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Sample records for gene expressing cancer

  1. Expression of KLK2 gene in prostate cancer

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    Sajad Shafai

    2018-01-01

    Conclusion: The expression of KLK2 gene in people with prostate cancer is the higher than the healthy person; finally, according to the results, it could be mentioned that the KLK2 gene considered as a useful factor in prostate cancer, whose expression is associated with progression and development of the prostate cancer.

  2. Glycosyltransferase Gene Expression Profiles Classify Cancer Types and Propose Prognostic Subtypes

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    Ashkani, Jahanshah; Naidoo, Kevin J.

    2016-05-01

    Aberrant glycosylation in tumours stem from altered glycosyltransferase (GT) gene expression but can the expression profiles of these signature genes be used to classify cancer types and lead to cancer subtype discovery? The differential structural changes to cellular glycan structures are predominantly regulated by the expression patterns of GT genes and are a hallmark of neoplastic cell metamorphoses. We found that the expression of 210 GT genes taken from 1893 cancer patient samples in The Cancer Genome Atlas (TCGA) microarray data are able to classify six cancers; breast, ovarian, glioblastoma, kidney, colon and lung. The GT gene expression profiles are used to develop cancer classifiers and propose subtypes. The subclassification of breast cancer solid tumour samples illustrates the discovery of subgroups from GT genes that match well against basal-like and HER2-enriched subtypes and correlates to clinical, mutation and survival data. This cancer type glycosyltransferase gene signature finding provides foundational evidence for the centrality of glycosylation in cancer.

  3. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each...... pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226...

  4. Identification of Human HK Genes and Gene Expression Regulation Study in Cancer from Transcriptomics Data Analysis

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    Zhang, Zhang; Liu, Jingxing; Wu, Jiayan; Yu, Jun

    2013-01-01

    The regulation of gene expression is essential for eukaryotes, as it drives the processes of cellular differentiation and morphogenesis, leading to the creation of different cell types in multicellular organisms. RNA-Sequencing (RNA-Seq) provides researchers with a powerful toolbox for characterization and quantification of transcriptome. Many different human tissue/cell transcriptome datasets coming from RNA-Seq technology are available on public data resource. The fundamental issue here is how to develop an effective analysis method to estimate expression pattern similarities between different tumor tissues and their corresponding normal tissues. We define the gene expression pattern from three directions: 1) expression breadth, which reflects gene expression on/off status, and mainly concerns ubiquitously expressed genes; 2) low/high or constant/variable expression genes, based on gene expression level and variation; and 3) the regulation of gene expression at the gene structure level. The cluster analysis indicates that gene expression pattern is higher related to physiological condition rather than tissue spatial distance. Two sets of human housekeeping (HK) genes are defined according to cell/tissue types, respectively. To characterize the gene expression pattern in gene expression level and variation, we firstly apply improved K-means algorithm and a gene expression variance model. We find that cancer-associated HK genes (a HK gene is specific in cancer group, while not in normal group) are expressed higher and more variable in cancer condition than in normal condition. Cancer-associated HK genes prefer to AT-rich genes, and they are enriched in cell cycle regulation related functions and constitute some cancer signatures. The expression of large genes is also avoided in cancer group. These studies will help us understand which cell type-specific patterns of gene expression differ among different cell types, and particularly for cancer. PMID:23382867

  5. ANALYSES ON DIFFERENTIALLY EXPRESSED GENES ASSOCIATED WITH HUMAN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    MENG Xu-li; DING Xiao-wen; XU Xiao-hong

    2006-01-01

    Objective: To investigate the molecular etiology of breast cancer by way of studying the differential expression and initial function of the related genes in the occurrence and development of breast cancer. Methods: Two hundred and eighty-eight human tumor related genes were chosen for preparation of the oligochips probe. mRNA was extracted from 16 breast cancer tissues and the corresponding normal breast tissues, and cDNA probe was prepared through reverse-transcription and hybridized with the gene chip. A laser focused fluorescent scanner was used to scan the chip. The different gene expressions were thereafter automatically compared and analyzed between the two sample groups. Cy3/Cy5>3.5 meant significant up-regulation. Cy3/Cy5<0.25 meant significant down-regulation. Results: The comparison between the breast cancer tissues and their corresponding normal tissues showed that 84 genes had differential expression in the Chip. Among the differently expressed genes, there were 4 genes with significant down-regulation and 6 with significant up-regulation. Compared with normal breast tissues, differentially expressed genes did partially exist in the breast cancer tissues. Conclusion: Changes in multi-gene expression regulations take place during the occurrence and development of breast cancer; and the research on related genes can help understanding the mechanism of tumor occurrence.

  6. GOBO: gene expression-based outcome for breast cancer online.

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    Markus Ringnér

    Full Text Available Microarray-based gene expression analysis holds promise of improving prognostication and treatment decisions for breast cancer patients. However, the heterogeneity of breast cancer emphasizes the need for validation of prognostic gene signatures in larger sample sets stratified into relevant subgroups. Here, we describe a multifunctional user-friendly online tool, GOBO (http://co.bmc.lu.se/gobo, allowing a range of different analyses to be performed in an 1881-sample breast tumor data set, and a 51-sample breast cancer cell line set, both generated on Affymetrix U133A microarrays. GOBO supports a wide range of applications including: 1 rapid assessment of gene expression levels in subgroups of breast tumors and cell lines, 2 identification of co-expressed genes for creation of potential metagenes, 3 association with outcome for gene expression levels of single genes, sets of genes, or gene signatures in multiple subgroups of the 1881-sample breast cancer data set. The design and implementation of GOBO facilitate easy incorporation of additional query functions and applications, as well as additional data sets irrespective of tumor type and array platform.

  7. A Classification Framework Applied to Cancer Gene Expression Profiles

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    Hussein Hijazi

    2013-01-01

    Full Text Available Classification of cancer based on gene expression has provided insight into possible treatment strategies. Thus, developing machine learning methods that can successfully distinguish among cancer subtypes or normal versus cancer samples is important. This work discusses supervised learning techniques that have been employed to classify cancers. Furthermore, a two-step feature selection method based on an attribute estimation method (e.g., ReliefF and a genetic algorithm was employed to find a set of genes that can best differentiate between cancer subtypes or normal versus cancer samples. The application of different classification methods (e.g., decision tree, k-nearest neighbor, support vector machine (SVM, bagging, and random forest on 5 cancer datasets shows that no classification method universally outperforms all the others. However, k-nearest neighbor and linear SVM generally improve the classification performance over other classifiers. Finally, incorporating diverse types of genomic data (e.g., protein-protein interaction data and gene expression increase the prediction accuracy as compared to using gene expression alone.

  8. Gastric Cancer Associated Genes Identified by an Integrative Analysis of Gene Expression Data

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    Bing Jiang

    2017-01-01

    Full Text Available Gastric cancer is one of the most severe complex diseases with high morbidity and mortality in the world. The molecular mechanisms and risk factors for this disease are still not clear since the cancer heterogeneity caused by different genetic and environmental factors. With more and more expression data accumulated nowadays, we can perform integrative analysis for these data to understand the complexity of gastric cancer and to identify consensus players for the heterogeneous cancer. In the present work, we screened the published gene expression data and analyzed them with integrative tool, combined with pathway and gene ontology enrichment investigation. We identified several consensus differentially expressed genes and these genes were further confirmed with literature mining; at last, two genes, that is, immunoglobulin J chain and C-X-C motif chemokine ligand 17, were screened as novel gastric cancer associated genes. Experimental validation is proposed to further confirm this finding.

  9. Expression of circadian clock genes and proteins in urothelial cancer is related to cancer-associated genes

    International Nuclear Information System (INIS)

    Litlekalsoy, Jorunn; Rostad, Kari; Kalland, Karl-Henning; Hostmark, Jens G.; Laerum, Ole Didrik

    2016-01-01

    The purpose of this study was to evaluate invasive and metastatic potential of urothelial cancer by investigating differential expression of various clock genes/proteins participating in the 24 h circadian rhythms and to compare these gene expressions with transcription of other cancer-associated genes. Twenty seven paired samples of tumour and benign tissue collected from patients who underwent cystectomy were analysed and compared to 15 samples of normal bladder tissue taken from patients who underwent cystoscopy for benign prostate hyperplasia (unrelated donors). Immunohistochemical analyses were made for clock and clock-related proteins. In addition, the gene-expression levels of 22 genes (clock genes, casein kinases, oncogenes, tumour suppressor genes and cytokeratins) were analysed by real-time quantitative PCR (qPCR). Considerable up- or down-regulation and altered cellular distribution of different clock proteins, a reduction of casein kinase1A1 (CSNK1A1) and increase of casein kinase alpha 1 E (CSNK1E) were found. The pattern was significantly correlated with simultaneous up-regulation of stimulatory tumour markers, and a down-regulation of several suppressor genes. The pattern was mainly seen in aneuploid high-grade cancers. Considerable alterations were also found in the neighbouring bladder mucosa. The close correlation between altered expression of various clock genes and common tumour markers in urothelial cancer indicates that disturbed function in the cellular clock work may be an important additional mechanism contributing to cancer progression and malignant behaviour. The online version of this article (doi:10.1186/s12885-016-2580-y) contains supplementary material, which is available to authorized users

  10. Inferring causal genomic alterations in breast cancer using gene expression data

    Science.gov (United States)

    2011-01-01

    Background One of the primary objectives in cancer research is to identify causal genomic alterations, such as somatic copy number variation (CNV) and somatic mutations, during tumor development. Many valuable studies lack genomic data to detect CNV; therefore, methods that are able to infer CNVs from gene expression data would help maximize the value of these studies. Results We developed a framework for identifying recurrent regions of CNV and distinguishing the cancer driver genes from the passenger genes in the regions. By inferring CNV regions across many datasets we were able to identify 109 recurrent amplified/deleted CNV regions. Many of these regions are enriched for genes involved in many important processes associated with tumorigenesis and cancer progression. Genes in these recurrent CNV regions were then examined in the context of gene regulatory networks to prioritize putative cancer driver genes. The cancer driver genes uncovered by the framework include not only well-known oncogenes but also a number of novel cancer susceptibility genes validated via siRNA experiments. Conclusions To our knowledge, this is the first effort to systematically identify and validate drivers for expression based CNV regions in breast cancer. The framework where the wavelet analysis of copy number alteration based on expression coupled with the gene regulatory network analysis, provides a blueprint for leveraging genomic data to identify key regulatory components and gene targets. This integrative approach can be applied to many other large-scale gene expression studies and other novel types of cancer data such as next-generation sequencing based expression (RNA-Seq) as well as CNV data. PMID:21806811

  11. Gene Expression Correlation for Cancer Diagnosis: A Pilot Study

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    Binbing Ling

    2014-01-01

    Full Text Available Poor prognosis for late-stage, high-grade, and recurrent cancers has been motivating cancer researchers to search for more efficient biomarkers to identify the onset of cancer. Recent advances in constructing and dynamically analyzing biomolecular networks for different types of cancer have provided a promising novel strategy to detect tumorigenesis and metastasis. The observation of different biomolecular networks associated with normal and cancerous states led us to hypothesize that correlations for gene expressions could serve as valid indicators of early cancer development. In this pilot study, we tested our hypothesis by examining whether the mRNA expressions of three randomly selected cancer-related genes PIK3C3, PIM3, and PTEN were correlated during cancer progression and the correlation coefficients could be used for cancer diagnosis. Strong correlations (0.68≤r≤1.0 were observed between PIK3C3 and PIM3 in breast cancer, between PIK3C3 and PTEN in breast and ovary cancers, and between PIM3 and PTEN in breast, kidney, liver, and thyroid cancers during disease progression, implicating that the correlations for cancer network gene expressions could serve as a supplement to current clinical biomarkers, such as cancer antigens, for early cancer diagnosis.

