model was done on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239; CCND1 rs602652, rs3212879, rs649392...

  14. A sexual shift induced by silencing of a single insulin-like gene in crayfish: ovarian upregulation and testicular degeneration.

    Directory of Open Access Journals (Sweden)

    Ohad Rosen

    2010-12-01

    Full Text Available In sequential hermaphrodites, intersexuality occurs naturally, usually as a transition state during sexual re-differentiation processes. In crustaceans, male sexual differentiation is controlled by the male-specific androgenic gland (AG. An AG-specific insulin-like gene, previously identified in the red-claw crayfish Cherax quadricarinatus (designated Cq-IAG, was found in this study to be the prominent transcript in an AG cDNA subtractive library. In C. quadricarinatus, sexual plasticity is exhibited by intersex individuals in the form of an active male reproductive system and male secondary sex characters, along with a constantly arrested ovary. This intersexuality was exploited to follow changes caused by single gene silencing, accomplished via dsRNA injection. Cq-IAG silencing induced dramatic sex-related alterations, including male feature feminization, a reduction in sperm production, extensive testicular degeneration, expression of the vitellogenin gene, and accumulation of yolk proteins in the developing oocytes. Upon silencing of the gene, AG cells hypertrophied, possibly to compensate for low hormone levels, as reflected in the poor production of the insulin-like hormone (and revealed by immunohistochemistry. These results demonstrate both the functionality of Cq-IAG as an androgenic hormone-encoding gene and the dependence of male gonad viability on the Cq-IAG product. This study is the first to provide evidence that silencing an insulin-like gene in intersex C. quadricarinatus feminizes male-related phenotypes. These findings, moreover, contribute to the understanding of the regulation of sexual shifts, whether naturally occurring in sequential hermaphrodites or abnormally induced by endocrine disruptors found in the environment, and offer insight into an unusual gender-related link to the evolution of insulins.

  15. Altered Expression of Genes Encoding Neurotransmitter Receptors in GnRH Neurons of Proestrous Mice.

    Science.gov (United States)

    Vastagh, Csaba; Rodolosse, Annie; Solymosi, Norbert; Liposits, Zsolt

    2016-01-01

    Gonadotropin-releasing hormone (GnRH) neurons play a key role in the central regulation of reproduction. In proestrous female mice, estradiol triggers the pre-ovulatory GnRH surge, however, its impact on the expression of neurotransmitter receptor genes in GnRH neurons has not been explored yet. We hypothesized that proestrus is accompanied by substantial changes in the expression profile of genes coding for neurotransmitter receptors in GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact, proestrous, and metestrous female GnRH-GFP transgenic mice, respectively. About 1500 individual GnRH neurons were sampled from both groups and their transcriptome was analyzed using microarray hybridization and real-time PCR. In this study, changes in mRNA expression of genes involved in neurotransmitter signaling were investigated. Differential gene expression was most apparent in GABA-ergic ( Gabbr1, Gabra3, Gabrb3, Gabrb2, Gabrg2 ), glutamatergic ( Gria1, Gria2, Grin1, Grin3a, Grm1, Slc17a6 ), cholinergic ( Chrnb2, Chrm4 ) and dopaminergic ( Drd3, Drd4 ), adrenergic ( Adra1b, Adra2a, Adra2c ), adenosinergic ( Adora2a, Adora2b ), glycinergic ( Glra ), purinergic ( P2rx7 ), and serotonergic ( Htr1b ) receptors. In concert with these events, expression of genes in the signaling pathways downstream to the receptors, i.e., G-proteins ( Gnai1, Gnai2, Gnas ), adenylate-cyclases ( Adcy3, Adcy5 ), protein kinase A ( Prkaca, Prkacb ) protein kinase C ( Prkca ) and certain transporters ( Slc1a4, Slc17a6, Slc6a17 ) were also changed. The marked differences found in the expression of genes involved in neurotransmitter signaling of GnRH neurons at pro- and metestrous stages of the ovarian cycle indicate the differential contribution of these neurotransmitter systems to the induction of the pre-ovulatory GnRH surge, the known prerequisite of the subsequent hormonal cascade inducing ovulation.

  16. Altered expression of genes encoding neurotransmitter receptors in GnRH neurons of proestrous mice

    Directory of Open Access Journals (Sweden)

    Csaba Vastagh

    2016-10-01

    Full Text Available Gonadotropin-releasing hormone (GnRH neurons play a key role in the central regulation of reproduction. In proestrous female mice, estradiol triggers the pre-ovulatory GnRH surge, however, its impact on the expression of neurotransmitter receptor genes in GnRH neurons has not been explored yet. We hypothesized that proestrus is accompanied by substantial changes in the expression profile of genes coding for neurotransmitter receptors in GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact, proestrous and metestrous female GnRH-GFP transgenic mice, respectively. About 1500 individual GnRH neurons were sampled from both groups and their transcriptome was analyzed using microarray hybridization and real-time PCR. In this study, changes in mRNA expression of genes involved in neurotransmitter signaling were investigated. Differential gene expression was most apparent in GABA-ergic (Gabbr1, Gabra3, Gabrb3, Gabrb2, Gabrg2, glutamatergic (Gria1, Gria2, Grin1, Grin3a, Grm1, Slc17a6, cholinergic (Chrnb2, Chrm4 and dopaminergic (Drd3, Drd4, adrenergic (Adra1b, Adra2a, Adra2c, adenosinergic (Adora2a, Adora2b, glycinergic (Glra, purinergic (P2rx7 and serotonergic (Htr1b receptors. In concert with these events, expression of genes in the signaling pathways downstream to the receptors, i.e. G-proteins (Gnai1, Gnai2, Gnas, adenylate-cyclases (Adcy3, Adcy5, protein kinase A (Prkaca, Prkacb protein kinase C (Prkca and certain transporters (Slc1a4, Slc17a6, Slc6a17 were also changed. The marked differences found in the expression of genes involved in neurotransmitter signaling of GnRH neurons at pro- and metestrous stages of the ovarian cycle indicate the differential contribution of these neurotransmitter systems to the induction of the pre-ovulatory GnRH surge, the known prerequisite of the subsequent hormonal cascade inducing ovulation.

  17. Ovarian Cancer

    Science.gov (United States)

    ... contraceptives may have a reduced risk of ovarian cancer. But oral contraceptives do have risks, so discuss whether the benefits outweigh those risks based on your situation. Discuss your risk factors ... of breast and ovarian cancers, bring this up with your doctor. Your doctor ...

  18. Oxidative Stress Alters miRNA and Gene Expression Profiles in Villous First Trimester Trophoblasts

    Directory of Open Access Journals (Sweden)

    Courtney E. Cross

    2015-01-01

    Full Text Available The relationship between oxidative stress and miRNA changes in placenta as a potential mechanism involved in preeclampsia (PE is not fully elucidated. We investigated the impact of oxidative stress on miRNAs and mRNA expression profiles of genes associated with PE in villous 3A first trimester trophoblast cells exposed to H2O2 at 12 different concentrations (0-1 mM for 0.5, 4, 24, and 48 h. Cytotoxicity, determined using the SRB assay, was used to calculate the IC50 of H2O2. RNA was extracted after 4 h exposure to H2O2 for miRNA and gene expression profiling. H2O2 exerted a concentration- and time-dependent cytotoxicity on 3A trophoblast cells. Short-term exposure of 3A cells to low concentration of H2O2 (5% of IC50 significantly altered miRNA profile as evidenced by significant changes in 195 out of 595 evaluable miRNAs. Tool for annotations of microRNAs (TAM analysis indicated that these altered miRNAs fall into 43 clusters and 34 families, with 41 functions identified. Exposure to H2O2 altered mRNA expression of 22 out of 84 key genes involved in dysregulation of placental development. In conclusion, short-term exposure of villous first trimester trophoblasts to low concentrations of H2O2 significantly alters miRNA profile and expression of genes implicated in placental development.

  19. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes

    Directory of Open Access Journals (Sweden)

    Olschwang Sylviane

    2008-10-01

    Full Text Available Abstract Background Chronic myelomonocytic leukemia (CMML is a hematological disease close to, but separate from both myeloproliferative disorders (MPD and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML or myelodysplastic (MD-CMML features. Not much is known about the molecular biology of this disease. Methods We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH and sequencing of 12 candidate genes. Results Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q and gain or loss of genes (e.g. NF1, RB1 and CDK6. RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements. The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16. RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (~46% but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement occurred in both MP and MD classes (~38%. Conclusion We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage.

  20. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes

    International Nuclear Information System (INIS)

    Gelsi-Boyer, Véronique; Bentires-Alj, Mohamed; Olschwang, Sylviane; Vey, Norbert; Mozziconacci, Marie-Joëlle; Birnbaum, Daniel; Chaffanet, Max; Trouplin, Virginie; Adélaïde, José; Aceto, Nicola; Remy, Virginie; Pinson, Stephane; Houdayer, Claude; Arnoulet, Christine; Sainty, Danielle

    2008-01-01

    Chronic myelomonocytic leukemia (CMML) is a hematological disease close to, but separate from both myeloproliferative disorders (MPD) and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML) or myelodysplastic (MD-CMML) features. Not much is known about the molecular biology of this disease. We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases) from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH) and sequencing of 12 candidate genes. Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q) and gain or loss of genes (e.g. NF1, RB1 and CDK6). RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS) and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements). The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16. RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (~46%) but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement) occurred in both MP and MD classes (~38%). We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage

  1. Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing

    Directory of Open Access Journals (Sweden)

    Elisa Giorgetti

    2016-09-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA, a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR. Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO, a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations.

  2. Aging alters mRNA expression of amyloid transporter genes at the blood-brain barrier.

    Science.gov (United States)

    Osgood, Doreen; Miller, Miles C; Messier, Arthur A; Gonzalez, Liliana; Silverberg, Gerald D

    2017-09-01

    Decreased clearance of potentially toxic metabolites, due to aging changes, likely plays a significant role in the accumulation of amyloid-beta (Aβ) peptides and other macromolecules in the brain of the elderly and in the patients with Alzheimer's disease (AD). Aging is the single most important risk factor for AD development. Aβ transport receptor proteins expressed at the blood-brain barrier are significantly altered with age: the efflux transporters lipoprotein receptor-related protein 1 and P-glycoprotein are reduced, whereas the influx transporter receptor for advanced glycation end products is increased. These receptors play an important role in maintaining brain biochemical homeostasis. We now report that, in a rat model of aging, gene transcription is altered in aging, as measured by Aβ receptor gene messenger RNA (mRNA) at 3, 6, 9, 12, 15, 20, 30, and 36 months. Gene mRNA expression from isolated cerebral microvessels was measured by quantitative polymerase chain reaction. Lipoprotein receptor-related protein 1 and P-glycoprotein mRNA were significantly reduced in aging, and receptor for advanced glycation end products was increased, in parallel with the changes seen in receptor protein expression. Transcriptional changes appear to play a role in aging alterations in blood-brain barrier receptor expression and Aβ accumulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Gene expression profile altered by orthodontic tooth movement during healing of surgical alveolar defect.

    Science.gov (United States)

    Choi, Eun-Kyung; Lee, Jae-Hyung; Baek, Seung-Hak; Kim, Su-Jung

    2017-06-01

    We explored the gene expression profile altered by orthodontic tooth movement (OTM) during the healing of surgical alveolar defects in beagles. An OTM-related healing model was established where a maxillary second premolar was protracted into the critical-sized defect for 6 weeks (group DT6). As controls, natural healing models without OTM were set at 2 weeks (group D2) and at 6 weeks (group D6) after surgery. Total RNAs were extracted from dissected tissue blocks containing the regenerated defects and additionally from sound alveolar bone as a baseline (group C). mRNA profiling was performed using microarray analysis. Functional annotations of gene clusters based on differentially expressed genes among groups indicated that the gene expression profile of group DT6 had a stronger similarity to that of group D2 than to group D6. The genes participating in high woven-bone fraction in group DT6 could be identified as TNFSF11, MMP13, SPP1, and DMP1, which were verified by quantitative real-time polymerase chain reactions. We investigated at the gene level that OTM can affect the healing state of surgical defects serving as favorable matrices for OTM with defect regeneration. It would be a basis on selecting putative genes to be therapeutically applied for tissue-friendly accelerated orthodontics in the future. Copyright © 2017 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  4. Rhythmic expression of circadian clock genes in the preovulatory ovarian follicles of the laying hen.

    Directory of Open Access Journals (Sweden)

    Zhichao Zhang

    Full Text Available The circadian clock is reported to play a role in the ovaries in a variety of vertebrate species, including the domestic hen. However, the ovary is an organ that changes daily, and the laying hen maintains a strict follicular hierarchy. The aim of this study was to examine the spatial-temporal expression of several known canonical clock genes in the granulosa and theca layers of six hierarchy follicles. We demonstrated that the granulosa cells (GCs of the F1-F3 follicles harbored intrinsic oscillatory mechanisms in vivo. In addition, cultured granulosa cells (GCs from F1 follicles exposed to luteinizing hormone (LH synchronization displayed Per2 mRNA oscillations, whereas, the less mature GCs (F5 plus F6 displayed no circadian change in Per2 mRNA levels. Cultures containing follicle-stimulating hormone (FSH combined with LH expressed levels of Per2 mRNA that were 2.5-fold higher than those in cultures with LH or FSH alone. These results show that there is spatial specificity in the localization of clock cells in hen preovulatory follicles. In addition, our results support the hypothesis that gonadotropins provide a cue for the development of the functional cellular clock in immature GCs.