  12. Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.

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    I-Hsuan Lin

    Full Text Available Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs and the hypomethylation of the megabase-sized partially methylated domains (PMDs are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.

  13. Cancer Outlier Analysis Based on Mixture Modeling of Gene Expression Data

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    Keita Mori

    2013-01-01

    Full Text Available Molecular heterogeneity of cancer, partially caused by various chromosomal aberrations or gene mutations, can yield substantial heterogeneity in gene expression profile in cancer samples. To detect cancer-related genes which are active only in a subset of cancer samples or cancer outliers, several methods have been proposed in the context of multiple testing. Such cancer outlier analyses will generally suffer from a serious lack of power, compared with the standard multiple testing setting where common activation of genes across all cancer samples is supposed. In this paper, we consider information sharing across genes and cancer samples, via a parametric normal mixture modeling of gene expression levels of cancer samples across genes after a standardization using the reference, normal sample data. A gene-based statistic for gene selection is developed on the basis of a posterior probability of cancer outlier for each cancer sample. Some efficiency improvement by using our method was demonstrated, even under settings with misspecified, heavy-tailed t-distributions. An application to a real dataset from hematologic malignancies is provided.

  14. Alteration of gene expression and DNA methylation in drug-resistant gastric cancer.

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    Maeda, Osamu; Ando, Takafumi; Ohmiya, Naoki; Ishiguro, Kazuhiro; Watanabe, Osamu; Miyahara, Ryoji; Hibi, Yoko; Nagai, Taku; Yamada, Kiyofumi; Goto, Hidemi

    2014-04-01

    The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.

  15. Random Subspace Aggregation for Cancer Prediction with Gene Expression Profiles

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    Liying Yang

    2016-01-01

    Full Text Available Background. Precisely predicting cancer is crucial for cancer treatment. Gene expression profiles make it possible to analyze patterns between genes and cancers on the genome-wide scale. Gene expression data analysis, however, is confronted with enormous challenges for its characteristics, such as high dimensionality, small sample size, and low Signal-to-Noise Ratio. Results. This paper proposes a method, termed RS_SVM, to predict gene expression profiles via aggregating SVM trained on random subspaces. After choosing gene features through statistical analysis, RS_SVM randomly selects feature subsets to yield random subspaces and training SVM classifiers accordingly and then aggregates SVM classifiers to capture the advantage of ensemble learning. Experiments on eight real gene expression datasets are performed to validate the RS_SVM method. Experimental results show that RS_SVM achieved better classification accuracy and generalization performance in contrast with single SVM, K-nearest neighbor, decision tree, Bagging, AdaBoost, and the state-of-the-art methods. Experiments also explored the effect of subspace size on prediction performance. Conclusions. The proposed RS_SVM method yielded superior performance in analyzing gene expression profiles, which demonstrates that RS_SVM provides a good channel for such biological data.

  16. A Gene Expression Classifier of Node-Positive Colorectal Cancer

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    Paul F. Meeh

    2009-10-01

    Full Text Available We used digital long serial analysis of gene expression to discover gene expression differences between node-negative and node-positive colorectal tumors and developed a multigene classifier able to discriminate between these two tumor types. We prepared and sequenced long serial analysis of gene expression libraries from one node-negative and one node-positive colorectal tumor, sequenced to a depth of 26,060 unique tags, and identified 262 tags significantly differentially expressed between these two tumors (P < 2 x 10-6. We confirmed the tag-to-gene assignments and differential expression of 31 genes by quantitative real-time polymerase chain reaction, 12 of which were elevated in the node-positive tumor. We analyzed the expression levels of these 12 upregulated genes in a validation panel of 23 additional tumors and developed an optimized seven-gene logistic regression classifier. The classifier discriminated between node-negative and node-positive tumors with 86% sensitivity and 80% specificity. Receiver operating characteristic analysis of the classifier revealed an area under the curve of 0.86. Experimental manipulation of the function of one classification gene, Fibronectin, caused profound effects on invasion and migration of colorectal cancer cells in vitro. These results suggest that the development of node-positive colorectal cancer occurs in part through elevated epithelial FN1 expression and suggest novel strategies for the diagnosis and treatment of advanced disease.

  17. Suppression subtractive hybridization identified differentially expressed genes in lung adenocarcinoma: ERGIC3 as a novel lung cancer-related gene

    International Nuclear Information System (INIS)

    Wu, Mingsong; Tu, Tao; Huang, Yunchao; Cao, Yi

    2013-01-01

    To understand the carcinogenesis caused by accumulated genetic and epigenetic alterations and seek novel biomarkers for various cancers, studying differentially expressed genes between cancerous and normal tissues is crucial. In the study, two cDNA libraries of lung cancer were constructed and screened for identification of differentially expressed genes. Two cDNA libraries of differentially expressed genes were constructed using lung adenocarcinoma tissue and adjacent nonmalignant lung tissue by suppression subtractive hybridization. The data of the cDNA libraries were then analyzed and compared using bioinformatics analysis. Levels of mRNA and protein were measured by quantitative real-time polymerase chain reaction (q-RT-PCR) and western blot respectively, as well as expression and localization of proteins were determined by immunostaining. Gene functions were investigated using proliferation and migration assays after gene silencing and gene over-expression. Two libraries of differentially expressed genes were obtained. The forward-subtracted library (FSL) and the reverse-subtracted library (RSL) contained 177 and 59 genes, respectively. Bioinformatic analysis demonstrated that these genes were involved in a wide range of cellular functions. The vast majority of these genes were newly identified to be abnormally expressed in lung cancer. In the first stage of the screening for 16 genes, we compared lung cancer tissues with their adjacent non-malignant tissues at the mRNA level, and found six genes (ERGIC3, DDR1, HSP90B1, SDC1, RPSA, and LPCAT1) from the FSL were significantly up-regulated while two genes (GPX3 and TIMP3) from the RSL were significantly down-regulated (P < 0.05). The ERGIC3 protein was also over-expressed in lung cancer tissues and cultured cells, and expression of ERGIC3 was correlated with the differentiated degree and histological type of lung cancer. The up-regulation of ERGIC3 could promote cellular migration and proliferation in vitro. The

  18. Characterization of differentially expressed genes involved in pathways associated with gastric cancer.

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    Hao Li

    Full Text Available To explore the patterns of gene expression in gastric cancer, a total of 26 paired gastric cancer and noncancerous tissues from patients were enrolled for gene expression microarray analyses. Limma methods were applied to analyze the data, and genes were considered to be significantly differentially expressed if the False Discovery Rate (FDR value was 2. Subsequently, Gene Ontology (GO categories were used to analyze the main functions of the differentially expressed genes. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG database, we found pathways significantly associated with the differential genes. Gene-Act network and co-expression network were built respectively based on the relationships among the genes, proteins and compounds in the database. 2371 mRNAs and 350 lncRNAs considered as significantly differentially expressed genes were selected for the further analysis. The GO categories, pathway analyses and the Gene-Act network showed a consistent result that up-regulated genes were responsible for tumorigenesis, migration, angiogenesis and microenvironment formation, while down-regulated genes were involved in metabolism. These results of this study provide some novel findings on coding RNAs, lncRNAs, pathways and the co-expression network in gastric cancer which will be useful to guide further investigation and target therapy for this disease.

  19. Prostate cancer-associated gene expression alterations determined from needle biopsies.

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    Qian, David Z; Huang, Chung-Ying; O'Brien, Catherine A; Coleman, Ilsa M; Garzotto, Mark; True, Lawrence D; Higano, Celestia S; Vessella, Robert; Lange, Paul H; Nelson, Peter S; Beer, Tomasz M

    2009-05-01

    To accurately identify gene expression alterations that differentiate neoplastic from normal prostate epithelium using an approach that avoids contamination by unwanted cellular components and is not compromised by acute gene expression changes associated with tumor devascularization and resulting ischemia. Approximately 3,000 neoplastic and benign prostate epithelial cells were isolated using laser capture microdissection from snap-frozen prostate biopsy specimens provided by 31 patients who subsequently participated in a clinical trial of preoperative chemotherapy. cDNA synthesized from amplified total RNA was hybridized to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database. Expression differences for selected genes were verified using quantitative reverse transcription-PCR. Comparative analyses identified 954 transcript alterations associated with cancer (q transport. Genes down-regulated in prostate cancers were enriched in categories related to immune response, cellular responses to pathogens, and apoptosis. A heterogeneous pattern of androgen receptor expression changes was noted. In exploratory analyses, androgen receptor down-regulation was associated with a lower probability of cancer relapse after neoadjuvant chemotherapy followed by radical prostatectomy. Assessments of tumor phenotypes based on gene expression for treatment stratification and drug targeting of oncogenic alterations may best be ascertained using biopsy-based analyses where the effects of ischemia do not complicate interpretation.

  20. EVALUATION OF THE PROGNOSTIC VALUE OF nm23 GENE EXPRESSION IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    刘红; 毛慧生; 傅西林; 方志沂; 冯玉梅; 范宇; 李树玲

    2002-01-01

    Objective: To investigate the expression of nm23 gene and evaluate its prognostic value in breast cancer. Methods: nm23 expressions were detected in 101 breast cancer patients (group 1) by immunohistochemistry. RT-PCR and immunohistochemistry were used to measure expressions of nm23 gene in another 68 patients with breast cancer (group 2). Results: nm23 gene expression in group 1 was inversely associated with distant metastasis and lymph node metastasis (P<0.05). In 44 patients with negative lymph node, 9 cases progressed to distant metastasis, 7 of them (77.8%) showed low expression of nm23 gene (P<0.05). In 57 patients with positive lymph node, 24 our of 29 patients who had no distant metastasis (82.8%) expressed nm23 gene at high level (P<0.05). Meanwhile, there were 6 patients with distant metastasis in the group 2, all of thenm expressed nm23 gene mRNA at low level. Conclusion: The results showed that nm23 gene might play an independent role in predicting prognosis of breast cancer.

  1. Shared Gene Expression Alterations in Nasal and Bronchial Epithelium for Lung Cancer Detection.

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    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.