  5. Characteristics of nobiletin-mediated alteration of gene expression in cultured cell lines

    International Nuclear Information System (INIS)

    Nemoto, Kiyomitsu; Ikeda, Ayaka; Yoshida, Chiaki; Kimura, Junko; Mori, Junki; Fujiwara, Hironori; Yokosuka, Akihito; Mimaki, Yoshihiro; Ohizumi, Yasushi; Degawa, Masakuni

    2013-01-01

    Highlights: ► Nobiletin-mediated alterations of gene expression were examined with DNA microarrays. ► Three organ-derived cell lines were treated with 100 μM nobiletin for 24 h. ► In all cell lines, 3 endoplasmic reticulum stress-responsive genes were up-regulated. ► Some cell cycle-regulating and oxidative stress-promoting genes were down-regulated. ► These alterations may contribute to nobiletin-mediated biological effects. -- Abstract: Nobiletin, a polymethoxylated flavonoid that is highly contained in the peels of citrus fruits, exerts a wide variety of beneficial effects, including anti-proliferative effects in cancer cells, repressive effects in hyperlipidemia and hyperglycemia, and ameliorative effects in dementia at in vitro and in vivo levels. In the present study, to further understand the mechanisms of these actions of nobiletin, the nobiletin-mediated alterations of gene expression in three organ-derived cell lines – 3Y1 rat fibroblasts, HuH-7 human hepatocarcinoma cells, and SK-N-SH human neuroblastoma cells – were first examined with DNA microarrays. In all three cell lines, treatments with nobiletin (100 μM) for 24 h resulted in more than 200% increases in the expression levels of five genes, including the endoplasmic reticulum stress-responsive genes Ddit3, Trib3, and Asns, and in less than 50% decreases in the expression levels of seven genes, including the cell cycle-regulating genes Ccna2, Ccne2, and E2f8 and the oxidative stress-promoting gene Txnip. It was also confirmed that in each nobiletin-treated cell line, the levels of the DDIT3 (DNA-damage-inducible transcript 3, also known as CHOP and GADD153) and ASNS (asparagine synthetase) proteins were increased, while the level of the TXNIP (thioredoxin-interacting protein, also known as VDUP1 and TBP-2) protein was decreased. All these findings suggest that nobiletin exerts a wide variety of biological effects, at least partly, through induction of endoplasmic reticulum stress and

  6. Gene expression in developing fibres of Upland cotton (Gossypium hirsutum L.) was massively altered by domestication.

    Science.gov (United States)

    Rapp, Ryan A; Haigler, Candace H; Flagel, Lex; Hovav, Ran H; Udall, Joshua A; Wendel, Jonathan F

    2010-11-15

    Understanding the evolutionary genetics of modern crop phenotypes has a dual relevance to evolutionary biology and crop improvement. Modern upland cotton (Gossypium hirsutum L.) was developed following thousands of years of artificial selection from a wild form, G. hirsutum var. yucatanense, which bears a shorter, sparser, layer of single-celled, ovular trichomes ('fibre'). In order to gain an insight into the nature of the developmental genetic transformations that accompanied domestication and crop improvement, we studied the transcriptomes of cotton fibres from wild and domesticated accessions over a developmental time course. Fibre cells were harvested between 2 and 25 days post-anthesis and encompassed the primary and secondary wall synthesis stages. Using amplified messenger RNA and a custom microarray platform designed to interrogate expression for 40,430 genes, we determined global patterns of expression during fibre development. The fibre transcriptome of domesticated cotton is far more dynamic than that of wild cotton, with over twice as many genes being differentially expressed during development (12,626 versus 5273). Remarkably, a total of 9465 genes were diagnosed as differentially expressed between wild and domesticated fibres when summed across five key developmental time points. Human selection during the initial domestication and subsequent crop improvement has resulted in a biased upregulation of components of the transcriptional network that are important for agronomically advanced fibre, especially in the early stages of development. About 15% of the differentially expressed genes in wild versus domesticated cotton fibre have no homology to the genes in databases. We show that artificial selection during crop domestication can radically alter the transcriptional developmental network of even a single-celled structure, affecting nearly a quarter of the genes in the genome. Gene expression during fibre development within accessions and expression

  7. Characteristics of nobiletin-mediated alteration of gene expression in cultured cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Nemoto, Kiyomitsu, E-mail: nemoto@u-shizuoka-ken.ac.jp [Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan); Ikeda, Ayaka; Yoshida, Chiaki; Kimura, Junko; Mori, Junki [Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan); Fujiwara, Hironori [Department of Anti-Dementia Functional Food Development, Research Center of Supercritical Fluid Technology, Graduate School of Engineering, Tohoku University, 6-6-7 Aoba, Aramaki, Aoba-ku, Sendai 980-8579 (Japan); Yokosuka, Akihito; Mimaki, Yoshihiro [Department of Medicinal Pharmacognosy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji 192-0392 (Japan); Ohizumi, Yasushi [Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan); Department of Anti-Dementia Functional Food Development, Research Center of Supercritical Fluid Technology, Graduate School of Engineering, Tohoku University, 6-6-7 Aoba, Aramaki, Aoba-ku, Sendai 980-8579 (Japan); Laboratory of Kampo Medicines, Yokohama College of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066 (Japan); Degawa, Masakuni [Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan)

    2013-02-15

    Highlights: ► Nobiletin-mediated alterations of gene expression were examined with DNA microarrays. ► Three organ-derived cell lines were treated with 100 μM nobiletin for 24 h. ► In all cell lines, 3 endoplasmic reticulum stress-responsive genes were up-regulated. ► Some cell cycle-regulating and oxidative stress-promoting genes were down-regulated. ► These alterations may contribute to nobiletin-mediated biological effects. -- Abstract: Nobiletin, a polymethoxylated flavonoid that is highly contained in the peels of citrus fruits, exerts a wide variety of beneficial effects, including anti-proliferative effects in cancer cells, repressive effects in hyperlipidemia and hyperglycemia, and ameliorative effects in dementia at in vitro and in vivo levels. In the present study, to further understand the mechanisms of these actions of nobiletin, the nobiletin-mediated alterations of gene expression in three organ-derived cell lines – 3Y1 rat fibroblasts, HuH-7 human hepatocarcinoma cells, and SK-N-SH human neuroblastoma cells – were first examined with DNA microarrays. In all three cell lines, treatments with nobiletin (100 μM) for 24 h resulted in more than 200% increases in the expression levels of five genes, including the endoplasmic reticulum stress-responsive genes Ddit3, Trib3, and Asns, and in less than 50% decreases in the expression levels of seven genes, including the cell cycle-regulating genes Ccna2, Ccne2, and E2f8 and the oxidative stress-promoting gene Txnip. It was also confirmed that in each nobiletin-treated cell line, the levels of the DDIT3 (DNA-damage-inducible transcript 3, also known as CHOP and GADD153) and ASNS (asparagine synthetase) proteins were increased, while the level of the TXNIP (thioredoxin-interacting protein, also known as VDUP1 and TBP-2) protein was decreased. All these findings suggest that nobiletin exerts a wide variety of biological effects, at least partly, through induction of endoplasmic reticulum stress and

  8. Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells.

    Science.gov (United States)

    Marcinkiewicz, Katarzyna M; Gudas, Lorraine J

    2014-01-01

    To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 mark on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC-9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes. © 2013 Elsevier Inc. All rights reserved.

  9. The expression of petunia strigolactone pathway genes is altered as part of the endogenous developmental program

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    Revel S M Drummond

    2012-01-01

    Full Text Available Analysis of mutants with increased branching has revealed the strigolactone synthesis/perception pathway which regulates branching in plants. However, whether variation in this well conserved developmental signalling system contributes to the unique plant architectures of different species is yet to be determined. We examined petunia orthologues of the Arabidopsis MAX1 and MAX2 genes to characterise their role in petunia architecture. A single orthologue of MAX1, PhMAX1 which encodes a cytochrome P450, was identified and was able to complement the max1 mutant of Arabidopsis. Petunia has two copies of the MAX2 gene, PhMAX2A and PhMAX2B which encode F-Box proteins. Differences in the transcript levels of these two MAX2-like genes suggest diverging functions. Unlike PhMAX2B, PhMAX2A mRNA levels increase as leaves age. Nonetheless, this gene functionally complements the Arabidopsis max2 mutant indicating that the biochemical activity of the PhMAX2A protein is not significantly different from MAX2. The expression of the petunia strigolactone pathway genes (PhCCD7, PhCCD8, PhMAX1, PhMAX2A, and PhMAX2B was then further investigated throughout the development of wild-type petunia plants. Three of these genes showed changes in mRNA levels over the development series. Alterations to the expression of these genes over time, or in different regions of the plant, may influence the branching growth habit of the plant. Alterations to strigolactone production and/or sensitivity could allow both subtle and dramatic changes to branching within and between species.

  10. Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells

    Directory of Open Access Journals (Sweden)

    Eugenia Mata-Greenwood

    2017-05-01

    Full Text Available Background : Hypoxia inducible factor 1 alpha (HIF1A is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia.Results : We examined the effect of chronic hypoxia (3 days; 0.5% oxygen on human brain micro endothelial cells (HBMEC viability and apoptosis. Hypoxia caused a significant reduction in cell viability and an increase in apoptosis. Next, we examined chronic hypoxia associated changes in transcriptome and genome-wide promoter methylation. The data obtained was compared with 16 other microarray studies on chronic hypoxia. Nine genes were altered in response to chronic hypoxia in all 17 studies. Interestingly, HIF1A was not altered with chronic hypoxia in any of the studies. Furthermore, we compared our data to three other studies that identified HIF-responsive genes by various approaches. Only two genes were found to be HIF dependent. We silenced each of these 9 genes using CRISPR/Cas9 system. Downregulation of EGLN3 significantly increased the cell death under chronic hypoxia, whereas downregulation of ERO1L, ENO2, adrenomedullin, and spag4 reduced the cell death under hypoxia.Conclusions : We provide a core group of genes that regulates cellular acclimatization under chronic hypoxic stress, and most of them are HIF independent.

  11. JC virus induces altered patterns of cellular gene expression: Interferon-inducible genes as major transcriptional targets

    International Nuclear Information System (INIS)

    Verma, Saguna; Ziegler, Katja; Ananthula, Praveen; Co, Juliene K.G.; Frisque, Richard J.; Yanagihara, Richard; Nerurkar, Vivek R.

    2006-01-01

    Human polyomavirus JC (JCV) infects 80% of the population worldwide. Primary infection, typically occurring during childhood, is asymptomatic in immunocompetent individuals and results in lifelong latency and persistent infection. However, among the severely immunocompromised, JCV may cause a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Virus-host interactions influencing persistence and pathogenicity are not well understood, although significant regulation of JCV activity is thought to occur at the level of transcription. Regulation of the JCV early and late promoters during the lytic cycle is a complex event that requires participation of both viral and cellular factors. We have used cDNA microarray technology to analyze global alterations in gene expression in JCV-permissive primary human fetal glial cells (PHFG). Expression of more than 400 cellular genes was altered, including many that influence cell proliferation, cell communication and interferon (IFN)-mediated host defense responses. Genes in the latter category included signal transducer and activator of transcription 1 (STAT1), interferon stimulating gene 56 (ISG56), myxovirus resistance 1 (MxA), 2'5'-oligoadenylate synthetase (OAS), and cig5. The expression of these genes was further confirmed in JCV-infected PHFG cells and the human glioblastoma cell line U87MG to ensure the specificity of JCV in inducing this strong antiviral response. Results obtained by real-time RT-PCR and Western blot analyses supported the microarray data and provide temporal information related to virus-induced changes in the IFN response pathway. Our data indicate that the induction of an antiviral response may be one of the cellular factors regulating/controlling JCV replication in immunocompetent hosts and therefore constraining the development of PML

  12. Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk

    Science.gov (United States)

    Kar, Siddhartha P.; Tyrer, Jonathan P.; Li, Qiyuan; Lawrenson, Kate; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Chenevix-Trench, Georgia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjørge, Line; Bogdanova, Natalia; Brinton, Louise; Brooks-Wilson, Angela; Butzow, Ralf; Campbell, Ian; Carty, Karen; Chang-Claude, Jenny; Chen, Yian Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas F.; Edwards, Robert P.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus K.; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Paul, James; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kjaer, Susanne K.; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain A.; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston-Campbell, Lara E.; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Monteiro, Alvaro N. A.; Freedman, Matthew L.; Gayther, Simon A.; Pharoah, Paul D. P.

    2015-01-01

    Background Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by co-expression may also be enriched for additional EOC risk associations. Methods We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly co-expressed with each selected TF gene in the unified microarray data set of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this data set were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P<0.05 and FDR<0.05). These results were replicated (P<0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact Network analysis integrating large, context-specific data sets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. PMID:26209509

  13. FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib.

    Science.gov (United States)

    Hibi, Masaaki; Kaneda, Hiroyasu; Tanizaki, Junko; Sakai, Kazuko; Togashi, Yosuke; Terashima, Masato; De Velasco, Marco Antonio; Fujita, Yoshihiko; Banno, Eri; Nakamura, Yu; Takeda, Masayuki; Ito, Akihiko; Mitsudomi, Tetsuya; Nakagawa, Kazuhiko; Okamoto, Isamu; Nishio, Kazuto

    2016-11-01

    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  14. HC-Pro silencing suppressor significantly alters the gene expression profile in tobacco leaves and flowers

    Directory of Open Access Journals (Sweden)

    Lehto Kirsi

    2011-04-01

    Full Text Available Abstract Background RNA silencing is used in plants as a major defence mechanism against invasive nucleic acids, such as viruses. Accordingly, plant viruses have evolved to produce counter defensive RNA-silencing suppressors (RSSs. These factors interfere in various ways with the RNA silencing machinery in cells, and thereby disturb the microRNA (miRNA mediated endogene regulation and induce developmental and morphological changes in plants. In this study we have explored these effects using previously characterized transgenic tobacco plants which constitutively express (under CaMV 35S promoter the helper component-proteinase (HC-Pro derived from a potyviral genome. The transcript levels of leaves and flowers of these plants were analysed using microarray techniques (Tobacco 4 × 44 k, Agilent. Results Over expression of HC-Pro RSS induced clear phenotypic changes both in growth rate and in leaf and flower morphology of the tobacco plants. The expression of 748 and 332 genes was significantly changed in the leaves and flowers, respectively, in the HC-Pro expressing transgenic plants. Interestingly, these transcriptome alterations in the HC-Pro expressing tobacco plants were similar as those previously detected in plants infected with ssRNA-viruses. Particularly, many defense-related and hormone-responsive genes (e.g. ethylene responsive transcription factor 1, ERF1 were differentially regulated in these plants. Also the expression of several stress-related genes, and genes related to cell wall modifications, protein processing, transcriptional regulation and photosynthesis were strongly altered. Moreover, genes regulating circadian cycle and flowering time were significantly altered, which may have induced a late flowering phenotype in HC-Pro expressing plants. The results also suggest that photosynthetic oxygen evolution, sugar metabolism and energy levels were significantly changed in these transgenic plants. Transcript levels of S

  15. Alteration of Hepatic Gene Expression along with the Inherited Phenotype of Acquired Fatty Liver in Chicken

    Directory of Open Access Journals (Sweden)

    Yonghong Zhang

    2018-04-01

    Full Text Available Fatty liver is a widespread disease in chickens that causes a decrease in egg production and even death. The characteristics of the inherited phenotype of acquired fatty liver and the molecular mechanisms underlying it, however, are largely unknown. In the current study, fatty liver was induced in 3 breeds by a high-fat (HF diet and a methionine choline-deficient (MCD diet. The results showed that the dwarf Jingxing-Huang (JXH chicken was more susceptible to fatty liver compared with the layer White Leghorns (WL and local Beijing-You (BJY breeds. In addition, it was found that the paternal fatty livers induced by HF diet in JXH chickens were inherited. Compared to birds without fatty liver in the control group, both offsprings and their sires with fatty livers in the paternal group exhibited altered hepatic gene expression profiles, including upregulation of several key genes involved in fatty acid metabolism, lipid metabolism and glucose metabolism (ACACA, FASN, SCD, ACSL5, FADS2, FABP1, APOA4 and ME1. This study uniquely revealed that acquired fatty liver in cocks can be inherited. The hepatic gene expression profiles were altered in chickens with the inherited phenotype of acquired paternal fatty liver and several genes could be candidate biomarkers.

  16. Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes.

    Science.gov (United States)

    Barr, Tasha; Girke, Thomas; Sureshchandra, Suhas; Nguyen, Christina; Grant, Kathleen; Messaoudi, Ilhem

    2016-01-01

    Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post-modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set. Copyright © 2015 by The American Association of Immunologists, Inc.

  17. Expression of Siglec-11 by human and chimpanzee ovarian stromal cells, with uniquely human ligands: implications for human ovarian physiology and pathology

    Science.gov (United States)

    Wang, Xiaoxia; Chow, Renee; Deng, Liwen; Anderson, Dan; Weidner, Noel; Godwin, Andrew K; Bewtra, Chanda; Zlotnik, Albert; Bui, Jack; Varki, Ajit; Varki, Nissi

    2011-01-01

    Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are cell surface signaling receptors of the I-type lectin group that recognize sialic acid-bearing glycans. CD33-related-Siglecs are a subset with expression primarily in cells of hematopoietic origin and functional relevance to immune reactions. Earlier we reported a human-specific gene conversion event that markedly changed the coding region for the extracellular domain of Siglec-11, associated with human-specific expression in microglia (Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A. 2005. A human-specific gene in microglia. Science. 309:1693). Analyzing human gene microarrays to define new patterns of expression, we observed high levels of SIGLEC11 transcript in the ovary and adrenal cortex. Thus, we examined human and chimpanzee tissues using a well-characterized anti-Siglec-11 mouse monoclonal antibody. Although adrenal expression was variable and confined to infiltrating macrophages in capillaries, ovarian expression of Siglec-11 in both humans and chimpanzees was on fibroblasts, the first example of Siglec expression on mesenchyme-derived stromal cells. Cytokines from such ovarian stromal fibroblasts play important roles in follicle development and ovulation. Stable transfection of SIGLEC11 into a primary human ovarian stromal fibroblast cell line altered the secretion of growth-regulated oncogene α, interleukin (IL)-10, IL-7, transforming growth factor β1 and tumor necrosis factor-α, cytokines involved in ovarian physiology. Probing for Siglec-11 ligands revealed distinct and strong mast cell expression in human ovaries, contrasting to diffuse stromal ligands in chimpanzee ovaries. Interestingly, there was a trend of increased Siglec-11 expression in post-menopausal ovaries compared with pre-menopausal ones. Siglec-11 expression was also found on human ovarian stromal tumors and in polycystic ovarian syndrome, a human-specific disease. These results indicate potential

  18. Spaceflight induces both transient and heritable alterations in DNA methylation and gene expression in rice (Oryza sativa L.)

    International Nuclear Information System (INIS)

    Ou Xiufang; Long Likun; Zhang Yunhong; Xue Yiqun; Liu Jingchun; Lin Xiuyun; Liu Bao

    2009-01-01

    Spaceflight represents a complex environmental condition in which several interacting factors such as cosmic radiation, microgravity and space magnetic fields are involved, which may provoke stress responses and jeopardize genome integrity. Given the inherent property of epigenetic modifications to respond to intrinsic as well as external perturbations, it is conceivable that epigenetic markers like DNA methylation may undergo alterations in response to spaceflight. We report here that extensive alteration in both DNA methylation and gene expression occurred in rice plants subjected to a spaceflight, as revealed by a set of characterized sequences including 6 transposable elements (TEs) and 11 cellular genes. We found that several features characterize the alterations: (1) All detected alterations are hypermethylation events; (2) whereas alteration in both CG and CNG methylation occurred in the TEs, only alteration in CNG methylation occurred in the cellular genes; (3) alteration in expression includes both up- and down-regulations, which did not show a general correlation with alteration in methylation; (4) altered methylation patterns in both TEs and cellular genes are heritable to progenies at variable frequencies; however, stochastic reversion to wild-type patterns and further de novo changes in progenies are also apparent; and (5) the altered expression states in both TEs and cellular genes are also heritable to selfed progenies but with markedly lower transmission frequencies than altered DNA methylation states. Furthermore, we found that a set of genes encoding for the various putative DNA methyltransferases, 5-methylcytosine DNA glycosylases, the SWI/SNF chromatin remodeller (DDM1) and siRNA-related proteins are extremely sensitive to perturbation by spaceflight, which might be an underlying cause for the altered methylation patterns in the space-flown plants. We discuss implications of spaceflight-induced epigenetic variations with regard to health safety

  19. Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells

    International Nuclear Information System (INIS)

    Marcinkiewicz, Katarzyna M.; Gudas, Lorraine J.

    2014-01-01

    To gain insight into oral squamous cell carcinogenesis, we performed deep sequencing (RNAseq) of non-tumorigenic human OKF6-TERT1R and tumorigenic SCC-9 cells. Numerous homeobox genes are differentially expressed between OKF6-TERT1R and SCC-9 cells. Data from Oncomine, a cancer microarray database, also show that homeobox (HOX) genes are dysregulated in oral SCC patients. The activity of Polycomb repressive complexes (PRC), which causes epigenetic modifications, and retinoic acid (RA) signaling can control HOX gene transcription. HOXB7, HOXC10, HOXC13, and HOXD8 transcripts are higher in SCC-9 than in OKF6-TERT1R cells; using ChIP (chromatin immunoprecipitation) we detected PRC2 protein SUZ12 and the epigenetic H3K27me3 mark on histone H3 at these genes in OKF6-TERT1R, but not in SCC-9 cells. In contrast, IRX1, IRX4, SIX2 and TSHZ3 transcripts are lower in SCC-9 than in OKF6-TERT1R cells. We detected SUZ12 and the H3K27me3 mark at these genes in SCC-9, but not in OKF6-TERT1R cells. SUZ12 depletion increased HOXB7, HOXC10, HOXC13, and HOXD8 transcript levels and decreased the proliferation of OKF6-TERT1R cells. Transcriptional responses to RA are attenuated in SCC-9 versus OKF6-TERT1R cells. SUZ12 and H3K27me3 levels were not altered by RA at these HOX genes in SCC-9 and OKF6-TERT1R cells. We conclude that altered activity of PRC2 is associated with dysregulation of homeobox gene expression in human SCC cells, and that this dysregulation potentially plays a role in the neoplastic transformation of oral keratinocytes. - Highlights: • RNAseq elucidates differences between non-tumorigenic and tumorigenic oral keratinocytes. • Changes in HOX mRNA in SCC-9 vs. OKF6-TERT1R cells are a result of altered epigenetic regulation. • RNAseq shows that retinoic acid (RA) influences gene expression in both OKF6-TERT1R and SCC-9 cells

  20. Mutational analysis ofBRCA1andBRCA2genes in Peruvian families with hereditary breast and ovarian cancer.

    Science.gov (United States)

    Buleje, Jose; Guevara-Fujita, Maria; Acosta, Oscar; Huaman, Francia D P; Danos, Pierina; Murillo, Alexis; Pinto, Joseph A; Araujo, Jhajaira M; Aguilar, Alfredo; Ponce, Jaime; Vigil, Carlos; Castaneda, Carlos; Calderon, Gabriela; Gomez, Henry L; Fujita, Ricardo

    2017-09-01

    Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA1 and BRCA2 germline mutations. We performed a comprehensive analysis of BRCA1 and BRCA2 genes by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. In this series, we found four pathogenic mutations, three previously reported ( BRCA1 : c.302-1G>C and c.815_824dup10; BRCA2 : c.5946delT) and a duplication of adenines in exon 15 in BRCA1 gene (c.4647_4648dupAA, ClinVar SCV000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. This is the first report to determine the spectrum of mutations in the BRCA1/BRCA2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA1/BRCA2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA1/BRCA2 mutations and a BRCA1 c.4647_4648dupAA as a novel pathogenic mutation.

  1. Differential effects of rapalogues, dual kinase inhibitors on human ovarian carcinoma cells in vitro.

    Science.gov (United States)

    Rogers-Broadway, Karly-Rai; Chudasama, Dimple; Pados, George; Tsolakidis, Dimitris; Goumenou, Anastasia; Hall, Marcia; Karteris, Emmanouil

    2016-07-01

    Ovarian cancer is the second most common gynaecological malignancy and was diagnosed in over 7,000 women in 2011 in the UK. There are currently no reliable biomarkers available for use in a regular screening assay for ovarian cancer and due to characteristic late presentation (78% in stages III and IV) ovarian cancer has a low survival rate (35% after 10 years). The mTOR pathway is a central regulator of growth, proliferation, apoptosis and angiogenesis; providing balance between available resources such as amino acids and growth factors, and stresses such as hypoxia, to control cellular behaviour accordingly. Emerging data links mTOR with the aetiopathogenesis of ovarian cancer. We hypothesised that mTOR inhibitors could play a therapeutic role in ovarian cancer treatment. In this study we began by validating the expression of four main mTOR pathway components, mTOR, DEPTOR, rictor and raptor, at gene and protein level in in vitro models of endometrioid (MDAH‑2774) and clear cell (SKOV3) ovarian cancer using qPCR and ImageStream technology. Using a wound healing assay we show that inhibition of the mTOR pathway using rapamycin, rapalogues, resveratrol and NVP BEZ-235 induces a cytostatic and not cytotoxic response up to 18 h in these cell lines. We extended these findings up to 72 h with a proliferation assay and show that the effects of inhibition of the mTOR pathway are primarily mediated by the dephosphorylation of p70S6 kinase. We show that mTOR inhibition does not involve alteration of mTOR pathway components or induce caspase 9 cleavage. Preclinical studies including ovarian tissue of ovarian cancer patients, unaffected controls and patients with unrelated gynaecological conditions show that DEPTOR is reliably upregulated in ovarian cancer.

  2. Efficacy of Ginkgo biloba on vaginal estrous and ovarian histological alterations for evaluating anti-implantation and abortifacient potentials in albino female mice.

    Science.gov (United States)

    Elmazoudy, Reda H; Attia, Azza A

    2012-12-01

    Ginkgo extract, EGb 761 is known as a vasoregulatory variable for the conventional reproduction therapy. EGb 761 was orally administered in 0 (control), 3.7, 7.4, and 14.8 mg/kg bw/day for 28 days (thereafter mated with normal fertile male), from day 1 to day 7 of pregnancy or from the 10th to 18th day of pregnancy, respectively. Vaginal smears were performed daily. On 20th day of pregnancy, the females were killed by cervical dislocation and their kidneys, liver, brain, placenta, spleen and ovaries were removed and weighed. The ovaries were prepared for histological examinations, and then ovarian follicles were counted. Maternal toxicity, estrous cycle, reproductive hormones, ovarian follicle counts, resorption index, implantation index, fetal viability and fetuses, and placenta mean weights were evaluated. There was a dose-dependent ovarian toxic effect of EGb 761. Ovarian follicle counts, resorption index, implantation index, fetal viability were significantly reduced in 14.8 mg/kg bw/day dose. Treatment with 14.8 mg/kg bw/day EGb 761 induced disruption of estrous cycle and caused maternal toxicity, in addition to fetal toxicity. Therefore, the data obtained indicate that Ginkgo biloba extract at 14.8 mg/kg bw/day dose level exhibit toxic effect on reproductive cyclicity and could have anti-implantation and abotifacient properties in female mice. © 2012 Wiley Periodicals, Inc.

  3. Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.

    Directory of Open Access Journals (Sweden)

    Katrina Soderquest

    2017-02-01

    Full Text Available The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21 specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

  4. Simultaneous Targeting of Multiple Gene Homeologs to Alter Seed Oil Production in Camelina sativa.

    Science.gov (United States)

    Aznar-Moreno, J A; Durrett, T P

    2017-07-01

    The ability to transform Camelina sativa easily with biosynthetic enzymes derived from other plants has made this oil seed crop an ideal platform for the production of unusual lipids valuable for different applications. However, in addition to expressing transgenic enzymes, the suppression of endogenous enzyme activity to reduce competition for common substrates or cofactors is also required to enhance the production of target compounds. As camelina possesses a relatively undifferentiated hexaploid genome, up to three gene homeologs can code for any particular enzymatic activity, complicating efforts to alter endogenous biosynthetic pathways. New genome editing technologies, such as that offered by the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) system, offer the capability to introduce mutations into specifically targeted genomic sites. Here, by using a carefully designed guide RNA identical to all three homeologs, we demonstrate the ability of the CRISPR/Cas genome editing system to introduce mutations in all three CsDGAT1 or CsPDAT1 homeologous genes important for triacylglycerol (TAG) synthesis in developing seeds. Sequence analysis from transgenic T1 plants revealed that each CsDGAT1 or each CsPDAT1 homeolog was altered by multiple mutations, resulting in a genetic mosaic in the plants. Interestingly, seed harvested from both CsDGAT1- and CsPDAT1-targeted lines was often shrunken and wrinkled. Further, lipid analysis revealed that many lines produced seed with reduced oil content and altered fatty acid composition, consistent with the role of the targeted genes in seed oil biosynthesis. The CRISPR/Cas system therefore represents a useful method to alter endogenous biosynthetic pathways efficiently in polyploid species such as camelina. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  5. Alterations in Mc1r gene expression are associated with regressive pigmentation in Astyanax cavefish.