  2. Bone Metastasis in Advanced Breast Cancer: Analysis of Gene Expression Microarray.

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    Cosphiadi, Irawan; Atmakusumah, Tubagus D; Siregar, Nurjati C; Muthalib, Abdul; Harahap, Alida; Mansyur, Muchtarruddin

    2018-03-08

    Approximately 30% to 40% of breast cancer recurrences involve bone metastasis (BM). Certain genes have been linked to BM; however, none have been able to predict bone involvement. In this study, we analyzed gene expression profiles in advanced breast cancer patients to elucidate genes that can be used to predict BM. A total of 92 advanced breast cancer patients, including 46 patients with BM and 46 patients without BM, were identified for this study. Immunohistochemistry and gene expression analysis was performed on 81 formalin-fixed paraffin-embedded samples. Data were collected through medical records, and gene expression of 200 selected genes compiled from 6 previous studies was performed using NanoString nCounter. Genetic expression profiles showed that 22 genes were significantly differentially expressed between breast cancer patients with metastasis in bone and other organs (BM+) and non-BM, whereas subjects with only BM showed 17 significantly differentially expressed genes. The following genes were associated with an increasing incidence of BM in the BM+ group: estrogen receptor 1 (ESR1), GATA binding protein 3 (GATA3), and melanophilin with an area under the curve (AUC) of 0.804. In the BM group, the following genes were associated with an increasing incidence of BM: ESR1, progesterone receptor, B-cell lymphoma 2, Rab escort protein, N-acetyltransferase 1, GATA3, annexin A9, and chromosome 9 open reading frame 116. ESR1 and GATA3 showed an increased strength of association with an AUC of 0.928. A combination of the identified 3 genes in BM+ and 8 genes in BM showed better prediction than did each individual gene, and this combination can be used as a training set. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Gene expression profiling of liver cancer stem cells by RNA-sequencing.

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    David W Y Ho

    Full Text Available BACKGROUND: Accumulating evidence supports that tumor growth and cancer relapse are driven by cancer stem cells. Our previous work has demonstrated the existence of CD90(+ liver cancer stem cells (CSCs in hepatocellular carcinoma (HCC. Nevertheless, the characteristics of these cells are still poorly understood. In this study, we employed a more sensitive RNA-sequencing (RNA-Seq to compare the gene expression profiling of CD90(+ cells sorted from tumor (CD90(+CSCs with parallel non-tumorous liver tissues (CD90(+NTSCs and elucidate the roles of putative target genes in hepatocarcinogenesis. METHODOLOGY/PRINCIPAL FINDINGS: CD90(+ cells were sorted respectively from tumor and adjacent non-tumorous human liver tissues using fluorescence-activated cell sorting. The amplified RNAs of CD90(+ cells from 3 HCC patients were subjected to RNA-Seq analysis. A differential gene expression profile was established between CD90(+CSCs and CD90(+NTSCs, and validated by quantitative real-time PCR (qRT-PCR on the same set of amplified RNAs, and further confirmed in an independent cohort of 12 HCC patients. Five hundred genes were differentially expressed (119 up-regulated and 381 down-regulated genes between CD90(+CSCs and CD90(+NTSCs. Gene ontology analysis indicated that the over-expressed genes in CD90(+CSCs were associated with inflammation, drug resistance and lipid metabolism. Among the differentially expressed genes, glypican-3 (GPC3, a member of glypican family, was markedly elevated in CD90(+CSCs compared to CD90(+NTSCs. Immunohistochemistry demonstrated that GPC3 was highly expressed in forty-two human liver tumor tissues but absent in adjacent non-tumorous liver tissues. Flow cytometry indicated that GPC3 was highly expressed in liver CD90(+CSCs and mature cancer cells in liver cancer cell lines and human liver tumor tissues. Furthermore, GPC3 expression was positively correlated with the number of CD90(+CSCs in liver tumor tissues. CONCLUSIONS

  4. Gene Expression Profiling of Liver Cancer Stem Cells by RNA-Sequencing

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    Lam, Chi Tat; Ng, Michael N. P.; Yu, Wan Ching; Lau, Joyce; Wan, Timothy; Wang, Xiaoqi; Yan, Zhixiang; Liu, Hang; Fan, Sheung Tat

    2012-01-01

    Background Accumulating evidence supports that tumor growth and cancer relapse are driven by cancer stem cells. Our previous work has demonstrated the existence of CD90+ liver cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). Nevertheless, the characteristics of these cells are still poorly understood. In this study, we employed a more sensitive RNA-sequencing (RNA-Seq) to compare the gene expression profiling of CD90+ cells sorted from tumor (CD90+CSCs) with parallel non-tumorous liver tissues (CD90+NTSCs) and elucidate the roles of putative target genes in hepatocarcinogenesis. Methodology/Principal Findings CD90+ cells were sorted respectively from tumor and adjacent non-tumorous human liver tissues using fluorescence-activated cell sorting. The amplified RNAs of CD90+ cells from 3 HCC patients were subjected to RNA-Seq analysis. A differential gene expression profile was established between CD90+CSCs and CD90+NTSCs, and validated by quantitative real-time PCR (qRT-PCR) on the same set of amplified RNAs, and further confirmed in an independent cohort of 12 HCC patients. Five hundred genes were differentially expressed (119 up-regulated and 381 down-regulated genes) between CD90+CSCs and CD90+NTSCs. Gene ontology analysis indicated that the over-expressed genes in CD90+CSCs were associated with inflammation, drug resistance and lipid metabolism. Among the differentially expressed genes, glypican-3 (GPC3), a member of glypican family, was markedly elevated in CD90+CSCs compared to CD90+NTSCs. Immunohistochemistry demonstrated that GPC3 was highly expressed in forty-two human liver tumor tissues but absent in adjacent non-tumorous liver tissues. Flow cytometry indicated that GPC3 was highly expressed in liver CD90+CSCs and mature cancer cells in liver cancer cell lines and human liver tumor tissues. Furthermore, GPC3 expression was positively correlated with the number of CD90+CSCs in liver tumor tissues. Conclusions/Significance The identified genes

  5. Gene expression analysis of FABP4 in gastric cancer

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    Abdulkarim Yasin Karim

    2016-06-01

    Full Text Available Purpose: Gastric cancer has high incidence and mortality rate in several countries and is still one of the most frequent and lethal disease. In this study, we aimed to determine diagnostic markers in gastric cancer by molecular techniques; include mRNA expression analysis of FABP4 gene. Fatty acid binding protein 4 (FABP4 gene encodes the fatty acid binding protein found in adipocytes. The protein encoded by FABP4 are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake, transport, and metabolism. Material and Methods: Total RNA were extracted from paired tumor and normal tissues of 47 gastric cancer. The mRNA expression level of FABP4 was measured employing semi- quantitative reverse transcription- polymerase chain reaction (RT- PCR. Results: The mRNA expression level of FABP4 was significantly decreased (down- regulated. Conclusion: Down-regulation of FABP4 gene seems to occur at the initial steps of gastric cancer development. In order to confirm the relationship between the gastric tumor and FABP4 gene, further analysis like immunohistochemistry and epigenetc techniques are necessary. [Cukurova Med J 2016; 41(2.000: 248-252

  6. Blood Gene Expression Profiling of Breast Cancer Survivors Experiencing Fibrosis

    International Nuclear Information System (INIS)

    Landmark-Hoyvik, Hege; Dumeaux, Vanessa; Reinertsen, Kristin V.; Edvardsen, Hege; Fossa, Sophie D.; Borresen-Dale, Anne-Lise

    2011-01-01

    Purpose: To extend knowledge on the mechanisms and pathways involved in maintenance of radiation-induced fibrosis (RIF) by performing gene expression profiling of whole blood from breast cancer (BC) survivors with and without fibrosis 3-7 years after end of radiotherapy treatment. Methods and Materials: Gene expression profiles from blood were obtained for 254 BC survivors derived from a cohort of survivors, treated with adjuvant radiotherapy for breast cancer 3-7 years earlier. Analyses of transcriptional differences in blood gene expression between BC survivors with fibrosis (n = 31) and BC survivors without fibrosis (n = 223) were performed using R version 2.8.0 and tools from the Bioconductor project. Gene sets extracted through a literature search on fibrosis and breast cancer were subsequently used in gene set enrichment analysis. Results: Substantial differences in blood gene expression between BC survivors with and without fibrosis were observed, and 87 differentially expressed genes were identified through linear analysis. Transforming growth factor-β1 signaling was identified as the most significant gene set, showing a down-regulation of most of the core genes, together with up-regulation of a transcriptional activator of the inhibitor of fibrinolysis, Plasminogen activator inhibitor 1 in the BC survivors with fibrosis. Conclusion: Transforming growth factor-β1 signaling was found down-regulated during the maintenance phase of fibrosis as opposed to the up-regulation reported during the early, initiating phase of fibrosis. Hence, once the fibrotic tissue has developed, the maintenance phase might rather involve a deregulation of fibrinolysis and altered degradation of extracellular matrix components.

  7. Lineage relationship of prostate cancer cell types based on gene expression

    Directory of Open Access Journals (Sweden)

    Ware Carol B

    2011-05-01

    Full Text Available Abstract Background Prostate tumor heterogeneity is a major factor in disease management. Heterogeneity could be due to multiple cancer cell types with distinct gene expression. Of clinical importance is the so-called cancer stem cell type. Cell type-specific transcriptomes are used to examine lineage relationship among cancer cell types and their expression similarity to normal cell types including stem/progenitor cells. Methods Transcriptomes were determined by Affymetrix DNA array analysis for the following cell types. Putative prostate progenitor cell populations were characterized and isolated by expression of the membrane transporter ABCG2. Stem cells were represented by embryonic stem and embryonal carcinoma cells. The cancer cell types were Gleason pattern 3 (glandular histomorphology and pattern 4 (aglandular sorted from primary tumors, cultured prostate cancer cell lines originally established from metastatic lesions, xenografts LuCaP 35 (adenocarcinoma phenotype and LuCaP 49 (neuroendocrine/small cell carcinoma grown in mice. No detectable gene expression differences were detected among serial passages of the LuCaP xenografts. Results Based on transcriptomes, the different cancer cell types could be clustered into a luminal-like grouping and a non-luminal-like (also not basal-like grouping. The non-luminal-like types showed expression more similar to that of stem/progenitor cells than the luminal-like types. However, none showed expression of stem cell genes known to maintain stemness. Conclusions Non-luminal-like types are all representatives of aggressive disease, and this could be attributed to the similarity in overall gene expression to stem and progenitor cell types.

  8. mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer

    Directory of Open Access Journals (Sweden)

    Calin George A

    2007-08-01

    Full Text Available Abstract Background Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. Results We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H for genome-wide expression of microRNA (miRNA and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. Conclusion This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer.

  9. Gene expression signatures for colorectal cancer microsatellite status and HNPCC

    DEFF Research Database (Denmark)

    Kruhøffer, M; Jensen, J L; Laiho, P

    2005-01-01

    The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI...... of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated...... is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression...

  10. Gene expression analysis in prostate cancer: the importance of the endogenous control.

    LENUS (Irish Health Repository)

    Vajda, Alice

    2013-03-01

    Aberrant gene expression is a hallmark of cancer. Quantitative reverse-transcription PCR (qRT-PCR) is the gold-standard for quantifying gene expression, and commonly employs a house-keeping gene (HKG) as an endogenous control to normalize results; the choice of which is critical for accurate data interpretation. Many factors, including sample type, pathological state, and oxygen levels influence gene expression including putative HKGs. The aim of this study was to determine the suitability of commonly used HKGs for qRT-PCR in prostate cancer.