    Science.gov (United States)

    Stahl, Bethany A; Gross, Joshua B

    2015-11-01

    Diverse changes in coloration across distant taxa are mediated through alterations in certain highly conserved pigmentation genes. Among these genes, Mc1r is a frequent target for mutation, and many documented alterations involve coding sequence changes. We investigated whether regulatory mutations in Mc1r may also contribute to pigmentation loss in the blind Mexican cavefish, Astyanax mexicanus. This species comprises multiple independent cave populations that have evolved reduced (or absent) melanic pigmentation as a consequence of living in darkness for millions of generations. Among the most salient cave-associated traits, complete absence (albinism) or reduced levels of pigmentation (brown) have long been the focus of degenerative pigmentation research in Astyanax. These two Mendelian traits have been linked to specific coding mutations in Oca2 (albinism) and Mc1r (brown). However, four of the seven caves harboring the brown phenotype exhibit unaffected coding sequences compared to surface fish. Thus, diverse genetic changes involving the same genes likely impact reduced pigmentation among cavefish populations. Using both sequence and expression analyses, we show that certain cave-dwelling populations harboring the brown mutation have substantial alterations to the putative Mc1r cis-regulatory region. Several of these sequence mutations in the Mc1r 5' region were present across multiple, independent cave populations. This study suggests that pigmentation reduction in Astyanax cavefish evolves through a combination of both coding and cis-regulatory mutations. Moreover, this study represents one of the first attempts to identify regulatory alterations linked to regressive changes in cave-dwelling populations of A. mexicanus.

  6. Altered clock gene expression in obese visceral adipose tissue is associated with metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Elaine Vieira

    Full Text Available Clock gene expression was associated with different components of metabolic syndrome (MS in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21-25 kg/m2; n = 21 and morbidly obese women (BMI >40 kg/m2; n = 28. The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.

  7. Alterations in gene expression profiles between radioresistant and radiosensitive cell lines

    International Nuclear Information System (INIS)

    Zhou Fuxiang; Zhou Yunfeng; Xie Conghua; Dai Jing; Cao Zhen; Yu Haijun; Liao Zhengkai; Luo Zhiguo

    2007-01-01

    Objective: To study the-difference of gene expressions by the contrastive model including the cells with same pathological origin and genetic background, but definitely different radioresponse, and to find the main molecular targets related to radiosensitivity. Methods: Human larynx squamous carcinoma cell, Hep -2 was irradiated with dose of 637 cGy repeatedly to establish a radioresistant daughter cell line. The radiobiology characteristics were obtained using clone forming assay. The difference of gene expression between parent and daughter cells was detected by cDNA microarray using two different arrays including 14000 genes respectively. Results: A radioresistant cell strain Hep-2R was isolated from its parental strain Hep-2 cell. The SF 2 , D 0 , α, β for Hep-2R cell line were 0.6798, 3.24, 0.2951 and 0.0363, respectively, while 0.4148, 2.06, 0.1074 and 0.0405 for Hep-2, respectively (for SF 2 , χ 2 =63.957, P<0.001). Compared with Hep-2 cells, the expressions of 41 genes were significantly altered in the radioresistant Hep-2R cells, including 22 genes up-regulated and 19 genes down-regulated, which were involved in DNA repair, regulation of the cell cycle, cell proliferation, cytoskeleton, protein synthesis, cellular metabolism and especially apoptosis which is responsible for the different radiosensitivity between these two larynx cancer cells. The telomere protection protein gene, POT1, was the mostly up-regulated by 3.348 times. Conclusions: There is difference of gene expression between the radioresistant contrastive models. POT1 gene may be the target of radiosensitization. (authors)

  8. Addiction and Reward-related Genes Show Altered Expression in the Postpartum Nucleus Accumbens

    Directory of Open Access Journals (Sweden)

    Changjiu eZhao

    2014-11-01

    Full Text Available Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET indicated that postpartum (relative to virgin NAC gene expression profile was significantly enriched for genes related to addiction and reward in 5 of 5 independently curated databases (e.g., Malacards, Phenopedia. Over 100 addiction/reward related genes were identified and these included: Per1, Per2, Arc, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder, and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions.

  9. Altered Global Gene Expression in First Trimester Placentas of Women Destined to Develop Preeclampsia

    Science.gov (United States)

    Founds, Sandra A.; Conley, Yvette P.; Lyons-Weiler, James F.; Jeyabalan, Arun; Hogge, W. Allen; Conrad, Kirk P.

    2009-01-01

    Background Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely-held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia. Methods Surplus chorionic villus sampling (CVS) tissues were collected at 10–12 weeks gestation in 160 patients with singleton fetuses. Four patients developed preeclampsia, and their banked CVS specimens were matched to 8 control samples from patients with unaffected pregnancies. Affymetrix HG-U133 Plus 2.0 GeneChips were utilized for microarray analysis. Naïve Bayes prediction modeling and pathway analysis were conducted. qRT-PCR examined three of the dysregulated genes. Results Thirty-six differentially expressed genes were identified in the preeclampsia placentas. qRT-PCR verified the microarray analysis. Thirty-one genes were down-regulated. Many were related to inflammation/immunoregulation and cell motility. Decidual gene dysregulation was prominent. No evidence was found for alterations in hypoxia and oxidative stress regulated genes. Conclusions To our knowledge, this is the first study to show dysregulation of gene expression in the early placentas of women ~6 months before developing preeclampsia, thereby reinforcing a placental origin of the disorder. We hypothesize that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization, or both, thereby impairing trophoblast invasion. Several of the genes provide potential targets for the development of clinical biomarkers in maternal blood during the first trimester. Supplementary

  10. Alterations in the K-ras and p53 genes in rat lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Belinsky, S.A.; Swafford, D.S.; Finch, G.L.; Mitchell, C.E. [Inhalation Toxicology Research Institute, Albuquerque, NM (United States)] [and others

    1997-06-01

    Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. The transition mutations formed could have been derived from deamination of cytosine. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 of 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors. 2 figs., 2 tabs., 48 refs.

  11. Premature estrogen exposure alters endometrial gene expression to disrupt pregnancy in the pig.

    Science.gov (United States)

    Ross, Jason W; Ashworth, Morgan D; White, Frankie J; Johnson, Greg A; Ayoubi, Patricia J; DeSilva, Udaya; Whitworth, Kristin M; Prather, Randall S; Geisert, Rodney D

    2007-10-01

    Establishment and maintenance of pregnancy in the pig involve intricate communication between the developing conceptuses and maternal endometrium. Conceptus synthesis and release of estrogen during trophoblastic elongation are essential factors involved with establishing conceptus-uterine communication. The present study identified endometrial changes in gene expression associated with implantation failure and complete pregnancy loss after premature exposure of pregnant gilts to exogenous estrogen. Gilts were treated with either 5 mg estradiol cypionate (EC) or corn oil on d-9 and -10 gestation, which was associated with complete conceptus degeneration by d-17 gestation. Microarray analysis of gene expression revealed that a total of eight, 32, and five genes were up-regulated in the EC endometrium, whereas one, 39, and 16 genes were down-regulated, on d 10, 13, and 15, respectively. Four endometrial genes altered by EC, aldose reductase (AKR1B1), secreted phosphoprotein 1 (SPP1), CD24 antigen (CD24), and neuromedin B (NMB), were evaluated using quantitative RT-PCR and in situ hybridization. In situ hybridization localized gene expression for NMB, CD24, AKR1B1, and SPP1 in the luminal epithelium, and confirmed the expression patterns from RT-PCR analysis. The aberrant expression patterns of endometrial AKR1B1, SPP1, CD24, and NMB 3-4 d after premature estrogen exposure to pregnant gilts may be involved with conceptus attachment failure to the uterine surface epithelium and induction of endometrial responses that disrupt the establishment of a viable pregnancy.

  12. Altered expression of genes for Kir ion channels in dilated cardiomyopathy.

    Science.gov (United States)

    Szuts, Viktoria; Ménesi, Dalma; Varga-Orvos, Zoltán; Zvara, Ágnes; Houshmand, Nazanin; Bitay, Miklós; Bogáts, Gábor; Virág, László; Baczkó, István; Szalontai, Balázs; Geramipoor, Amir; Cotella, Diego; Wettwer, Erich; Ravens, Ursula; Deák, Ferenc; Puskás, László G; Papp, Julius Gy; Kiss, Ibolya; Varró, András; Jost, Norbert

    2013-08-01

    Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K⁺ channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1-2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.

  13. Long-term oil contamination alters the molecular ecological networks of soil microbial functional genes

    Directory of Open Access Journals (Sweden)

    Yuting eLiang

    2016-02-01

    Full Text Available With knowledge on microbial composition and diversity, investigation of within-community interactions is a further step to elucidate microbial ecological functions, such as the biodegradation of hazardous contaminants. In this work, microbial functional molecular ecological networks were studied in both contaminated and uncontaminated soils to determine the possible influences of oil contamination on microbial interactions and potential functions. Soil samples were obtained from an oil-exploring site located in South China, and the microbial functional genes were analyzed with GeoChip, a high-throughput functional microarray. By building random networks based on null model, we demonstrated that overall network structures and properties were significantly different between contaminated and uncontaminated soils (P < 0.001. Network connectivity, module numbers, and modularity were all reduced with contamination. Moreover, the topological roles of the genes (module hub and connectors were altered with oil contamination. Subnetworks of genes involved in alkane and polycyclic aromatic hydrocarbon degradation were also constructed. Negative co-occurrence patterns prevailed among functional genes, thereby indicating probable competition relationships. The potential keystone genes, defined as either hubs or genes with highest connectivities in the network, were further identified. The network constructed in this study predicted the potential effects of anthropogenic contamination on microbial community co-occurrence interactions.

  14. Transcriptional activity of detoxification genes is altered by ultraviolet filters in Chironomus riparius.

    Science.gov (United States)

    Martínez-Guitarte, José-Luis

    2018-03-01

    Ultraviolet (UV) filters are compounds used to prevent the damage produced by UV radiation in personal care products, plastics, etc. They have been associated with endocrine disruption, showing anti-estrogen activity in vertebrates and altering the ecdysone pathway in invertebrates. Although they have attracted the attention of multiple research teams there is a lack of data about how animals activate detoxification systems, especially in invertebrates. Here, analysis of the effects of two UV filters, benzophenone-3 (BP3) and 4-methylbenzylidene camphor (4MBC), on the transcriptional activity of nine genes covering the three steps of the detoxification process has been performed. Four cytochrome P450 genes belonging to different members of this family, five GST genes, and the multidrug resistance protein 1 (MRP1) gene were studied by RT-PCR to analyze their transcriptional activity in fourth instar larvae exposed to the UV filters for 8 and 24h. The obtained results show a differential response with downregulation of the different Cyp450s tested by 4MBC while BP3 seems not to modify their expression. On the other hand, some of the GST genes were affected by one or other of the filters, showing a less homogenous response. Finally, MRP1 was activated by both filters but at different times. These results demonstrate for first time that UV filters alter the expression of genes involved in the different steps of the detoxification process and that they can be processed by phase I enzymes other than Cyp450s. They also suggest that UV filters affect biotransformation processes, compromising the ability of the individual to respond to chemical stress, so further research is needed to know the extent of the damage that they can produce in the resistance of the cell to chemicals. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Prevalence of BRCA1 and BRCA2 gene mutations in families with medium and high risk of breast and ovarian cancer in Brazil

    Directory of Open Access Journals (Sweden)

    V.F. Esteves

    2009-05-01

    Full Text Available Of all malignant neoplasias affecting women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to determine the frequency of genetic modifications in families with medium and high risk for breast and ovarian cancer from different regions of Brazil. An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high-risk families for breast and/or ovarian cancer. After heredogram construction, a blood sample was taken and DNA extraction was performed in all index cases. The protein truncation test was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Of the 612 individuals submitted to genetic testing, 21 (3.4%, 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. Of the 19 BRCA1 mutations found in the 18 participants, 7 consisted of ins6kb mutations, 4 were 5382insC, 3 were 2156delGinsCC, 2 were 185delAG, 1 was C1201G, 1 was C3522T, and 1 was 3450del4. With respect to the BRCA2 gene, 3 mutations were found: 5878del10, 5036delA and 4232insA (one case each. The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies on high-risk Brazilian populations. The inclusion of individuals with medium risk may have contributed to the lower prevalence observed.

  16. Application of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes for gene transfer into human ovarian carcinoma cells.

    NARCIS (Netherlands)

    Verbaan, F.J.; Klouwenberg, P.K.; Steenis, J.H. van; Snel, C.J.; Boerman, O.C.; Hennink, W.E.; Storm, G.

    2005-01-01

    Previously, attempts were made in our laboratory to transfect human ovarian cancer (OVCAR-3) cells, growing in the peritoneal cavity of nude mice, by intraperitoneal administration of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-based polyplexes. However, hardly any transfection of the

  17. Genetic profiles distinguish different types of hereditary ovarian cancer

    DEFF Research Database (Denmark)

    Domanska, Katarina; Malander, Susanne; Staaf, Johan

    2010-01-01

    Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer...... as a control group. Unsupervised cluster analysis identified two distinct subgroups related to genetic complexity. Sporadic and HBOC associated tumors had complex genetic profiles with an average 41% of the genome altered, whereas the mismatch repair defective tumors had stable genetic profiles...... that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer....

  18. Ovarian cancer

    International Nuclear Information System (INIS)

    Wakabayashi, Yukari; Yachida, Meri; Akata, Soichi; Kawana, Koji; Kotake, Fumio; Kakizaki, Dai; Abe, Kimihiko; Negishi, Noriyuki; Akiya, Kiyoshi

    1988-01-01

    In 40 patients undergoing pre-treatment for an ovarian tumor, a CT scan of the pelvis and measurements of their CA 125, CA 19 - 9, IAP (immunosupressive acidic antigen), and TPA (tissue polypeptide antigen were performed. The specificity and sensitivity of the CT diagnosis was found to be better than any of other tumor markers measurements. Comparison of the 4 markers showed that the CA 125 testing had the greatest sensitivity in detecting an ovarian cancer. Moreover, the sensitivity of CA 125, was better than a combination of the 4 markers. Thus, a CT scan still remains necessary for the diagnosis of an ovarian cancer. (author)

  19. Genome wide transcriptome analysis of dendritic cells identifies genes with altered expression in psoriasis.

    Directory of Open Access Journals (Sweden)

    Kata Filkor

    Full Text Available Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS or peptidoglycan (PGN induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs upon PGN induced tolerance. Using SAGE-Seq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (Kegg analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified

  20. Silver nanoparticles mediated altered gene expression of melanin biosynthesis genes in Bipolaris sorokiniana.

    Science.gov (United States)

    Mishra, Sandhya; Singh, H B

    2015-03-01

    Melanin production in many fungal phytopathogens has been investigated to play direct or indirect role in pathogenesis. However, in Bipolaris sorokiniana, the spot blotch pathogen of wheat, much less is known about the role melanin play in pathogenesis. As an extension of our previous report, the present study aims to investigate the plausible association between melanin production and virulence factor in B. sorokiniana. In the previous study, we carried out analysis on the antifungal efficacy of biosynthesized silver nanoparticles (AgNPs) against B. sorokiniana. The present investigation revealed the gene expression analysis of melanin biosynthesis genes viz. polyketide synthase (PKS1) and scytalone dehydratase (SCD1) under the influence of AgNPs. The 0.05mg/ml concentration of AgNPs yielded noticeable inhibition of B. sorokiniana growth, while 0.1mg/ml concentration of AgNPs accounted for complete inhibition of pathogen growth. In addition, the semiquantitative RT-PCR analysis exhibited reduced expression of PKS1 and SCD1 under the influence of AgNPs treatment. Furthermore, the qRT-PCR demonstrated 6.47 and 1.808 fold significant decrease in the expression pattern of PKS1 and SCD1, respectively, in B. sorokiniana treated with AgNPs. The present study provides probable understanding of molecular events underlying the antifungal role of AgNPs against B. sorokiniana. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. Altered gene expression profile in a mouse model of SCN8A encephalopathy.

    Science.gov (United States)

    Sprissler, Ryan S; Wagnon, Jacy L; Bunton-Stasyshyn, Rosie K; Meisler, Miriam H; Hammer, Michael F

    2017-02-01

    SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na v 1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3-fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Kidney gene expression analysis in a rat model of intrauterine growth restriction reveals massive alterations of coagulation genes.

    Science.gov (United States)

    Buffat, Christophe; Boubred, Farid; Mondon, Françoise; Chelbi, Sonia T; Feuerstein, Jean-Marc; Lelièvre-Pégorier, Martine; Vaiman, Daniel; Simeoni, Umberto

    2007-11-01

    In this study, low birth weight was induced in rats by feeding the dams with a low-protein diet during pregnancy. Kidneys from the fetuses at the end of gestation were collected and showed a reduction in overall and relative weight, in parallel with other tissues (heart and liver). This reduction was associated with a reduction in nephrons number. To better understand the molecular basis of this observation, a transcriptome analysis contrasting kidneys from control and protein-deprived rats was performed, using a platform based upon long isothermic oligonucleotides, strengthening the robustness of the results. We could identify over 1800 transcripts modified more than twice (772 induced and 1040 repressed). Genes of either category were automatically classified according to functional criteria, making it possible to bring to light a large cluster of genes involved in coagulation and complement cascades. The promoters of the most induced and most repressed genes were contrasted for their composition in putative transcription factor binding sites, suggesting an overrepresentation of the AP1R binding site, together with the transcription induction of factors actually binding to this site in the set of induced genes. The induction of coagulation cascades in the kidney of low-birth-weight rats provides a putative rationale for explaining thrombo-endothelial disorders also observed in intrauterine growth-restricted human newborns. These alterations in the kidneys have been reported as a probable cause for cardiovascular diseases in the adult.

  3. Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors

    Directory of Open Access Journals (Sweden)

    Hamm Christopher A

    2010-09-01

    Full Text Available Abstract Background Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established - namely, the Swarm Rat Chondrosarcoma (SRC - and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. Methods To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. Results The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression. Conclusion This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that

  4. Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors

    International Nuclear Information System (INIS)

    Hamm, Christopher A; Wang, Deli; Malchenko, Sergey; Fatima Bonaldo, Maria de; Casavant, Thomas L; Hendrix, Mary JC; Soares, Marcelo B; Stevens, Jeff W; Xie, Hehuang; Vanin, Elio F; Morcuende, Jose A; Abdulkawy, Hakeem; Seftor, Elisabeth A; Sredni, Simone T; Bischof, Jared M

    2010-01-01

    Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established - namely, the Swarm Rat Chondrosarcoma (SRC) - and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression. This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that thymosin-β4 may have a role in chondrosarcoma metastasis

  5. New insights on the pathogenesis of ovarian carcinoma: molecular basis and clinical implications.

    Science.gov (United States)

    Gadducci, Angiolo; Guerrieri, Maria Elena; Genazzani, Andrea Riccardo

    2012-08-01

    Ovarian carcinoma can be subdivided into two categories termed type I and type II. Type I tumours, usually having an indolent clinical behaviour, are often detected in early stage, and rarely harbour p53 gene mutations. Each histological type has a distinct molecular profile with mutations of genes involved in different signalling transduction pathways, such as KRAS, BRAF, CTNNB1, PTEN, PIK3CA and ARID1A. Type II tumours, accounting for 75% of the cases, have a very aggressive biological behaviour, are usually in advanced stage at presentation, harbour p53 gene mutations in 80% of the cases, and sometimes have alterations of homologous recombination (HR). Both type I and type II tumours arise from extra-ovarian precursors. Serous carcinomas derive from tubal epithelium, endometrioid and clear cell carcinomas from endometrial tissue, and mucinous and Brenner tumours from transitional epithelial cells located near the tubo-peritoneal junction. These new concepts on the pathogenesis of ovarian carcinoma could deeply modify both the preventive approach in women with germ-line BRCA₁ or BRCA₂ mutations and the treatment of patients with advanced or recurrent disease. For instance, BRAF inhibitors could be used in low-grade serous carcinomas, PIK3CA inhibitors could be employed in clear cell carcinoma, and poly (ADP-ribose) polymerase inhibitors could be used not only in hereditary ovarian carcinoma but also in non-hereditary, high-grade serous ovarian carcinoma which sometimes shows defective HR.

  6. Gene expression of sphingolipid metabolism pathways is altered in hidradenitis suppurativa.

    Science.gov (United States)

    Dany, Mohammed; Elston, Dirk

    2017-08-01

    Hidradenitis suppurativa (HS) is a debilitating skin disease characterized by painful recurrent nodules and abscesses caused by chronic inflammation. Early events in the development of HS are believed to occur in the folliculopilosebaceous unit; however, the signaling pathways behind this mechanism are unknown. Sphingolipids, such as ceramide, are essential components of the skin and appendages and have important structural and signaling roles. We sought to explore whether the gene expression of enzymes involved in sphingolipid metabolic pathways is altered in HS. A microarray data set including 30 samples was used to compare the expression of sphingolipid-related enzymes in inflammatory skin lesions from HS patients (n = 17) with the expression in clinically healthy skin tissue (n = 13). Differential expression of sphingolipid metabolism-related genes was analyzed using Gene Expression Omnibus 2R. HS lesional skin samples have significantly decreased expression of enzymes generating ceramide and sphingomyelin, increased expression of enzymes catabolizing ceramide to sphingosine, and increased expression of enzymes converting ceramide to galactosylceramide and gangliosides. Limitations of this study include assessing the expression of sphingolipid-related enzymes without assessing the levels of the related sphingolipids. Our study suggests that sphingolipid metabolism is altered in HS lesional skin compared with normal skin. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  7. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Marilanda Ferreira Bellini

    2012-01-01

    Full Text Available TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH, overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.

  8. Bisphenol A exposure alters developmental gene expression in the fetal rhesus macaque uterus.

    Directory of Open Access Journals (Sweden)

    Kathryn C Calhoun

    Full Text Available Bisphenol A (BPA exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 µg/kg BPA or vehicle control daily from gestation day (GD 50-100 or GD100-165. Fetal uteri were collected at the completion of treatment (GD100 or GD165; tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERα and progesterone receptor (PR were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERα, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life.

  9. Ovarian Cancer

    Science.gov (United States)

    ... I find more information about ovarian and other gynecologic cancers? Centers for Disease Control and Prevention: 800-CDC-INFO or www. cdc. gov/ cancer/ gynecologic National Cancer Institute: 800-4-CANCER or www. ...

  10. Recreational Music-Making alters gene expression pathways in patients with coronary heart disease.

    Science.gov (United States)

    Bittman, Barry; Croft, Daniel T; Brinker, Jeannie; van Laar, Ryan; Vernalis, Marina N; Ellsworth, Darrell L

    2013-02-25

    Psychosocial stress profoundly impacts long-term cardiovascular health through adverse effects on sympathetic nervous system activity, endothelial dysfunction, and atherosclerotic development. Recreational Music Making (RMM) is a unique stress amelioration strategy encompassing group music-based activities that has great therapeutic potential for treating patients with stress-related cardiovascular disease. Participants (n=34) with a history of ischemic heart disease were subjected to an acute time-limited stressor, then randomized to RMM or quiet reading for one hour. Peripheral blood gene expression using GeneChip® Human Genome U133A 2.0 arrays was assessed at baseline, following stress, and after the relaxation session. Full gene set enrichment analysis identified 16 molecular pathways differentially regulated (Pstress that function in immune response, cell mobility, and transcription. During relaxation, two pathways showed a significant change in expression in the control group, while 12 pathways governing immune function and gene expression were modulated among RMM participants. Only 13% (2/16) of pathways showed differential expression during stress and relaxation. Human stress and relaxation responses may be controlled by different molecular pathways. Relaxation through active engagement in Recreational Music Making may be more effective than quiet reading at altering gene expression and thus more clinically useful for stress amelioration.

  11. Evaluation of germline BRCA1 and BRCA2 mutations in a multi-ethnic Asian cohort of ovarian cancer patients.

    Science.gov (United States)

    Hasmad, Hanis Nazihah; Lai, Kah Nyin; Wen, Wei Xiong; Park, Daniel Jonathan; Nguyen-Dumont, Tú; Kang, Peter Choon Eng; Thirthagiri, Eswary; Ma'som, Mahirah; Lim, Boon Kiong; Southey, Melissa; Woo, Yin Ling; Teo, Soo-Hwang

    2016-05-01

    Despite the discovery of breast and ovarian cancer predisposition genes BRCA1 and BRCA2 more than two decades ago, almost all the available data relate to women of European ancestry, with only a handful of studies in Asian populations. In this study, we determined the frequency of germline alterations in BRCA1 and BRCA2 in ovarian cancer patients from a multi-ethnic cross-sectional cohort of Asian ovarian cancer patients from Malaysia. From October 2008 to February 2015, we established a hospital-based cohort of ovarian cancer patients and the germline status of all 218 women with invasive epithelial ovarian cancer was tested using targeted amplification and sequencing of the intron-exon junctions and exonic sequences of BRCA1, BRCA2, PALB2 and TP53. BRCA1 and BRCA2 mutations were found in 8% (17 cases) and 3% (7 cases) of the ovarian cancer patients, respectively. Mutation carriers were diagnosed at a similar age to non-carriers, but were more likely to be Indian, have serous ovarian cancer, and have more relatives with breast or ovarian cancer. Nonetheless, 42% (10/24) of mutation carriers did not have any family history of breast or ovarian cancer and offering genetic counselling and genetic testing only to women with family history would mean that 35% (6/17) of BRCA1 mutation carriers and 57% (4/7) of BRCA2 mutation carriers would not be offered genetic testing. Our data suggest that, similar to Caucasians, a significant proportion of Asian ovarian cancer was attributed to germline mutations in BRCA1 and to a lesser extent in BRCA2. Copyright © 2015. Published by Elsevier Inc.

  12. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Pearce, C L; Near, A M; Van Den Berg, D J

    2009-01-01

    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had...... been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P... and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted....

  13. Inactivating Mutation screening of Exon 6 and Exon 10E of FSHR gene in women with Polycystic Ovarian Syndrome in Vellore population

    Science.gov (United States)

    Sekar, Nishu; Sapre, Madhura; Kale, Vaikhari; Prabhu, Yogamaya D.; Renu, Kaviyarasi; Ramgir, Shalaka S.; Abilash, V. G.

    2017-11-01

    Polycystic Ovarian syndrome (PCOS) is a major cause of infertility in females of reproducing age and is typified by oligo-anovulation, hyperandrogenism, hirsutism and polycystic ovaries. FSHR gene located on chromosome 2 p21 is responsible for the normal follicular development and any deletion or mutation in the gene affects the interaction of FSH with its receptor. Thus, it becomes the candidate gene for PCOS study. Inactivating mutation in FSHR gene limits the receptor’s function by creating a complete block, changing the receptor-ligand complex or the basic hormone signal transduction.To screen the inactivating mutations in Exon 6 and Exon 10E of FSHR gene in women diagnosed with PCOS.PCR-RFLP analysis indicated that there were no inactivating mutations found in Exon 6 and Exon 10E. Variations in hormone levels were seen amongst the PCOS patients. There were no inactivating mutations found in FSHR gene of the women diagnosed with PCOS according to the Rotterdam criteria in Vellore population.

  14. Lentiviral CRISPR/Cas9 vector mediated miR-21 gene editing inhibits the epithelial to mesenchymal transition in ovarian cancer cells.