  11. Gene expression profiles in stages II and III colon cancers

    DEFF Research Database (Denmark)

    Thorsteinsson, Morten; Kirkeby, Lene T; Hansen, Raino

    2012-01-01

    PURPOSE: A 128-gene signature has been proposed to predict outcome in patients with stages II and III colorectal cancers. In the present study, we aimed to reproduce and validate the 128-gene signature in external and independent material. METHODS: Gene expression data from the original material...... were retrieved from the Gene Expression Omnibus (GEO) (n¿=¿111) in addition to a Danish data set (n¿=¿37). All patients had stages II and III colon cancers. A Prediction Analysis of Microarray classifier, based on the 128-gene signature and the original training set of stage I (n¿=¿65) and stage IV (n...... correctly predicted as stage IV-like, and the remaining patients were predicted as stage I-like and unclassifiable, respectively. Stage II patients could not be stratified. CONCLUSIONS: The 128-gene signature showed reproducibility in stage III colon cancer, but could not predict recurrence in stage II...

  12. Human cancer cells express Slug-based epithelial-mesenchymal transition gene expression signature obtained in vivo

    International Nuclear Information System (INIS)

    Anastassiou, Dimitris; Rumjantseva, Viktoria; Cheng, Weiyi; Huang, Jianzhong; Canoll, Peter D; Yamashiro, Darrell J; Kandel, Jessica J

    2011-01-01

    The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT). We used xenograft models of human cancer cells in immunocompromised mice, profiling the harvested tumors separately with species-specific probes and computationally analyzing the results. Here we show that human cancer cells express in vivo a precise multi-cancer invasion-associated gene expression signature that prominently includes many EMT markers, among them the transcription factor Slug, fibronectin, and α-SMA. We found that human, but not mouse, cells express the signature and Slug is the only upregulated EMT-inducing transcription factor. The signature is also present in samples from many publicly available cancer gene expression datasets, suggesting that it is produced by the cancer cells themselves in multiple cancer types, including nonepithelial cancers such as neuroblastoma. Furthermore, we found that the presence of the signature in human xenografted cells was associated with a downregulation of adipocyte markers in the mouse tissue adjacent to the invasive tumor, suggesting that the signature is triggered by contextual microenvironmental interactions when the cancer cells encounter adipocytes, as previously reported. The known, precise and consistent gene composition of this cancer mesenchymal transition signature, particularly when combined with simultaneous analysis of the adjacent microenvironment, provides unique opportunities for shedding light on the underlying mechanisms of cancer invasiveness as well as identifying potential diagnostic markers and targets for metastasis-inhibiting therapeutics

  13. Bronchial airway gene expression in smokers with lung or head and neck cancer

    International Nuclear Information System (INIS)

    Van Dyck, Eric; Nazarov, Petr V; Muller, Arnaud; Nicot, Nathalie; Bosseler, Manon; Pierson, Sandrine; Van Moer, Kris; Palissot, Valérie; Mascaux, Céline; Knolle, Ulrich; Ninane, Vincent; Nati, Romain; Bremnes, Roy M; Vallar, Laurent; Berchem, Guy; Schlesser, Marc

    2014-01-01

    Cigarette smoking is the major cause of cancers of the respiratory tract, including non-small cell lung cancer (NSCLC) and head and neck cancer (HNC). In order to better understand carcinogenesis of the lung and upper airways, we have compared the gene expression profiles of tumor-distant, histologically normal bronchial biopsy specimens obtained from current smokers with NSCLC or HNC (SC, considered as a single group), as well as nonsmokers (NS) and smokers without cancer (SNC). RNA from a total of 97 biopsies was used for gene expression profiling (Affymetrix HG-U133 Plus 2.0 array). Differentially expressed genes were used to compare NS, SNC, and SC, and functional analysis was carried out using Ingenuity Pathway Analysis (IPA). Smoking-related cancer of the respiratory tract was found to affect the expression of genes encoding xenobiotic biotransformation proteins, as well as proteins associated with crucial inflammation/immunity pathways and other processes that protect the airway from the chemicals in cigarette smoke or contribute to carcinogenesis. Finally, we used the prediction analysis for microarray (PAM) method to identify gene signatures of cigarette smoking and cancer, and uncovered a 15-gene signature that distinguished between SNC and SC with an accuracy of 83%. Thus, gene profiling of histologically normal bronchial biopsy specimens provided insight into cigarette-induced carcinogenesis of the respiratory tract and gene signatures of cancer in smokers

  14. Cyclooxygenase and lipoxygenase gene expression in the inflammogenesis of breast cancer.

    Science.gov (United States)

    Kennedy, Brian M; Harris, Randall E

    2018-05-07

    We examined the expression of major inflammatory genes, cyclooxygenase-1 and 2 (COX1, COX2) and arachidonate 5-lipoxygenase (ALOX5) in 1090 tumor samples of invasive breast cancer from The Cancer Genome Atlas (TCGA). Mean cyclooxygenase expression (COX1 + COX2) ranked in the upper 99th percentile of all 20,531 genes and surprisingly, the mean expression of COX1 was more than tenfold higher than COX2. Highly significant correlations were observed between COX2 with eight tumor-promoting genes (EGR2, IL6, RGS2, B3GNT5, SGK1, SLC2A3, SFRP1 and ETS2) and between ALOX5 and ten tumor promoter genes (CD33, MYOF1, NLRP1, GAB3, CD4, IFR8, CYTH4, BTK, FGR, CD37). Expression of CYP19A1 (aromatase) was significantly correlated with COX2, but only in tumors positive for ER, PR and HER2. Tumor-promoting genes correlated with the expression of COX1, COX2, and ALOX5 are known to effectively increase mitogenesis, mutagenesis, angiogenesis, cell survival, immunosuppression and metastasis in the pathogenesis of breast cancer.

  15. GSEH: A Novel Approach to Select Prostate Cancer-Associated Genes Using Gene Expression Heterogeneity.

    Science.gov (United States)

    Kim, Hyunjin; Choi, Sang-Min; Park, Sanghyun

    2018-01-01

    When a gene shows varying levels of expression among normal people but similar levels in disease patients or shows similar levels of expression among normal people but different levels in disease patients, we can assume that the gene is associated with the disease. By utilizing this gene expression heterogeneity, we can obtain additional information that abets discovery of disease-associated genes. In this study, we used collaborative filtering to calculate the degree of gene expression heterogeneity between classes and then scored the genes on the basis of the degree of gene expression heterogeneity to find "differentially predicted" genes. Through the proposed method, we discovered more prostate cancer-associated genes than 10 comparable methods. The genes prioritized by the proposed method are potentially significant to biological processes of a disease and can provide insight into them.

  16. Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Toshiaki; Ikeda, Kazuhiro; Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241 (Japan); Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 (Japan); Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 (Japan)

    2014-09-26

    Highlights: • APP knockdown reduced proliferation and migration of prostate cancer cells. • APP knockdown reduced expression of metalloproteinase and EMT-related genes. • APP overexpression promoted LNCaP cell migration. • APP overexpression increased expression of metalloproteinase and EMT-related genes. - Abstract: Amyloid precursor protein (APP) is a type I transmembrane protein, and one of its processed forms, β-amyloid, is considered to play a central role in the development of Alzheimer’s disease. We previously showed that APP is a primary androgen-responsive gene in prostate cancer and that its increased expression is correlated with poor prognosis for patients with prostate cancer. APP has also been implicated in several human malignancies. Nevertheless, the mechanism underlying the pro-proliferative effects of APP on cancers is still not well-understood. In the present study, we explored a pathophysiological role for APP in prostate cancer cells using siRNA targeting APP (siAPP). The proliferation and migration of LNCaP and DU145 prostate cancer cells were significantly suppressed by siAPP. Differentially expressed genes in siAPP-treated cells compared to control siRNA-treated cells were identified by microarray analysis. Notably, several metalloproteinase genes, such as ADAM10 and ADAM17, and epithelial–mesenchymal transition (EMT)-related genes, such as VIM, and SNAI2, were downregulated in siAPP-treated cells as compared to control cells. The expression of these genes was upregulated in LNCaP cells stably expressing APP when compared with control cells. APP-overexpressing LNCaP cells exhibited enhanced migration in comparison to control cells. These results suggest that APP may contribute to the proliferation and migration of prostate cancer cells by modulating the expression of metalloproteinase and EMT-related genes.

  17. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer.

    Directory of Open Access Journals (Sweden)

    Sofie Claerhout

    Full Text Available Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future.Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern.We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

  18. Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium

    Directory of Open Access Journals (Sweden)

    Dhir Rajiv

    2004-08-01

    Full Text Available Abstract Background Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations. Results Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using

  19. In silico analysis and verification of S100 gene expression in gastric cancer

    International Nuclear Information System (INIS)

    Liu, Ji; Li, Xue; Dong, Guang-Long; Zhang, Hong-Wei; Chen, Dong-Li; Du, Jian-Jun; Zheng, Jian-Yong; Li, Ji-Peng; Wang, Wei-Zhong

    2008-01-01

    The S100 protein family comprises 22 members whose protein sequences encompass at least one EF-hand Ca 2+ binding motif. They were involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. However, the expression status of S100 family members in gastric cancer was not known yet. Combined with analysis of series analysis of gene expression, virtual Northern blot and microarray data, the expression levels of S100 family members in normal and malignant stomach tissues were systematically investigated. The expression of S100A3 was further evaluated by quantitative RT-PCR. At least 5 S100 genes were found to be upregulated in gastric cance by in silico analysis. Among them, four genes, including S100A2, S100A4, S100A7 and S100A10, were reported to overexpressed in gastric cancer previously. The expression of S100A3 in eighty patients of gastric cancer was further examined. The results showed that the mean expression levels of S100A3 in gastric cancer tissues were 2.5 times as high as in adjacent non-tumorous tissues. S100A3 expression was correlated with tumor differentiation and TNM (Tumor-Node-Metastasis) stage of gastric cancer, which was relatively highly expressed in poorly differentiated and advanced gastric cancer tissues (P < 0.05). To our knowledge this is the first report of systematic evaluation of S100 gene expressions in gastric cancers by multiple in silico analysis. The results indicated that overexpression of S100 gene family members were characteristics of gastric cancers and S100A3 might play important roles in differentiation and progression of gastric cancer

  20. A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer.

    Science.gov (United States)

    Govindarajan, Rangaswamy; Posey, James; Chao, Calvin Y; Lu, Ruixiao; Jadhav, Trafina; Javed, Ahmed Y; Javed, Awais; Mahmoud, Fade A; Osarogiagbon, Raymond U; Manne, Upender

    2016-06-18

    African American (AA) colon cancer patients have a worse prognosis than Caucasian (CA) colon cancer patients, however, reasons for this disparity are not well understood. To determine if tumor biology might contribute to differential prognosis, we measured recurrence risk and gene expression using the Oncotype DX® Colon Cancer Assay (12-gene assay) and compared the Recurrence Score results and gene expression profiles between AA patients and CA patients with stage II colon cancer. We retrieved demographic, clinical, and archived tumor tissues from stage II colon cancer patients at four institutions. The 12-gene assay and mismatch repair (MMR) status were performed by Genomic Health (Redwood City, California). Student's t-test and the Wilcoxon rank sum test were used to compare Recurrence Score data and gene expression data from AA and CA patients (SAS Enterprise Guide 5.1). Samples from 122 AA and 122 CA patients were analyzed. There were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median age was 66 years for AA patients and 68 for CA patients. Age, gender, year of surgery, pathologic T-stage, tumor location, the number of lymph nodes examined, lymphovascular invasion, and MMR status were not significantly different between groups (p = 0.93). The mean Recurrence Score result for AA patients (27.9 ± 12.8) and CA patients (28.1 ± 11.8) was not significantly different and the proportions of patients with high Recurrence Score values (≥41) were similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC and GADD45B), was significantly different between the racial groups. After controlling for clinical and pathologic covariates, the means and distributions of Recurrence Score results and gene expression profiles showed no statistically significant difference between patient groups. The distribution of