    Science.gov (United States)

    Huo, Wenying; Zhao, Guannan; Yin, Jinggang; Ouyang, Xuan; Wang, Yinan; Yang, Chuanhe; Wang, Baojing; Dong, Peixin; Wang, Zhixiang; Watari, Hidemichi; Chaum, Edward; Pfeffer, Lawrence M; Yue, Junming

    2017-01-01

    CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) mediated genome editing is a powerful approach for loss of function studies. Here we report that lentiviral CRISPR/Cas9 vectors are highly efficient in introducing mutations in the precursor miRNA sequence, thus leading to the loss of miRNA expression and function. We constructed four different lentiviral CRISPR/Cas9 vectors that target different regions of the precursor miR-21 sequence and found that these lentiviral CRISPR/Cas9 miR-21 gRNA vectors induced mutations in the precursor sequences as shown by DNA surveyor mutation assay and Sanger sequencing. Two miR-21 lentiviral CRISPR/Cas9 gRNA vectors were selected to probe miR-21 function in ovarian cancer SKOV3 and OVCAR3 cell lines. Our data demonstrate that disruption of pre-miR-21 sequences leads to reduced cell proliferation, migration and invasion. Moreover, CRISPR/Cas9-mediated miR-21 gene editing sensitizes both SKOV3 and OVCAR3 cells to chemotherapeutic drug treatment. Disruption of miR-21 leads to the inhibition of epithelial to mesenchymal transition (EMT) in both SKOV3 and OVCAR3 cells as evidenced by the upregulation of epithelial cell marker E-cadherin and downregulation of mesenchymal marker genes, vimentin and Snai2. The miR-21 target genes PDCD4 and SPRY2 were upregulated in cells transduced with miR-21gRNAs compared to controls. Our study indicates that lentiviral CRISPR/Cas9-mediated miRNA gene editing is an effective approach to address miRNA function, and disruption of miR-21 inhibits EMT in ovarian cancer cells.

  15. Altered amygdalar resting-state connectivity in depression is explained by both genes and environment.

    Science.gov (United States)

    Córdova-Palomera, Aldo; Tornador, Cristian; Falcón, Carles; Bargalló, Nuria; Nenadic, Igor; Deco, Gustavo; Fañanás, Lourdes

    2015-10-01

    Recent findings indicate that alterations of the amygdalar resting-state fMRI connectivity play an important role in the etiology of depression. While both depression and resting-state brain activity are shaped by genes and environment, the relative contribution of genetic and environmental factors mediating the relationship between amygdalar resting-state connectivity and depression remain largely unexplored. Likewise, novel neuroimaging research indicates that different mathematical representations of resting-state fMRI activity patterns are able to embed distinct information relevant to brain health and disease. The present study analyzed the influence of genes and environment on amygdalar resting-state fMRI connectivity, in relation to depression risk. High-resolution resting-state fMRI scans were analyzed to estimate functional connectivity patterns in a sample of 48 twins (24 monozygotic pairs) informative for depressive psychopathology (6 concordant, 8 discordant and 10 healthy control pairs). A graph-theoretical framework was employed to construct brain networks using two methods: (i) the conventional approach of filtered BOLD fMRI time-series and (ii) analytic components of this fMRI activity. Results using both methods indicate that depression risk is increased by environmental factors altering amygdalar connectivity. When analyzing the analytic components of the BOLD fMRI time-series, genetic factors altering the amygdala neural activity at rest show an important contribution to depression risk. Overall, these findings show that both genes and environment modify different patterns the amygdala resting-state connectivity to increase depression risk. The genetic relationship between amygdalar connectivity and depression may be better elicited by examining analytic components of the brain resting-state BOLD fMRI signals. © 2015 Wiley Periodicals, Inc.

  16. [Correlation between epigenetic alterations in the insulin growth factor-II gene and hepatocellular carcinoma].

    Science.gov (United States)

    Dong, Zhi-zhen; Yao, Deng-fu; Wu, Wei; Qiu, Li-wei; Yao, Ning-hua; Yan, Xiao-di; Yu, Dan-dan; Chen, Jie

    2012-08-01

    To investigate whether epigenetic alterations in the insulin-like growth factor-II (IGF-II) gene that cause differential transcription or expression are correlated with onset and severity of hepatocellular carcinoma (HCC). Patient-matched specimens of HCC, paracancerous, and non-cancerous tissues were collected from 40 primary liver cancer patients. Epigenetic alterations in the promoter (P3) sequence of the IGF-II gene were analyzed by methylation-specific PCR (MSP) and IGF-II transcription was measured by RT-PCR. IGF-II protein expression and clinicopathological features were assessed by immunohistochemistry and microscopic observation. The rate of IGF-II P3 methylation was significantly lower in HCC tissues (0%) than in paracancerous tissues (vs. 47.5%; x2 = 24.918, P less than 0.001) and non-cancerous tissues (vs. 100%; x2 = 80.000, P less than 0.001). IGF-II mRNA expression was significantly higher in HCC tissues (100%) than in paracancerous tissues (vs. 52.5%; x2 = 24.918, P less than 0.001) and non-cancerous tissues (vs. 0%; x2 = 80.000, P less than 0.001). IGF-II protein expression was significantly higher in HCC tissues (82.5%) than in paracancerous tissues (vs. 45.0%; x2 = 12.170, P less than 0.001) and non-cancerous tissues (vs. 0%; x2 = 56.170, P less than 0.001). IGF-II overexpression in HCC was significantly associated with degree of differentiation, extent of infiltrated serosa, size of tumor, and HBV-positive infection status. Epigenetic alterations in the IGF-II gene regulate its transcription and expression and are closely associated with HCC development and progression.

  17. Novel germline mutations and unclassified variants of BRCA1 and BRCA2 genes in Chinese women with familial breast/ovarian cancer.

    Science.gov (United States)

    Cao, Wen-Ming; Gao, Yun; Yang, Hong-Jian; Xie, Shang-Nao; Ding, Xiao-Wen; Pan, Zhi-Wen; Ye, Wei-Wu; Wang, Xiao-Jia

    2016-02-06

    Germline mutations in the BRCA1 and BRCA2 genes greatly increase a woman's risk of developing breast and/or ovarian cancer. The prevalence and distribution of such mutations differ across races/ethnicities. Several studies have investigated Chinese women with high-risk breast cancer, but the full spectrum of the mutations in these two genes remains unclear. In this study, 133 unrelated Chinese women with familial breast/ovarian cancer living in Zhejiang, eastern China, were enrolled between the years 2008 and 2014. The complete coding regions and exon-intron boundaries of BRCA1 and BRCA2 were screened by PCR-sequencing assay. Haplotype analysis was performed to confirm BRCA1 and BRCA2 founder mutations. In silico predictions were performed to identify the non-synonymous amino acid changes that were likely to disrupt the functions of BRCA1 and BRCA2. A total of 23 deleterious mutations were detected in the two genes in 31 familial breast/ovarian cancer patients with a total mutation frequency of 23.3% (31/133). The highest frequency of 50.0% (8/16) was found in breast cancer patients with a history of ovarian cancer. The frequencies of BRCA1 and BRCA2 mutations were 13.5 % (18/133) and 9.8% (13/133), respectively. We identified five novel deleterious mutations (c.3295delC, c.3780_3781delAG, c.4063_4066delAATC, c.5161 > T and c.5173insA) in BRCA1 and seven (c.1-40delGA, c.4487delC, c.469_473delAAGTC, c.5495delC, c.6141T > A, c.6359C > G and c.7588C > T) in BRCA2, which accounted for 52.2% (12/23) of the total mutations. Six recurrent mutations were found, including four (c.3780_3781delAG, c.5154G > A, c.5468-1del8 and c.5470_5477del8) in BRCA1 and two (c.3109C > T and c.5682C > G) in BRCA2. Two recurrent BRCA1 mutations (c.5154G > A and c.5468-1del8) were identified as putative founder mutations. We also found 11 unclassified variants, and nine of these are novel. The possibility was that each of the non-synonymous amino acid changes would disrupt the function of

  18. The Expression of Petunia Strigolactone Pathway Genes is Altered as Part of the Endogenous Developmental Program

    Science.gov (United States)

    Drummond, Revel S. M.; Sheehan, Hester; Simons, Joanne L.; Martínez-Sánchez, N. Marcela; Turner, Rebecca M.; Putterill, Joanna; Snowden, Kimberley C.

    2012-01-01

    Analysis of mutants with increased branching has revealed the strigolactone synthesis/perception pathway which regulates branching in plants. However, whether variation in this well conserved developmental signaling system contributes to the unique plant architectures of different species is yet to be determined. We examined petunia orthologs of the Arabidopsis MAX1 and MAX2 genes to characterize their role in petunia architecture. A single ortholog of MAX1, PhMAX1 which encodes a cytochrome P450, was identified and was able to complement the max1 mutant of Arabidopsis. Petunia has two copies of the MAX2 gene, PhMAX2A and PhMAX2B which encode F-Box proteins. Differences in the transcript levels of these two MAX2-like genes suggest diverging functions. Unlike PhMAX2B, PhMAX2A mRNA levels change in leaves of differing age/position on the plant. Nonetheless, this gene functionally complements the Arabidopsis max2 mutant indicating that the biochemical activity of the PhMAX2A protein is not significantly different from MAX2. The expression of the petunia strigolactone pathway genes (PhCCD7, PhCCD8, PhMAX1, PhMAX2A, and PhMAX2B) was then further investigated throughout the development of wild-type petunia plants. Three of these genes showed changes in mRNA levels over a development series. Alterations to the expression patterns of these genes may influence the branching growth habit of plants by changing strigolactone production and/or sensitivity. These changes could allow both subtle and dramatic changes to branching within and between species. PMID:22645562

  19. Is gene transcription in mussel gills altered after exposure to Ag nanoparticles?

    Science.gov (United States)

    Bebianno, M J; Gonzalez-Rey, M; Gomes, T; Mattos, J J; Flores-Nunes, F; Bainy, A C D

    2015-11-01

    Nanotechnology is a rapid field of development with the enhancement of the production of different types of nanoparticles (NPs) applied in several industrial and commercial applications which increase the risk of their presence in the aquatic environment. Ag NPs have a wide application in everyday life products. However, there is concern about the exposure effects on aquatic organisms to these NPs. Therefore, this study aims to assess gene transcription alterations in mussels Mytilus galloprovincialis gills exposed for 2 weeks to Ag NPs (42 ± 10 nm, 10 μg.L(-1)). The genes were selected based on previous biomarkers and proteomic results and included superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST), caspase 3/7-1 (CAS), cathepsin L (CATH), heat-shock protein 70 (HSP 70), cytochrome P450 4YA (CYP 4YA), the elongation factor (EF1), actin and α- tubulin. No significant changes in gene transcription profiles were observed after exposure of M. galloprovincialis to Ag NPs for 15 days. The lack of significant gene transcription responses is in light with previous results obtained for mussels exposed to these NPs and may be related to the fact that enzyme kinetics and relative abundance of proteins (increase of antioxidant enzymes and metalllothioneins (MTs) with the time of exposure) do not always directly reflect their relative mRNA levels. Nevertheless, their overall expression maintenance may signify that, at end of the exposure period (15 days), the transcription of the respective genes is no longer required, pointing out to a possible adaptation effect to nanoparticles or due to the levels of Ag NPs accumulated in this tissue at this exposure time. This study highlights that gene transcription application and role as an additional and/or alternative end point approach is important to understand the mode of action of these emergent contaminants in aquatic organisms. However, in future studies, the time window needs to be adjusted, as

  20. Molecular epigenetics in the management of ovarian cancer: Are we investigating a rational clinical promise?

    Directory of Open Access Journals (Sweden)

    Ha eNguyen

    2014-04-01

    Full Text Available Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. While liquid tumors are benefitting from epigenetically-related therapies, solid tumors like ovarian cancer are not (yet?. Herein we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Preclinical and clinical research on the role of epigenetic modifications is summarized as well. Sadly, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have preclinical utility in pharmacology and clinical applications for prognosis and diagnosis. Lastly, drugs currently in clinical trials (i.e. histone deacetylase inhibitors are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; what we have now is hope.

  1. Targeting of p38 mitogen-activated protein kinases to early growth response gene 1 (EGR-1) in the human paclitaxel-resistance ovarian carcinoma cells.

    Science.gov (United States)

    Lu, Meisong; Xiao, Lan; Hu, Jianli; Deng, Suo; Xu, Yan

    2008-08-01

    To investigate the relationship between the expression of early growth response gene 1 (EGR-1) and p38MAPK pathway in the paclitaxel resistance of ovarian carcinoma cells, the effect of p38MAPK inhibitor SB203580 on cell apoptosis was examined by using Hoechst 33258 staining. The intracellular Rh123 (Rhodamine 123) accumulation was detected by the flow cytometry (FCM). The 50% inhibition concentration (IC50) of paclitaxel for A2780/Taxol cells was determined by MTT method. Electrophoretic motility shift assay (EMSA) was employed to examine the EGR-1DNA binding activity. MDR1 and EGR-1 mRNA were assessed by RT-PCR. The expressed of p-gp, phosphorylated p53 and p38 were detected by Western blotting. SB203580 could remarkably promote the apoptosis of A2780/Taxol cells, and the cell apoptosis was in a time-dependent manner. Cellular Rh123 accumulation was increased, and the IC50 of paclitaxel for A2780/Taxol cells was decreased significantly. A2780/Taxol cell line after SB203580 treatment was shown to have a significantly higher level of EGR-1 DNA binding activity. SB203580 down-regulated the activity of p38MAPK pathway, but up-regulated EGR-1 expression. SB203580 significantly increased the level of cellular phosphorylated p53 protein, but decreased the p-gp protein level and MDR1 mRNA level in A2780/Taxol cells. There existed a close relationship between p38MAPK pathway and the paclitaxel resistance of ovarian carcinoma cells. The expression of EGR-1 mediated by p38MAPK pathway plays a critical role in paclitaxel resistance of ovarian carcinoma cells.

  2. Candidate Tumor-Suppressor Gene DLEC1 Is Frequently Downregulated by Promoter Hypermethylation and Histone Hypoacetylation in Human Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Joseph Kwong

    2006-04-01

    Full Text Available Suppression of ovarian tumor growth by chromosome 3p was demonstrated in a previous study. Deleted in Lung and Esophageal Cancer 1 (DLEC1 on 3p22.3 is a candidate tumor suppressor in lung, esophageal, and renal cancers. The potential involvement of DLEC1 in epithelial ovarian cancer remains unknown. In the present study, DLEC1 downregulation was found in ovarian cancer cell lines and primary ovarian tumors. Focus-expressed DLEC1 in two ovarian cancer cell lines resulted in 41% to 52% inhibition of colony formation. No chromosomal loss of chromosome 3p22.3 in any ovarian cancer cell line or tissue was found. Promoter hypermethylation of DLEC1 was detected in ovarian cancer cell lines with reduced DLEC1 transcripts, whereas methylation was not detected in normal ovarian epithelium and DLEC1-expressing ovarian cancer cell lines. Treatment with demethylating agent enhanced DLEC1 expression in 90% (9 of 10 of ovarian cancer cell lines. DLEC1 promoter methylation was examined in 13 high-grade ovarian tumor tissues with DLEC1 downregulation, in which 54% of the tumors showed DLEC1 methylation. In addition, 80% of ovarian cancer cell lines significantly upregulated DLEC1 transcripts after histone deacetylase inhibitor treatment. Therefore, our results suggested that DLEC1 suppressed the growth of ovarian cancer cells and that its downregulation was closely associated with promoter hypermethylation and histone hypoacetylation.

  3. Multiplex PCR screening detects small p53 deletions and insertions in human ovarian cancer cell lines.

    Science.gov (United States)

    Runnebaum, I B; Tong, X W; Moebus, V; Heilmann, V; Kieback, D G; Kreienberg, R

    1994-06-01

    Mutations at the p53 tumor suppressor gene locus are a frequent genetic alteration associated with human ovarian carcinoma. Little information exists regarding whether mutational events occur other than point mutations and large deletions, causing loss of heterozygosity. Small intragenic deletions and insertions in the p53 gene have been observed in various human neoplasias. We developed a multiplex polymerase chain reaction (MPCR) screening assay to amplify the complete p53 coding region from genomic DNA in a single step. Deletions and/or insertions were found in six out of 11 newly established ovarian carcinoma cell lines. MPCR detected deletions as small as 2 bp, as confirmed by nucleotide sequence analysis. Most of the observed alterations (6/7) were homozygous or hemizygous. Structural aberrations of the p53 gene possibly leading to loss of p53 cell cycle control may be a consequence of a slipped-mispairing mechanism in rapid DNA replication during repetitious ovulation and wound repair of ovarian epithelial cells. MPCR may be a valuable tool for screening for possible p53 deletion and insertion mutations not only in ovarian cancer but also in other malignancies.

  4. Vinclozolin alters the expression of hormonal and stress genes in the midge Chironomus riparius.

    Science.gov (United States)

    Aquilino, Mónica; Sánchez-Argüello, Paloma; Martínez-Guitarte, José-Luis

    2016-05-01

    Vinclozolin is a fungicide used in agriculture that can reach aquatic ecosystems and affect the organisms living there. Its effects have been intensively studied in vertebrates, where it acts as an antiandrogen, but there is a lack of information about its mechanistic effects on invertebrates. In this work, we analyzed the response of genes related to the endocrine system, the stress response, and the detoxification mechanisms of Chironomus riparius fourth instar larvae after 24h and 48h exposures to 20 (69.9nM), 200 (699nM), and 2000μg/L (6.99μM) of Vinclozolin. Survival analysis showed that this compound has low toxicity, as it was not lethal for this organism at the concentrations used. However, this fungicide was shown to modify the transcriptional activity of the ecdysone response pathway genes EcR, E74, and Kr-h1 by increasing their mRNA levels. While no changes were observed in disembodied, a gene related with the ecdysone synthesis metabolic pathway, Cyp18A1, which is involved in the inactivation of the active form of ecdysone, was upregulated. Additionally, the expression of two genes related to other hormones, FOXO and MAPR, did not show any changes when Vinclozolin was present. The analysis of stress response genes showed significant changes in the mRNA levels of Hsp70, Hsp24, and Gp93, indicating that Vinclozolin activates the cellular stress mechanisms. Finally, the expressions of the genes Cyp4G and GstD3, which encode enzymes involved in phase I and phase II detoxification, respectively, were analyzed. It was found that their mRNA levels were altered by Vinclozolin, suggesting their involvement in the degradation of this compound. For the first time, these results show evidence that Vinclozolin can modulate gene expression, leading to possible significant endocrine alterations of the insect endocrine system. These results also offer new clues about the mode of action of this compound in invertebrates. Copyright © 2016 Elsevier B.V. All rights

  5. Novel Functional MAR Elements of Double Minute Chromosomes in Human Ovarian Cells Capable of Enhancing Gene Expression

    OpenAIRE

    Jin, Yan; Liu, Zheng; Cao, Wei; Ma, Xinying; Fan, Yihui; Yu, Yang; Bai, Jing; Chen, Feng; Rosales, Jesusa; Lee, Ki-Young; Fu, Songbin

    2012-01-01

    Double minute chromosomes or double minutes (DMs) are cytogenetic hallmarks of extrachromosomal genomic amplification and play a critical role in tumorigenesis. Amplified copies of oncogenes in DMs have been associated with increased growth and survival of cancer cells but DNA sequences in DMs which are mostly non-coding remain to be characterized. Following sequencing and bioinformatics analyses, we have found 5 novel matrix attachment regions (MARs) in a 682 kb DM in the human ovarian cance...

  6. Clock Genes and Altered Sleep–Wake Rhythms: Their Role in the Development of Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Annaëlle Charrier

    2017-04-01

    Full Text Available In mammals, the circadian clocks network (central and peripheral oscillators controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder. However, the underlying mechanisms of these associations remain to be ascertained and the cause–effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep–wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders. First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep–wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

  7. Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders.

    Science.gov (United States)

    Charrier, Annaëlle; Olliac, Bertrand; Roubertoux, Pierre; Tordjman, Sylvie

    2017-04-29

    In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause-effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep-wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep-wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

  8. Gene alterations in radiation-induced F344 rat lung tumors

    International Nuclear Information System (INIS)

    Kelly, G.; Hahn, F.F.

    1994-01-01

    The p53 tumor suppressor gene is frequently altered in all major histopathologic types of human lung tumors. Reported p53 mutations include base substitutions, allelic loss, rearrangements, and deletions. Point mutations resulting in base substitutions are clustered within a highly conserved region of the gene encoding exons 508, and mutations in this region substantially extend the half-life of the p53 protein. In addition to its prominent importance in lung carcinogenesis, the p53 gene plays a critical role in the cellular response to genetic damage caused by radiation. Specifically, the protein product of p53 induces a pause or block at the G 1 to S boundary of the cell cycle following radiation-caused DNA damage. This G 1 block may allow the cell time to repair the damaged DNA prior to replication. Cells lacking a functional p53 protein fail to pause for repair and consequently accumulate mutations in the genome at an accelerated rate. p53 has also been implicated as a controlling factor in apoptosis or in programmed cell death induced by DNA-damaging agents, such as ionizing radiation. The p53 gene is mutated in approximately 50% of squamous cell carcinomas from uranium miners who inhaled high doses of radon daughters. The purpose of the present study was to determine if a similar percentage of squamous cell carcinomas with p53 mutations developed in the lungs of rats exposed to aerosols of 239 PuO 2

  9. Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway.

    Science.gov (United States)

    Correa, Stephanie M; Washburn, Linda L; Kahlon, Ravi S; Musson, Michelle C; Bouma, Gerrit J; Eicher, Eva M; Albrecht, Kenneth H

    2012-01-01

    Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XY(B6) mice impaired testis differentiation, but no ovarian tissue developed. If, however, a Y(AKR) chromosome replaced the Y(B6) chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/- B6 XY(AKR), Wt1+/- B6 XY(AKR), B6 XY(POS), and B6 XY(AKR) fetuses. We propose that Wt1(B6) and Sf1(B6) are hypomorphic alleles of testis-determining pathway genes and that Wnt4(B6) is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1(B6) and/or Sf1(B6) alleles that compromise testis differentiation and a Wnt4(B6) allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a "weak" Sry allele, such as the one on the Y(POS) chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal. © 2012 Correa et al.

  10. Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway.

    Directory of Open Access Journals (Sweden)

    Stephanie M Correa

    Full Text Available Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6 mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XY(B6 mice impaired testis differentiation, but no ovarian tissue developed. If, however, a Y(AKR chromosome replaced the Y(B6 chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/- B6 XY(AKR, Wt1+/- B6 XY(AKR, B6 XY(POS, and B6 XY(AKR fetuses. We propose that Wt1(B6 and Sf1(B6 are hypomorphic alleles of testis-determining pathway genes and that Wnt4(B6 is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1(B6 and/or Sf1(B6 alleles that compromise testis differentiation and a Wnt4(B6 allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a "weak" Sry allele, such as the one on the Y(POS chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal.

  11. Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.

    Science.gov (United States)

    Charbonneau, Bridget; Block, Matthew S; Bamlet, William R; Vierkant, Robert A; Kalli, Kimberly R; Fogarty, Zachary; Rider, David N; Sellers, Thomas A; Tworoger, Shelley S; Poole, Elizabeth; Risch, Harvey A; Salvesen, Helga B; Kiemeney, Lambertus A; Baglietto, Laura; Giles, Graham G; Severi, Gianluca; Trabert, Britton; Wentzensen, Nicolas; Chenevix-Trench, Georgia; Whittemore, Alice S; Sieh, Weiva; Chang-Claude, Jenny; Bandera, Elisa V; Orlow, Irene; Terry, Kathryn; Goodman, Marc T; Thompson, Pamela J; Cook, Linda S; Rossing, Mary Anne; Ness, Roberta B; Narod, Steven A; Kupryjanczyk, Jolanta; Lu, Karen; Butzow, Ralf; Dörk, Thilo; Pejovic, Tanja; Campbell, Ian; Le, Nhu D; Bunker, Clareann H; Bogdanova, Natalia; Runnebaum, Ingo B; Eccles, Diana; Paul, James; Wu, Anna H; Gayther, Simon A; Hogdall, Estrid; Heitz, Florian; Kaye, Stanley B; Karlan, Beth Y; Anton-Culver, Hoda; Gronwald, Jacek; Hogdall, Claus K; Lambrechts, Diether; Fasching, Peter A; Menon, Usha; Schildkraut, Joellen; Pearce, Celeste Leigh; Levine, Douglas A; Kjaer, Susanne Kruger; Cramer, Daniel; Flanagan, James M; Phelan, Catherine M; Brown, Robert; Massuger, Leon F A G; Song, Honglin; Doherty, Jennifer A; Krakstad, Camilla; Liang, Dong; Odunsi, Kunle; Berchuck, Andrew; Jensen, Allan; Lubinski, Jan; Nevanlinna, Heli; Bean, Yukie T; Lurie, Galina; Ziogas, Argyrios; Walsh, Christine; Despierre, Evelyn; Brinton, Louise; Hein, Alexander; Rudolph, Anja; Dansonka-Mieszkowska, Agnieszka; Olson, Sara H; Harter, Philipp; Tyrer, Jonathan; Vitonis, Allison F; Brooks-Wilson, Angela; Aben, Katja K; Pike, Malcolm C; Ramus, Susan J; Wik, Elisabeth; Cybulski, Cezary; Lin, Jie; Sucheston, Lara; Edwards, Robert; McGuire, Valerie; Lester, Jenny; du Bois, Andreas; Lundvall, Lene; Wang-Gohrke, Shan; Szafron, Lukasz M; Lambrechts, Sandrina; Yang, Hannah; Beckmann, Matthias W; Pelttari, Liisa M; Van Altena, Anne M; van den Berg, David; Halle, Mari K; Gentry-Maharaj, Aleksandra; Schwaab, Ira; Chandran, Urmila; Menkiszak, Janusz; Ekici, Arif B; Wilkens, Lynne R; Leminen, Arto; Modugno, Francesmary; Friel, Grace; Rothstein, Joseph H; Vergote, Ignace; Garcia-Closas, Montserrat; Hildebrandt, Michelle A T; Sobiczewski, Piotr; Kelemen, Linda E; Pharoah, Paul D P; Moysich, Kirsten; Knutson, Keith L; Cunningham, Julie M; Fridley, Brooke L; Goode, Ellen L

    2014-02-01

    A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

  12. Predictive and therapeutic markers in ovarian cancer

    Science.gov (United States)

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  13. Genetic alterations in mesiodens as revealed by targeted next-generation sequencing and gene co-occurrence network analysis.

    Science.gov (United States)

    Kim, Y Y; Hwang, J; Kim, H-S; Kwon, H J; Kim, S; Lee, J H; Lee, J H

    2017-10-01

    Mesiodens is the most common type of supernumerary tooth which includes a population prevalence of 0.15%-1.9%. Alongside evidence that the condition is heritable, mutations in single genes have been reported in few human supernumerary tooth cases. Gene sequencing methods in tradition way are time-consuming and labor-intensive, whereas next-generation sequencing and bioinformatics are cost-effective for large samples and target sizes. We describe the application of a targeted next-generation sequencing (NGS) and bioinformatics approach to samples from 17 mesiodens patients. Subjects were diagnosed on the basis of panoramic radiograph. A total of 101 candidate genes which were captured custom genes were sequenced on the Illumina HiSeq 2500. Multistep bioinformatics processing was performed including variant identification, base calling, and in silico analysis of putative disease-causing variants. Targeted capture identified 88 non-synonymous, rare, exonic variants involving 42 of the 101 candidate genes. Moreover, we investigated gene co-occurrence relationships between the genomic alterations and identified 88 significant relationships among 18 most recurrent driver alterations. Our search for co-occurring genetic alterations revealed that such alterations interact cooperatively to drive mesiodens. We discovered a gene co-occurrence network in mesiodens patients with functionally enriched gene groups in the sonic hedgehog (SHH), bone morphogenetic proteins (BMP), and wingless integrated (WNT) signaling pathways. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

  14. Identification of genes with altered expression in medullary breast cancer vs. ductal breast cancer and normal breast epithelia

    DEFF Research Database (Denmark)

    Gjerstorff, Morten; Benoit, Vivian; Laenkholm, Anne-Vibeke

    2006-01-01

    ) gene families, Vav1, monoglyceride lipase and NADP+-dependent malic enzyme, exhibited altered expression in MCB vs. ductal breast cancer, and the differences for some of these genes were confirmed on an extended panel of cell lines by quantitative PCR. Immunohistochemical analysis further established...