  1. A comparison of 12-gene colon cancer assay gene expression in African American and Caucasian patients with stage II colon cancer

    International Nuclear Information System (INIS)

    Govindarajan, Rangaswamy; Posey, James; Chao, Calvin Y.; Lu, Ruixiao; Jadhav, Trafina; Javed, Ahmed Y.; Javed, Awais; Mahmoud, Fade A.; Osarogiagbon, Raymond University; Manne, Upender

    2016-01-01

    African American (AA) colon cancer patients have a worse prognosis than Caucasian (CA) colon cancer patients, however, reasons for this disparity are not well understood. To determine if tumor biology might contribute to differential prognosis, we measured recurrence risk and gene expression using the Oncotype DX® Colon Cancer Assay (12-gene assay) and compared the Recurrence Score results and gene expression profiles between AA patients and CA patients with stage II colon cancer. We retrieved demographic, clinical, and archived tumor tissues from stage II colon cancer patients at four institutions. The 12-gene assay and mismatch repair (MMR) status were performed by Genomic Health (Redwood City, California). Student’s t-test and the Wilcoxon rank sum test were used to compare Recurrence Score data and gene expression data from AA and CA patients (SAS Enterprise Guide 5.1). Samples from 122 AA and 122 CA patients were analyzed. There were 118 women (63 AA, 55 CA) and 126 men (59 AA, 67 CA). Median age was 66 years for AA patients and 68 for CA patients. Age, gender, year of surgery, pathologic T-stage, tumor location, the number of lymph nodes examined, lymphovascular invasion, and MMR status were not significantly different between groups (p = 0.93). The mean Recurrence Score result for AA patients (27.9 ± 12.8) and CA patients (28.1 ± 11.8) was not significantly different and the proportions of patients with high Recurrence Score values (≥41) were similar between the groups (17/122 AA; 15/122 CA). None of the gene expression variables, either single genes or gene groups (cell cycle group, stromal group, BGN1, FAP, INHBA1, Ki67, MYBL2, cMYC and GADD45B), was significantly different between the racial groups. After controlling for clinical and pathologic covariates, the means and distributions of Recurrence Score results and gene expression profiles showed no statistically significant difference between patient groups. The distribution of Recurrence Score

  2. Expression of glucocorticoid and progesterone nuclear receptor genes in archival breast cancer tissue

    International Nuclear Information System (INIS)

    Smith, Robert A; Lea, Rod A; Curran, Joanne E; Weinstein, Stephen R; Griffiths, Lyn R

    2003-01-01

    Previous studies in our laboratory have shown associations of specific nuclear receptor gene variants with sporadic breast cancer. In order to investigate these findings further, we conducted the present study to determine whether expression levels of the progesterone and glucocorticoid nuclear receptor genes vary in different breast cancer grades. RNA was extracted from paraffin-embedded archival breast tumour tissue and converted into cDNA. Sample cDNA underwent PCR using labelled primers to enable quantitation of mRNA expression. Expression data were normalized against the 18S ribosomal gene multiplex and analyzed using analysis of variance. Analysis of variance indicated a variable level of expression of both genes with regard to breast cancer grade (P = 0.00033 for glucocorticoid receptor and P = 0.023 for progesterone receptor). Statistical analysis indicated that expression of the progesterone nuclear receptor is elevated in late grade breast cancer tissue

  3. Identification of valid reference genes for gene expression studies of human stomach cancer by reverse transcription-qPCR

    International Nuclear Information System (INIS)

    Rho, Hyun-Wook; Lee, Byoung-Chan; Choi, Eun-Seok; Choi, Il-Ju; Lee, Yeon-Su; Goh, Sung-Ho

    2010-01-01

    Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is a powerful method for the analysis of gene expression. Target gene expression levels are usually normalized to a consistently expressed reference gene also known as internal standard, in the same sample. However, much effort has not been expended thus far in the search for reference genes suitable for the study of stomach cancer using RT-qPCR, although selection of optimal reference genes is critical for interpretation of results. We assessed the suitability of six possible reference genes, beta-actin (ACTB), glyceraldehydes-3-phosphate dehydrogenase (GAPDH), hypoxanthine phosphoribosyl transferase 1 (HPRT1), beta-2-microglobulin (B2M), ribosomal subunit L29 (RPL29) and 18S ribosomal RNA (18S rRNA) in 20 normal and tumor stomach tissue pairs of stomach cancer patients and 6 stomach cancer cell lines, by RT-qPCR. Employing expression stability analyses using NormFinder and geNorm algorithms we determined the order of performance of these reference genes and their variation values. This RT-qPCR study showed that there are statistically significant (p < 0.05) differences in the expression levels of HPRT1 and 18S rRNA in 'normal-' versus 'tumor stomach tissues'. The stability analyses by geNorm suggest B2M-GAPDH, as best reference gene combination for 'stomach cancer cell lines'; RPL29-HPRT1, for 'all stomach tissues'; and ACTB-18S rRNA, for 'all stomach cell lines and tissues'. NormFinder also identified B2M as the best reference gene for 'stomach cancer cell lines', RPL29-B2M for 'all stomach tissues', and 18S rRNA-ACTB for 'all stomach cell lines and tissues'. The comparisons of normalized expression of the target gene, GPNMB, showed different interpretation of target gene expression depend on best single reference gene or combination. This study validated RPL29 and RPL29-B2M as the best single reference

  4. SATB1 tethers multiple gene loci to reprogram expression profiledriving breast cancer metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Han, Hye-Jung; Kohwi, Yoshinori; Kohwi-Shigematsu, Terumi

    2006-07-13

    Global changes in gene expression occur during tumor progression, as indicated by expression profiling of metastatic tumors. How this occurs is poorly understood. SATB1 functions as a genome organizer by folding chromatin via tethering multiple genomic loci and recruiting chromatin remodeling enzymes to regulate chromatin structure and expression of a large number of genes. Here we show that SATB1 is expressed at high levels in aggressive breast cancer cells, and is undetectable in non-malignant breast epithelial cells. Importantly, RNAi-mediated removal of SATB1 from highly-aggressive MDA-MB-231 cells altered the expression levels of over 1200 genes, restored breast-like acinar polarity in three-dimensional cultures, and prevented the metastastic phenotype in vivo. Conversely, overexpression of SATB1 in the less-aggressive breast cancer cell line Hs578T altered the gene expression profile and increased metastasis dramatically in vivo. Thus, SATB1 is a global regulator of gene expression in breast cancer cells, directly regulating crucial metastasis-associated genes, including ERRB2 (HER2/NEU), TGF-{beta}1, matrix metalloproteinase 3, and metastasin. The identification of SATB1 as a protein that re-programs chromatin organization and transcription profiles to promote breast cancer metastasis suggests a new model for metastasis and may provide means of therapeutic intervention.

  5. Comparative analysis of gene expression in normal and cancer human prostate cell lines

    Directory of Open Access Journals (Sweden)

    E. E. Rosenberg

    2014-04-01

    Full Text Available Prostate cancer is one of the main causes of mortality in men with malignant tumors. The urgent problem was a search for biomarkers of prostate cancer, which would allow distinguishing between aggressive metastatic and latent tumors. The aim of this work was to search for differentially expressed genes in normal epithelial cells PNT2 and prostate cancer cell lines LNCaP, DU145 and PC3, produced from tumors with different aggressiveness and metas­tatic ability. Such genes might be used to create a panel of prognostic markers for aggressiveness and metastasis. Relative gene expression of 65 cancer-related genes was determined by the quantitative polymerase chain reaction (Q-PCR. Expression of 29 genes was changed in LNCaP cells, 20 genes in DU145 and 16 genes in PC3 cell lines, compared with normal line PNT2. The obtained data make it possible to conclude that the epithelial-mesenchymal cell transition took place, which involved the loss of epithelial markers, reduced cell adhesion and increased migration. We have also found few differentially expressed genes among 3 prostate cancer cell lines. We have found that genes, involved in cell adhesion (CDH1, invasiveness and metastasis (IL8, CXCL2 and cell cycle control (P16, CCNE1 underwent most changes. These genes might be used for diagnosis and prognosis of invasive metastatic prostate tumors.

  6. GSNFS: Gene subnetwork biomarker identification of lung cancer expression data.

    Science.gov (United States)

    Doungpan, Narumol; Engchuan, Worrawat; Chan, Jonathan H; Meechai, Asawin

    2016-12-05

    Gene expression has been used to identify disease gene biomarkers, but there are ongoing challenges. Single gene or gene-set biomarkers are inadequate to provide sufficient understanding of complex disease mechanisms and the relationship among those genes. Network-based methods have thus been considered for inferring the interaction within a group of genes to further study the disease mechanism. Recently, the Gene-Network-based Feature Set (GNFS), which is capable of handling case-control and multiclass expression for gene biomarker identification, has been proposed, partly taking into account of network topology. However, its performance relies on a greedy search for building subnetworks and thus requires further improvement. In this work, we establish a new approach named Gene Sub-Network-based Feature Selection (GSNFS) by implementing the GNFS framework with two proposed searching and scoring algorithms, namely gene-set-based (GS) search and parent-node-based (PN) search, to identify subnetworks. An additional dataset is used to validate the results. The two proposed searching algorithms of the GSNFS method for subnetwork expansion are concerned with the degree of connectivity and the scoring scheme for building subnetworks and their topology. For each iteration of expansion, the neighbour genes of a current subnetwork, whose expression data improved the overall subnetwork score, is recruited. While the GS search calculated the subnetwork score using an activity score of a current subnetwork and the gene expression values of its neighbours, the PN search uses the expression value of the corresponding parent of each neighbour gene. Four lung cancer expression datasets were used for subnetwork identification. In addition, using pathway data and protein-protein interaction as network data in order to consider the interaction among significant genes were discussed. Classification was performed to compare the performance of the identified gene subnetworks with three

  7. Expression analysis of cancer-testis genes in prostate cancer reveals candidates for immunotherapy.

    Science.gov (United States)

    Faramarzi, Sepideh; Ghafouri-Fard, Soudeh

    2017-09-01

    Prostate cancer is a prevalent disorder among men with a heterogeneous etiological background. Several molecular events and signaling perturbations have been found in this disorder. Among genes whose expressions have been altered during the prostate cancer development are cancer-testis antigens (CTAs). This group of antigens has limited expression in the normal adult tissues but aberrant expression in cancers. This property provides them the possibility to be used as cancer biomarkers and immunotherapeutic targets. Several CTAs have been shown to be immunogenic in prostate cancer patients and some of the have entered clinical trials. Based on the preliminary data obtained from these trials, it is expected that CTA-based therapeutic options are beneficial for at least a subset of prostate cancer patients.