  15. Evidence of molecular alterations in the tumour suppressor gene WWOX in benign and malignant bone related lesions of the jaws.

    Science.gov (United States)

    Diniz, Marina Gonçalves; Borges, Erica Rievrs; Pimenta, Flavio Juliano; De Mesquita Netto, Ana Carolina; De Marco, Luiz; Gomez, Ricardo Santiago; Gomes, Carolina Cavaliéri

    2011-02-01

    WWOX is a tumour suppressor gene altered in various human neoplasms. Deletion of WWOX is associated with bone metabolic defects and development of osteosarcoma in mice. We hypothesized that alterations of this gene are associated with the development of benign and malignant mesenchymal bone related lesions of the jaws. We investigated WWOX mRNA by nested reverse transcription-PCR and direct sequencing and quantitative real-time PCR in two osteosarcoma, two fibrosarcoma, eight ossifying fibroma and two fibrous dysplasia fresh samples. Malignancy was associated with a decreased WWOX mRNA expression. Aberrant transcription pattern was found in five samples; however, the relative quantification (RQ) of the WWOX mRNA in such lesions was not different from those carrying only the wild-type. We provide new evidence of WWOX alterations in osteosarcomas and demonstrate for the first time alterations of this gene in fibrosarcomas as well as in ossifying fibromas of the jaws.

  16. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation.

    Science.gov (United States)

    Chassaing, Benoit; Van de Wiele, Tom; De Bodt, Jana; Marzorati, Massimo; Gewirtz, Andrew T

    2017-08-01

    The intestinal microbiota plays a central role in the development of many chronic inflammatory diseases including IBD and metabolic syndrome. Administration of substances that alter microbiota composition, including the synthetic dietary emulsifiers polysorbate 80 (P80) and carboxymethylcellulose (CMC), can promote such inflammatory disorders. However, that inflammation itself impacts microbiota composition has obfuscated defining the extent to which these compounds or other substances act directly upon the microbiota versus acting on host parameters that promote inflammation, which subsequently reshapes the microbiota. We examined the direct impact of CMC and P80 on the microbiota using the mucosal simulator of the human intestinal microbial ecosystem (M-SHIME) model that maintains a complex stable human microbiota in the absence of a live host. This approach revealed that both P80 and CMC acted directly upon human microbiota to increase its proinflammatory potential, as revealed by increased levels of bioactive flagellin. The CMC-induced increase in flagellin was rapid (1 day) and driven by altered microbiota gene expression. In contrast, the P80-induced flagellin increase occurred more slowly and was closely associated with altered species composition. Transfer of both emulsifier-treated M-SHIME microbiotas to germ-free recipient mice recapitulated many of the host and microbial alterations observed in mice directly treated with emulsifiers. These results demonstrate a novel paradigm of deconstructing host-microbiota interactions and indicate that the microbiota can be directly impacted by these commonly used food additives, in a manner that subsequently drives intestinal inflammation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate.

    Science.gov (United States)

    Liu, F; Killian, J K; Yang, M; Walker, R L; Hong, J A; Zhang, M; Davis, S; Zhang, Y; Hussain, M; Xi, S; Rao, M; Meltzer, P A; Schrump, D S

    2010-06-24

    Limited information is available regarding epigenomic events mediating initiation and progression of tobacco-induced lung cancers. In this study, we established an in vitro system to examine epigenomic effects of cigarette smoke in respiratory epithelia. Normal human small airway epithelial cells and cdk-4/hTERT-immortalized human bronchial epithelial cells (HBEC) were cultured in normal media with or without cigarette smoke condensate (CSC) for up to 9 months under potentially relevant exposure conditions. Western blot analysis showed that CSC mediated dose- and time-dependent diminution of H4K16Ac and H4K20Me3, while increasing relative levels of H3K27Me3; these histone alterations coincided with decreased DNA methyltransferase 1 (DNMT1) and increased DNMT3b expression. Pyrosequencing and quantitative RT-PCR experiments revealed time-dependent hypomethylation of D4Z4, NBL2, and LINE-1 repetitive DNA sequences; up-regulation of H19, IGF2, MAGE-A1, and MAGE-A3; activation of Wnt signaling; and hypermethylation of tumor suppressor genes such as RASSF1A and RAR-beta, which are frequently silenced in human lung cancers. Array-based DNA methylation profiling identified additional novel DNA methylation targets in soft-agar clones derived from CSC-exposed HBEC; a CSC gene expression signature was also identified in these cells. Progressive genomic hypomethylation and locoregional DNA hypermethylation induced by CSC coincided with a dramatic increase in soft-agar clonogenicity. Collectively, these data indicate that cigarette smoke induces 'cancer-associated' epigenomic alterations in cultured respiratory epithelia. This in vitro model may prove useful for delineating early epigenetic mechanisms regulating gene expression during pulmonary carcinogenesis.

  18. Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma.

    Science.gov (United States)

    Marcinkiewicz, Katarzyna M; Gudas, Lorraine J

    2014-10-01

    We recently reported a role of polycomb repressive complex 2 (PRC2) and PRC2 trimethylation of histone 3 lysine 27 (H3K27me3) in the regulation of homeobox (HOX) (Marcinkiewicz and Gudas, 2013, Exp Cell Res) gene transcript levels in human oral keratinocytes (OKF6-TERT1R) and tongue squamous cell carcinoma (SCC) cells. Here, we assessed both the levels of various histone modifications at a subset of homeobox genes and genome wide DNA methylation patterns in OKF6-TERT1R and SCC-9 cells by using ERRBS (enhanced reduced representation bisulfite sequencing). We detected the H3K9me3 mark at HOXB7, HOXC10, HOXC13, and HOXD8 at levels higher in OKF6-TERT1R than in SCC-9 cells; at IRX1 and SIX2 the H3K9me3 levels were conversely higher in SCC-9 than in OKF6-TERT1R. The H3K79me3 mark was detectable only at IRX1 in OKF6-TERT1R and at IRX4 in SCC-9 cells. The levels of H3K4me3 and H3K36me3 marks correlate with the transcript levels of the assessed homeobox genes in both OKF6-TERT1R and SCC-9. We detected generally lower CpG methylation levels on DNA in SCC-9 cells at annotated genomic regions which were differentially methylated between OKF6-TERT1R and SCC-9 cells; however, some genomic regions, including the HOX gene clusters, showed DNA methylation at higher levels in SCC-9 than OKF6-TERT1R. Thus, both altered histone modification patterns and changes in DNA methylation are associated with dysregulation of homeobox gene expression in human oral cavity SCC cells, and this dysregulation potentially plays a role in the neoplastic phenotype of oral keratinocytes. © 2014 Wiley Periodicals, Inc.

  19. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.

    Science.gov (United States)

    Desai, Radha; Frazier, Ann E; Durigon, Romina; Patel, Harshil; Jones, Aleck W; Dalla Rosa, Ilaria; Lake, Nicole J; Compton, Alison G; Mountford, Hayley S; Tucker, Elena J; Mitchell, Alice L R; Jackson, Deborah; Sesay, Abdul; Di Re, Miriam; van den Heuvel, Lambert P; Burke, Derek; Francis, David; Lunke, Sebastian; McGillivray, George; Mandelstam, Simone; Mochel, Fanny; Keren, Boris; Jardel, Claude; Turner, Anne M; Ian Andrews, P; Smeitink, Jan; Spelbrink, Johannes N; Heales, Simon J; Kohda, Masakazu; Ohtake, Akira; Murayama, Kei; Okazaki, Yasushi; Lombès, Anne; Holt, Ian J; Thorburn, David R; Spinazzola, Antonella

    2017-06-01

    Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data. We report deletions that generate chimeric ATAD3B/ATAD3A fusion genes in individuals from four unrelated families with fatal congenital pontocerebellar hypoplasia, whereas a case with genomic rearrangements affecting the ATAD3C/ATAD3B genes on one allele and ATAD3B/ATAD3A genes on the other displays later-onset encephalopathy with cerebellar atrophy, ataxia and dystonia. Fibroblasts from affected individuals display mitochondrial DNA abnormalities, associated with multiple indicators of altered cholesterol metabolism. Moreover, drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization in control cells, while mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol. These data demonstrate the integration of mitochondria in cellular cholesterol homeostasis, in which ATAD3 plays a critical role. The dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction could be widespread in neurological and neurodegenerative diseases. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

  20. Dietary Phenethyl Isothiocyanate Alters Gene Expression in Human Breast Cancer Cells

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    Young Jin Moon

    2011-01-01

    Full Text Available Phenethyl isothiocyanate (PEITC, a component in cruciferous vegetables, can block chemical carcinogenesis in animal models. Our objective was to determine the effect of treatment with PEITC on gene expression changes in MCF-7 human breast cancer cells in order to evaluate potential mechanisms involved in its chemopreventive effects. MCF-7 cells were treated for 48 hours with either PEITC (3 μM or the vehicle. Total RNA was extracted from cell membrane preparations, and labeled cDNA's representing the mRNA pool were reverse-transcribed directly from total RNA isolated for use in the microarray hybridizations. Two specific human GE Array Kits (Superarray Inc. that both contain 23 marker genes, related to signal transduction pathways or cancer/tumor suppression, plus 2 housekeeping genes (β-actin and GAPDH, were utilized. Arrays from treated and control cells (n=4 per group were evaluated using a Student's t-test. Gene expression was significantly induced for tumor protein p53 (p53, cyclin-dependent kinase inhibitor 1C (p57 Kip2, breast cancer Type 2 early onset (BRCA2, cAMP responsive element binding protein 2 (ATF-2, interleukin 2 (IL-2, heat shock 27 KD protein (hsp27, and CYP19 (aromatase. Induction of p57 Kip2, p53, BRCA2, IL-2, and ATF-2 would be expected to decrease cellular proliferation and increase tumor suppression and/or apoptosis. PEITC treatment produced significant alterations in some genes involved in tumor suppression and cellular proliferation/apoptosis that may be important in explaining the chemopreventive effects of PEITC.

  1. Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes.

    Science.gov (United States)

    Kolesar, Jill M; Traynor, Anne M; Holen, Kyle D; Hoang, Tien; Seo, Songwon; Kim, Kyungmann; Alberti, Dona; Espinoza-Delgado, Igor; Wright, John J; Wilding, George; Bailey, Howard H; Schelman, William R

    2013-09-01

    Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis. Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples. In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 (p vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p vorinostat in tissue biopsies in most patients. Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3.

  2. Stratification of clear cell renal cell carcinoma (ccRCC) genomes by gene-directed copy number alteration (CNA) analysis.

    Science.gov (United States)

    Thiesen, H-J; Steinbeck, F; Maruschke, M; Koczan, D; Ziems, B; Hakenberg, O W

    2017-01-01

    Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs) presented in 48 clear cell renal cell carcinoma (ccRCC) genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25) and 20 G3 (ratio 0.58). Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes) has been successfully validated on published Swiss data (GSE19949) leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and predictive value.

  3. Stratification of clear cell renal cell carcinoma (ccRCC genomes by gene-directed copy number alteration (CNA analysis.

    Directory of Open Access Journals (Sweden)

    H-J Thiesen

    Full Text Available Tumorigenic processes are understood to be driven by epi-/genetic and genomic alterations from single point mutations to chromosomal alterations such as insertions and deletions of nucleotides up to gains and losses of large chromosomal fragments including products of chromosomal rearrangements e.g. fusion genes and proteins. Overall comparisons of copy number alterations (CNAs presented in 48 clear cell renal cell carcinoma (ccRCC genomes resulted in ratios of gene losses versus gene gains between 26 ccRCC Fuhrman malignancy grades G1 (ratio 1.25 and 20 G3 (ratio 0.58. Gene losses and gains of 15762 CNA genes were mapped to 795 chromosomal cytoband loci including 280 KEGG pathways. CNAs were classified according to their contribution to Fuhrman tumour gradings G1 and G3. Gene gains and losses turned out to be highly structured processes in ccRCC genomes enabling the subclassification and stratification of ccRCC tumours in a genome-wide manner. CNAs of ccRCC seem to start with common tumour related gene losses flanked by CNAs specifying Fuhrman grade G1 losses and CNA gains favouring grade G3 tumours. The appearance of recurrent CNA signatures implies the presence of causal mechanisms most likely implicated in the pathogenesis and disease-outcome of ccRCC tumours distinguishing lower from higher malignant tumours. The diagnostic quality of initial 201 genes (108 genes supporting G1 and 93 genes G3 phenotypes has been successfully validated on published Swiss data (GSE19949 leading to a restricted CNA gene set of 171 CNA genes of which 85 genes favour Fuhrman grade G1 and 86 genes Fuhrman grade G3. Regarding these gene sets overall survival decreased with the number of G3 related gene losses plus G3 related gene gains. CNA gene sets presented define an entry to a gene-directed and pathway-related functional understanding of ongoing copy number alterations within and between individual ccRCC tumours leading to CNA genes of prognostic and

  4. Sequence Alterations of I(Ks Potassium Channel Genes in Kazakhstani Patients with Atrial Fibrillation

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    Ainur Akilzhanova

    2014-12-01

    Full Text Available Introduction. Atrial fibrillation (AF is the most common sustained arrhythmia, and it results in significant morbidity and mortality. However, the pathogenesis of AF remains unclear to date. Recently, more pieces of evidence indicated that AF is a multifactorial disease resulting from the interaction between environmental factors and genetics. Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks may underlie AF.Objective. To investigate sequence alterations of I(Ks potassium channel genes