  8. Gene expression in early stage cervical cancer

    NARCIS (Netherlands)

    Biewenga, Petra; Buist, Marrije R.; Moerland, Perry D.; van Thernaat, Emiel Ver Loren; van Kampen, Antoine H. C.; ten Kate, Fiebo J. W.; Baas, Frank

    2008-01-01

    Objective. Pelvic lymph node metastases are the main prognostic factor for survival in early stage cervical cancer, yet accurate detection methods before surgery are lacking. In this study, we examined whether gene expression profiling can predict the presence of lymph node metastasis in early stage

  9. Gene expression analysis identifies global gene dosage sensitivity in cancer

    DEFF Research Database (Denmark)

    Fehrmann, Rudolf S. N.; Karjalainen, Juha M.; Krajewska, Malgorzata

    2015-01-01

    Many cancer-associated somatic copy number alterations (SCNAs) are known. Currently, one of the challenges is to identify the molecular downstream effects of these variants. Although several SCNAs are known to change gene expression levels, it is not clear whether each individual SCNA affects gen...

  10. Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer

    Science.gov (United States)

    Choi, Woonyoung; Park, Yun-Yong; Kim, KyoungHyun; Kim, Sang-Bae; Lee, Ju-Seog; Mills, Gordon B.; Cho, Jae Yong

    2011-01-01

    Background Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings Using microarray technology, we generated a gene expression profile of human gastric cancer–specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment. PMID:21931799

  11. Identification of valid reference genes for gene expression studies of human stomach cancer by reverse transcription-qPCR

    Directory of Open Access Journals (Sweden)

    Lee Yeon-Su

    2010-05-01

    Full Text Available Abstract Background Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR is a powerful method for the analysis of gene expression. Target gene expression levels are usually normalized to a consistently expressed reference gene also known as internal standard, in the same sample. However, much effort has not been expended thus far in the search for reference genes suitable for the study of stomach cancer using RT-qPCR, although selection of optimal reference genes is critical for interpretation of results. Methods We assessed the suitability of six possible reference genes, beta-actin (ACTB, glyceraldehydes-3-phosphate dehydrogenase (GAPDH, hypoxanthine phosphoribosyl transferase 1 (HPRT1, beta-2-microglobulin (B2M, ribosomal subunit L29 (RPL29 and 18S ribosomal RNA (18S rRNA in 20 normal and tumor stomach tissue pairs of stomach cancer patients and 6 stomach cancer cell lines, by RT-qPCR. Employing expression stability analyses using NormFinder and geNorm algorithms we determined the order of performance of these reference genes and their variation values. Results This RT-qPCR study showed that there are statistically significant (p Conclusion This study validated RPL29 and RPL29-B2M as the best single reference genes and combination, for RT-qPCR analysis of 'all stomach tissues', and B2M and B2M-GAPDH as the best single reference gene and combination, for 'stomach cancer cell lines'. Use of these validated reference genes should provide more exact interpretation of differential gene expressions at transcription level in stomach cancer.

  12. The rapamycin-regulated gene expression signature determines prognosis for breast cancer

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    Tsavachidis Spiridon

    2009-09-01

    Full Text Available Abstract Background Mammalian target of rapamycin (mTOR is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Results Colony formation and sulforhodamine B (IC50 in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI, of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%. In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile RMI was significantly associated with longer survival (P = 0.015. On multivariate analysis, RMI (P = 0.029, tumor size (P = 0.015 and lymph node status (P = 0.001 were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41. In the Wang dataset, RMI predicted time to disease relapse (P = 0.009. Conclusion Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment.

  13. Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer.

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    Cem Kuscu

    Full Text Available Emerging evidence has demonstrated that upregulated expression of KIAA1199 in human cancer bodes for poor survival. The regulatory mechanism controlling KIAA1199 expression in cancer remains to be characterized. In the present study, we have isolated and characterized the human KIAA1199 promoter in terms of regulation of KIAA1199 gene expression. A 3.3 kb fragment of human genomic DNA containing the 5'-flanking sequence of the KIAA1199 gene possesses both suppressive and activating elements. Employing a deletion mutagenesis approach, a 1.4 kb proximal region was defined as the basic KIAA1199 promoter containing a TATA-box close to the transcription start site. A combination of 5'-primer extension study with 5'RACE DNA sequencing analysis revealed one major transcription start site that is utilized in the human KIAA1199 gene. Bioinformatics analysis suggested that the 1.4 kb KIAA1199 promoter contains putative activating regulatory elements, including activator protein-1(AP-1, Twist-1, and NF-κB sites. Sequential deletion and site-direct mutagenesis analysis demonstrated that the AP-1 and distal NF-κB sites are required for KIAA1199 gene expression. Further analyses using an electrophoretic mobility-shift assay and chromatin immunoprecipitation confirmed the requirement of these cis- and trans-acting elements in controlling KIAA1199 gene expression. Finally, we found that upregulated KIAA1199 expression in human breast cancer specimens correlated with hypomethylation of the regulatory region. Involvement of DNA methylation in regulation of KIAA1199 expression was recapitulated in human breast cancer cell lines. Taken together, our study unraveled the regulatory mechanisms controlling KIAA1199 gene expression in human cancer.

  14. Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer.

    Directory of Open Access Journals (Sweden)

    Malin Lando

    2009-11-01

    Full Text Available Integrative analysis of gene dosage, expression, and ontology (GO data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these patients were also analyzed with the Illumina expression method to confirm the gene expression results. An independent cohort of 41 patients was used for validation of gene expressions associated with clinical outcome. Statistical analysis identified 29 recurrent gains and losses and 3 losses (on 3p, 13q, 21q associated with poor outcome after chemoradiotherapy. The intratumor heterogeneity, assessed from the gene dosage profiles, was low for these alterations, showing that they had emerged prior to many other alterations and probably were early events in carcinogenesis. Integration of the alterations with gene expression and GO data identified genes that were regulated by the alterations and revealed five biological processes that were significantly overrepresented among the affected genes: apoptosis, metabolism, macromolecule localization, translation, and transcription. Four genes on 3p (RYBP, GBE1 and 13q (FAM48A, MED4 correlated with outcome at both the gene dosage and expression level and were satisfactorily validated in the independent cohort. These integrated analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. Further mapping of the connections among genetic events, drivers, and biological processes suggested that each individual event stimulates specific processes in carcinogenesis through the coordinated control of multiple genes. The present results may provide novel therapeutic opportunities of both early and advanced stage cervical cancers.

  15. Differential peripheral blood gene expression profile based on Her2 expression on primary tumors of breast cancer patients.

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    Oana Tudoran

    Full Text Available Breast cancer prognosis and treatment is highly dependent on the molecular features of the primary tumors. These tumors release specific molecules into the environment that trigger characteristic responses into the circulatory cells. In this study we investigated the expression pattern of 84 genes known to be involved in breast cancer signaling in the peripheral blood of breast cancer patients with ER-, PR- primary tumors. The patients were grouped according to Her2 expression on the primary tumors in Her2+ and Her2- cohorts. Transcriptional analysis revealed 15 genes to be differentially expressed between the two groups highlighting that Her2 signaling in primary tumors could be associated with specific blood gene expression. We found CCNA1 to be up-regulated, while ERBB2, RASSF1, CDH1, MKI67, GATA3, GLI1, SFN, PTGS2, JUN, NOTCH1, CTNNB1, KRT8, SRC, and HIC1 genes were down-regulated in the blood of triple negative breast cancer patients compared to Her2+ cohort. IPA network analysis predicts that the identified genes are interconnected and regulate each other. These genes code for cell cycle regulators, cell adhesion molecules, transcription factors or signal transducers that modulate immune signaling, several genes being also associated with cancer progression and treatment response. These results indicate an altered immune signaling in the peripheral blood of triple negative breast cancer patients. The involvement of the immune system is necessary in favorable treatment response, therefore these results could explain the low response rates observed for triple negative breast cancer patients.

  16. Cancer as quasi-attractor in the gene expression phase space

    Science.gov (United States)

    Giuliani, A.

    2017-09-01

    It takes no more than 250 tissue types to build up a metazoan, and each tissue has a specific and largely invariant gene expression signature. This implies the `viable configurations' correspondent to a given activated/inactivated expression pattern over the entire genome are very few. This points to the presence of few `low energy deep valleys' correspondent to the allowed states of the system and is a direct consequence of the fact genes do not work by alone but embedded into genetic expression networks. Statistical thermodynamics formalism focusing on the changes in the degree of correlation of the studied systems allows to detect transition behavior in gene expression phase space resembling the phase transition of physical-chemistry studies. In this realm cancer can be intended as a sort of `parasite' sub-attractor of the corresponding healthy tissue that, in the case of disease, is `kinetically entrapped' into a sub-optimal solution. The consequences of such a state of affair for cancer therapies are potentially huge.

  17. DNA copy-number alterations underlie gene expression differences between microsatellite stable and unstable colorectal cancers

    DEFF Research Database (Denmark)

    Jorissen, Robert N; Lipton, Lara; Gibbs, Peter

    2008-01-01

    Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes...... and downstream effects of differential gene expression. Experimental Design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene......-number data. Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P

  18. Classification of Breast Cancer Subtypes by combining Gene Expression and DNA Methylation Data

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    List Markus

    2014-06-01

    Full Text Available Selecting the most promising treatment strategy for breast cancer crucially depends on determining the correct subtype. In recent years, gene expression profiling has been investigated as an alternative to histochemical methods. Since databases like TCGA provide easy and unrestricted access to gene expression data for hundreds of patients, the challenge is to extract a minimal optimal set of genes with good prognostic properties from a large bulk of genes making a moderate contribution to classification. Several studies have successfully applied machine learning algorithms to solve this so-called gene selection problem. However, more diverse data from other OMICS technologies are available, including methylation. We hypothesize that combining methylation and gene expression data could already lead to a largely improved classification model, since the resulting model will reflect differences not only on the transcriptomic, but also on an epigenetic level. We compared so-called random forest derived classification models based on gene expression and methylation data alone, to a model based on the combined features and to a model based on the gold standard PAM50. We obtained bootstrap errors of 10-20% and classification error of 1-50%, depending on breast cancer subtype and model. The gene expression model was clearly superior to the methylation model, which was also reflected in the combined model, which mainly selected features from gene expression data. However, the methylation model was able to identify unique features not considered as relevant by the gene expression model, which might provide deeper insights into breast cancer subtype differentiation on an epigenetic level.

  19. Discretization of Gene Expression Data Unmasks Molecular Subgroups Recurring in Different Human Cancer Types.

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    Manfred Beleut

    Full Text Available Despite the individually different molecular alterations in tumors, the malignancy associated biological traits are strikingly similar. Results of a previous study using renal cell carcinoma (RCC as a model pointed towards cancer-related features, which could be visualized as three groups by microarray based gene expression analysis. In this study, we used a mathematic model to verify the presence of these groups in RCC as well as in other cancer types. We developed an algorithm for gene-expression deviation profiling for analyzing gene expression data of a total of 8397 patients with 13 different cancer types and normal tissues. We revealed three common Cancer Transcriptomic Profiles (CTPs which recurred in all investigated tumors. Additionally, CTPs remained robust regardless of the functions or numbers of genes analyzed. CTPs may represent common genetic fingerprints, which potentially reflect the closely related biological traits of human cancers.

  20. Prognostic significance of glucose transporter-1 (GLUT1) gene expression in rectal cancer after preoperative chemoradiotherapy

    International Nuclear Information System (INIS)

    Saigusa, Susumu; Toiyama, Yuji; Tanaka, Koji; Okugawa, Yoshinaga; Fujikawa, Hiroyuki; Matsushita, Kohei; Uchida, Keiichi; Inoue, Yasuhiro; Kusunoki, Masato

    2012-01-01

    Most cancer cells exhibit increased glycolysis. The elevated glucose transporter 1 (GLUT1) expression has been reported to be associated with resistance to therapeutic agents and a poor prognosis. We wondered whether GLUT1 expression was associated with the clinical outcome in rectal cancer after preoperative chemoradiotherapy (CRT), and whether glycolysis inhibition could represent a novel anticancer treatment. We obtained total RNA from residual cancer cells using microdissection from a total of 52 rectal cancer specimens from patients who underwent preoperative CRT. We performed transcriptional analyzes, and studied the association of the GLUT1 gene expression levels with the clinical outcomes. In addition, we examined each proliferative response of three selected colorectal cancer cell lines to a glycolysis inhibitor, 3-bromopyruvic acid (3-BrPA), with regard to their expression of the GLUT1 gene. An elevated GLUT1 gene expression was associated with a high postoperative stage, the presence of lymph node metastasis, and distant recurrence. Moreover, elevated GLUT1 gene expression independently predicted both the recurrence-free and overall survival. In the in vitro studies, we observed that 3-BrPA significantly suppressed the proliferation of colon cancer cells with high GLUT1 gene expression, compared with those with low expression. An elevated GLUT1 expression may be a useful predictor of distant recurrence and poor prognosis in rectal cancer patients after preoperative CRT. (author)

  1. A stochastic model for identifying differential gene pair co-expression patterns in prostate cancer progression

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    Mao Yu

    2009-07-01

    Full Text Available Abstract Background The identification of gene differential co-expression patterns between cancer stages is a newly developing method to reveal the underlying molecular mechanisms of carcinogenesis. Most researches of this subject lack an algorithm useful for performing a statistical significance assessment involving cancer progression. Lacking this specific algorithm is apparently absent in identifying precise gene pairs correlating to cancer progression. Results In this investigation we studied gene pair co-expression change by using a stochastic process model for approximating the underlying dynamic procedure of the co-expression change during cancer progression. Also, we presented a novel analytical method named 'Stochastic process model for Identifying differentially co-expressed Gene pair' (SIG method. This method has been applied to two well known prostate cancer data sets: hormone sensitive versus hormone resistant, and healthy versus cancerous. From these data sets, 428,582 gene pairs and 303,992 gene pairs were identified respectively. Afterwards, we used two different current statistical methods to the same data sets, which were developed to identify gene pair differential co-expression and did not consider cancer progression in algorithm. We then compared these results from three different perspectives: progression analysis, gene pair identification effectiveness analysis, and pathway enrichment analysis. Statistical methods were used to quantify the quality and performance of these different perspectives. They included: Re-identification Scale (RS and Progression Score (PS in progression analysis, True Positive Rate (TPR in gene pair analysis, and Pathway Enrichment Score (PES in pathway analysis. Our results show small values of RS and large values of PS, TPR, and PES; thus, suggesting that gene pairs identified by the SIG method are highly correlated with cancer progression, and highly enriched in disease-specific pathways. From

  2. Endosomal gene expression: a new indicator for prostate cancer patient prognosis?

    LENUS (Irish Health Repository)

    Johnson, Ian R D

    2015-11-10

    Prostate cancer continues to be a major cause of morbidity and mortality in men, but a method for accurate prognosis in these patients is yet to be developed. The recent discovery of altered endosomal biogenesis in prostate cancer has identified a fundamental change in the cell biology of this cancer, which holds great promise for the identification of novel biomarkers that can predict disease outcomes. Here we have identified significantly altered expression of endosomal genes in prostate cancer compared to non-malignant tissue in mRNA microarrays and confirmed these findings by qRT-PCR on fresh-frozen tissue. Importantly, we identified endosomal gene expression patterns that were predictive of patient outcomes. Two endosomal tri-gene signatures were identified from a previously published microarray cohort and had a significant capacity to stratify patient outcomes. The expression of APPL1, RAB5A, EEA1, PDCD6IP, NOX4 and SORT1 were altered in malignant patient tissue, when compared to indolent and normal prostate tissue. These findings support the initiation of a case-control study using larger cohorts of prostate tissue, with documented patient outcomes, to determine if different combinations of these new biomarkers can accurately predict disease status and clinical progression in prostate cancer patients.

  3. Gene expression patterns associated with p53 status in breast cancer

    International Nuclear Information System (INIS)

    Troester, Melissa A; Herschkowitz, Jason I; Oh, Daniel S; He, Xiaping; Hoadley, Katherine A; Barbier, Claire S; Perou, Charles M

    2006-01-01

    Breast cancer subtypes identified in genomic studies have different underlying genetic defects. Mutations in the tumor suppressor p53 occur more frequently in estrogen receptor (ER) negative, basal-like and HER2-amplified tumors than in luminal, ER positive tumors. Thus, because p53 mutation status is tightly linked to other characteristics of prognostic importance, it is difficult to identify p53's independent prognostic effects. The relation between p53 status and subtype can be better studied by combining data from primary tumors with data from isogenic cell line pairs (with and without p53 function). The p53-dependent gene expression signatures of four cell lines (MCF-7, ZR-75-1, and two immortalized human mammary epithelial cell lines) were identified by comparing p53-RNAi transduced cell lines to their parent cell lines. Cell lines were treated with vehicle only or doxorubicin to identify p53 responses in both non-induced and induced states. The cell line signatures were compared with p53-mutation associated genes in breast tumors. Each cell line displayed distinct patterns of p53-dependent gene expression, but cell type specific (basal vs. luminal) commonalities were evident. Further, a common gene expression signature associated with p53 loss across all four cell lines was identified. This signature showed overlap with the signature of p53 loss/mutation status in primary breast tumors. Moreover, the common cell-line tumor signature excluded genes that were breast cancer subtype-associated, but not downstream of p53. To validate the biological relevance of the common signature, we demonstrated that this gene set predicted relapse-free, disease-specific, and overall survival in independent test data. In the presence of breast cancer heterogeneity, experimental and biologically-based methods for assessing gene expression in relation to p53 status provide prognostic and biologically-relevant gene lists. Our biologically-based refinements excluded genes

  4. Differential expression patterns of housekeeping genes increase diagnostic and prognostic value in lung cancer

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    Yu-Chun Chang

    2018-05-01

    Full Text Available Background Using DNA microarrays, we previously identified 451 genes expressed in 19 different human tissues. Although ubiquitously expressed, the variable expression patterns of these “housekeeping genes” (HKGs could separate one normal human tissue type from another. Current focus on identifying “specific disease markers” is problematic as single gene expression in a given sample represents the specific cellular states of the sample at the time of collection. In this study, we examine the diagnostic and prognostic potential of the variable expressions of HKGs in lung cancers. Methods Microarray and RNA-seq data for normal lungs, lung adenocarcinomas (AD, squamous cell carcinomas of the lung (SQCLC, and small cell carcinomas of the lung (SCLC were collected from online databases. Using 374 of 451 HKGs, differentially expressed genes between pairs of sample types were determined via two-sided, homoscedastic t-test. Principal component analysis and hierarchical clustering classified normal lung and lung cancers subtypes according to relative gene expression variations. We used uni- and multi-variate cox-regressions to identify significant predictors of overall survival in AD patients. Classifying genes were selected using a set of training samples and then validated using an independent test set. Gene Ontology was examined by PANTHER. Results This study showed that the differential expression patterns of 242, 245, and 99 HKGs were able to distinguish normal lung from AD, SCLC, and SQCLC, respectively. From these, 70 HKGs were common across the three lung cancer subtypes. These HKGs have low expression variation compared to current lung cancer markers (e.g., EGFR, KRAS and were involved in the most common biological processes (e.g., metabolism, stress response. In addition, the expression pattern of 106 HKGs alone was a significant classifier of AD versus SQCLC. We further highlighted that a panel of 13 HKGs was an independent predictor of

  5. Genome-wide gene copy number and expression analysis of primary gastric tumors and gastric cancer cell lines

    International Nuclear Information System (INIS)

    Junnila, Siina; Kokkola, Arto; Karjalainen-Lindsberg, Marja-Liisa; Puolakkainen, Pauli; Monni, Outi

    2010-01-01

    Gastric cancer is one of the most common malignancies worldwide and the second most common cause of cancer related death. Gene copy number alterations play an important role in the development of gastric cancer and a change in gene copy number is one of the main mechanisms for a cancer cell to control the expression of potential oncogenes and tumor suppressor genes. To highlight genes of potential biological and clinical relevance in gastric cancer, we carried out a systematic array-based survey of gene expression and copy number levels in primary gastric tumors and gastric cancer cell lines and validated the results using an affinity capture based transcript analysis (TRAC assay) and real-time qRT-PCR. Integrated microarray analysis revealed altogether 256 genes that were located in recurrent regions of gains or losses and had at least a 2-fold copy number- associated change in their gene expression. The expression levels of 13 of these genes, ALPK2, ASAP1, CEACAM5, CYP3A4, ENAH, ERBB2, HHIPL2, LTB4R, MMP9, PERLD1, PNMT, PTPRA, and OSMR, were validated in a total of 118 gastric samples using either the qRT-PCR or TRAC assay. All of these 13 genes were differentially expressed between cancerous samples and nonmalignant tissues (p < 0.05) and the association between copy number and gene expression changes was validated for nine (69.2%) of these genes (p < 0.05). In conclusion, integrated gene expression and copy number microarray analysis highlighted genes that may be critically important for gastric carcinogenesis. TRAC and qRT-PCR analyses validated the microarray results and therefore the role of these genes as potential biomarkers for gastric cancer

  6. Prediction of metastasis from low-malignant breast cancer by gene expression profiling

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Eiriksdottir, Freyja

    2007-01-01

    examined in these studies is the low-risk patients for whom outcome is very difficult to predict with currently used methods. These patients do not receive adjuvant treatment according to the guidelines of the Danish Breast Cancer Cooperative Group (DBCG). In this study, 26 tumors from low-risk patients...... with different characteristics and risk, expression-based classification specifically developed in low-risk patients have higher predictive power in this group.......Promising results for prediction of outcome in breast cancer have been obtained by genome wide gene expression profiling. Some studies have suggested that an extensive overtreatment of breast cancer patients might be reduced by risk assessment with gene expression profiling. A patient group hardly...

  7. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer

    Science.gov (United States)

    Halabi, Najeeb M.; Martinez, Alejandra; Al-Farsi, Halema; Mery, Eliane; Puydenus, Laurence; Pujol, Pascal; Khalak, Hanif G.; McLurcan, Cameron; Ferron, Gwenael; Querleu, Denis; Al-Azwani, Iman; Al-Dous, Eman; Mohamoud, Yasmin A.; Malek, Joel A.; Rafii, Arash

    2016-01-01

    Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies. PMID:26735499

  8. Finding biological process modifications in cancer tissues by mining gene expression correlations

    Directory of Open Access Journals (Sweden)

    Storari Sergio

    2006-01-01

    Full Text Available Abstract Background Through the use of DNA microarrays it is now possible to obtain quantitative measurements of the expression of thousands of genes from a biological sample. This technology yields a global view of gene expression that can be used in several ways. Functional insight into expression profiles is routinely obtained by using Gene Ontology terms associated to the cellular genes. In this paper, we deal with functional data mining from expression profiles, proposing a novel approach that studies the correlations between genes and their relations to Gene Ontology (GO. By using this "functional correlations comparison" we explore all possible pairs of genes identifying the affected biological processes by analyzing in a pair-wise manner gene expression patterns and linking correlated pairs with Gene Ontology terms. Results We apply here this "functional correlations comparison" approach to identify the existing correlations in hepatocarcinoma (161 microarray experiments and to reveal functional differences between normal liver and cancer tissues. The number of well-correlated pairs in each GO term highlights several differences in genetic interactions between cancer and normal tissues. We performed a bootstrap analysis in order to compute false detection rates (FDR and confidence limits. Conclusion Experimental results show the main advantage of the applied method: it both picks up general and specific GO terms (in particular it shows a fine resolution in the specific GO terms. The results obtained by this novel method are highly coherent with the ones proposed by other cancer biology studies. But additionally they highlight the most specific and interesting GO terms helping the biologist to focus his/her studies on the most relevant biological processes.

  9. Mutation and Expression of the DCC Gene in Human Lung Cancer

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    Takashi Kohno

    2000-07-01

    Full Text Available Chromosome 18q is frequently deleted in lung cancers, a common region of 18q deletions was mapped to chromosome 18g21. Since the DCC candidate tumor suppressor gene has been mapped in this region, mutation and expression of the DCC gene were examined in 46 lung cancer cell lines, consisting of 14 small cell lung carcinomas (SCLCs and 32 non-small cell lung carcinomas (NSCLCs, to elucidate the pathogenetic significance of DCC alterations in human lung carcinogenesis. A heterozygous missense mutation was detected in a NSCLC cell line, Ma26, while homozygous deletion was not detected in any of the cell lines. The DCC gene was expressed in 11 (24% of the 46 cell lines, the incidence of DCC expression was significantly higher in SCLCs (7/14, 50% than in NSCLCs (4/32, 13% (P = .01, Fisher's exact test. Therefore, genetic alterations of DCC are infrequent; however, the levels of DCC expression vary among lung cancer cells, in particular, between SCLCs and NSCLCs. The present result does not implicate DCC as a specific mutational target of 18q deletions in human lung cancer; however, it suggests that DCC is a potential target of inactivation by genetic defects including intron or promoter mutations and/or epigenetic alterations. The present result also suggests that DCC expression is associated with some properties of SCLCs, such as a neuroendocrine (NE feature.

  10. 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...... ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified...

  11. Time- and dose-dependent effects of curcumin on gene expression in human colon cancer cells

    Directory of Open Access Journals (Sweden)

    van Erk Marjan J

    2004-05-01

    Full Text Available Abstract Background Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling. Methods Gene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours. Gene expression changes after short-term exposure (3 or 6 hours to curcumin were also studied in a second cell type, Caco-2 cells. Results Gene expression changes (>1.5-fold were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. Conclusions This study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase

  12. A Critical Perspective On Microarray Breast Cancer Gene Expression Profiling

    NARCIS (Netherlands)

    Sontrop, H.M.J.

    2015-01-01

    Microarrays offer biologists an exciting tool that allows the simultaneous assessment of gene expression levels for thousands of genes at once. At the time of their inception, microarrays were hailed as the new dawn in cancer biology and oncology practice with the hope that within a decade diseases

  13. A resampling-based meta-analysis for detection of differential gene expression in breast cancer

    International Nuclear Information System (INIS)

    Gur-Dedeoglu, Bala; Konu, Ozlen; Kir, Serkan; Ozturk, Ahmet Rasit; Bozkurt, Betul; Ergul, Gulusan; Yulug, Isik G

    2008-01-01

    Accuracy in the diagnosis of breast cancer and classification of cancer subtypes has improved over the years with the development of well-established immunohistopathological criteria. More recently, diagnostic gene-sets at the mRNA expression level have been tested as better predictors of disease state. However, breast cancer is heterogeneous in nature; thus extraction of differentially expressed gene-sets that stably distinguish normal tissue from various pathologies poses challenges. Meta-analysis of high-throughput expression data using a collection of statistical methodologies leads to the identification of robust tumor gene expression signatures. A resampling-based meta-analysis strategy, which involves the use of resampling and application of distribution statistics in combination to assess the degree of significance in differential expression between sample classes, was developed. Two independent microarray datasets that contain normal breast, invasive ductal carcinoma (IDC), and invasive lobular carcinoma (ILC) samples were used for the meta-analysis. Expression of the genes, selected from the gene list for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes were tested on 10 independent primary IDC samples and matched non-tumor controls by real-time qRT-PCR. Other existing breast cancer microarray datasets were used in support of the resampling-based meta-analysis. The two independent microarray studies were found to be comparable, although differing in their experimental methodologies (Pearson correlation coefficient, R = 0.9389 and R = 0.8465 for ductal and lobular samples, respectively). The resampling-based meta-analysis has led to the identification of a highly stable set of genes for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes. The expression results of the selected genes obtained through real-time qRT-PCR supported the meta-analysis results. The

  14. A resampling-based meta-analysis for detection of differential gene expression in breast cancer

    Directory of Open Access Journals (Sweden)

    Ergul Gulusan

    2008-12-01

    Full Text Available Abstract Background Accuracy in the diagnosis of breast cancer and classification of cancer subtypes has improved over the years with the development of well-established immunohistopathological criteria. More recently, diagnostic gene-sets at the mRNA expression level have been tested as better predictors of disease state. However, breast cancer is heterogeneous in nature; thus extraction of differentially expressed gene-sets that stably distinguish normal tissue from various pathologies poses challenges. Meta-analysis of high-throughput expression data using a collection of statistical methodologies leads to the identification of robust tumor gene expression signatures. Methods A resampling-based meta-analysis strategy, which involves the use of resampling and application of distribution statistics in combination to assess the degree of significance in differential expression between sample classes, was developed. Two independent microarray datasets that contain normal breast, invasive ductal carcinoma (IDC, and invasive lobular carcinoma (ILC samples were used for the meta-analysis. Expression of the genes, selected from the gene list for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes were tested on 10 independent primary IDC samples and matched non-tumor controls by real-time qRT-PCR. Other existing breast cancer microarray datasets were used in support of the resampling-based meta-analysis. Results The two independent microarray studies were found to be comparable, although differing in their experimental methodologies (Pearson correlation coefficient, R = 0.9389 and R = 0.8465 for ductal and lobular samples, respectively. The resampling-based meta-analysis has led to the identification of a highly stable set of genes for classification of normal breast samples and breast tumors encompassing both the ILC and IDC subtypes. The expression results of the selected genes obtained through real

  15. Gene expression profiling leads to discovery of correlation of matrix metalloproteinase 11 and heparanase 2 in breast cancer progression

    International Nuclear Information System (INIS)

    Fu, Junjie; Khaybullin, Ravil; Zhang, Yanping; Xia, Amy; Qi, Xin

    2015-01-01

    In order to identify biomarkers involved in breast cancer, gene expression profiling was conducted using human breast cancer tissues. Total RNAs were extracted from 150 clinical patient tissues covering three breast cancer subtypes (Luminal A, Luminal B, and Triple negative) as well as normal tissues. The expression profiles of a total of 50,739 genes were established from a training set of 32 samples using the Agilent Sure Print G3 Human Gene Expression Microarray technology. Data were analyzed using Agilent Gene Spring GX 12.6 software. The expression of several genes was validated using real-time RT-qPCR. Data analysis with Agilent GeneSpring GX 12.6 software showed distinct expression patterns between cancer and normal tissue samples. A group of 28 promising genes were identified with ≥ 10-fold changes of expression level and p-values < 0.05. In particular, MMP11 and HPSE2 were closely examined due to the important roles they play in cancer cell growth and migration. Real-time RT-qPCR analyses of both training and testing sets validated the gene expression profiles of MMP11 and HPSE2. Our findings identified these 2 genes as a novel breast cancer biomarker gene set, which may facilitate the diagnosis and treatment in breast cancer clinical therapies

  16. Effectiveness of gene expression profiling for response prediction of rectal cancer to preoperative radiotherapy

    International Nuclear Information System (INIS)

    Ojima, Eiki; Inoue, Yasuhiro; Miki, Chikao; Kusunoki, Masato; Mori, Masaki

    2007-01-01

    Our aim was to determine whether the expression levels of specific genes could predict clinical radiosensitivity in human colorectal cancer. Radioresistant colorectal cancer cell lines were established by repeated X-ray exposure (total, 100 Gy), and the gene expressions of the parent and radioresistant cell lines were compared in a microarray analysis. To verify the microarray data, we carried out a reverse transcriptase-polymerase chain reaction analysis of identified genes in clinical samples from 30 irradiated rectal cancer patients. A comparison of the intensity data for the parent and three radioresistant cell lines revealed 17 upregulated and 142 downregulated genes in all radioresistant cell lines. Next, we focused on two upregulated genes, PTMA (prothymosin α) and EIF5a2 (eukaryotic translation initiation factor 5A), in the radioresistant cell lines. In clinical samples, the expression of PTMA was significantly higher in the minor effect group than in the major effect group (P=0.004), but there were no significant differences in EIF5a2 expression between the two groups. We identified radiation-related genes in colorectal cancer and demonstrated that PTMA may play an important role in radiosensitivity. Our findings suggest that PTMA may be a novel marker for predicting the effectiveness of radiotherapy in clinical cases. (author)

  17. Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor.

    Science.gov (United States)

    Vasselli, James R; Shih, Joanna H; Iyengar, Shuba R; Maranchie, Jodi; Riss, Joseph; Worrell, Robert; Torres-Cabala, Carlos; Tabios, Ray; Mariotti, Andra; Stearman, Robert; Merino, Maria; Walther, McClellan M; Simon, Richard; Klausner, Richard D; Linehan, W Marston

    2003-06-10

    To identify potential molecular determinants of tumor biology and possible clinical outcomes, global gene-expression patterns were analyzed in the primary tumors of patients with metastatic renal cell cancer by using cDNA microarrays. We used grossly dissected tumor masses that included tumor, blood vessels, connective tissue, and infiltrating immune cells to obtain a gene-expression "profile" from each primary tumor. Two patterns of gene expression were found within this uniformly staged patient population, which correlated with a significant difference in overall survival between the two patient groups. Subsets of genes most significantly associated with survival were defined, and vascular cell adhesion molecule-1 (VCAM-1) was the gene most predictive for survival. Therefore, despite the complex biological nature of metastatic cancer, basic clinical behavior as defined by survival may be determined by the gene-expression patterns expressed within the compilation of primary gross tumor cells. We conclude that survival in patients with metastatic renal cell cancer can be correlated with the expression of various genes based solely on the expression profile in the primary kidney tumor.

  18. Differentially expressed androgen-regulated genes in androgen-sensitive tissues reveal potential biomarkers of early prostate cancer.

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    Dogus Murat Altintas

    Full Text Available BACKGROUND: Several data favor androgen receptor implication in prostate cancer initiation through the induction of several gene activation programs. The aim of the study is to identify potential biomarkers for early diagnosis of prostate cancer (PCa among androgen-regulated genes (ARG and to evaluate comparative expression of these genes in normal prostate and normal prostate-related androgen-sensitive tissues that do not (or rarely give rise to cancer. METHODS: ARG were selected in non-neoplastic adult human prostatic epithelial RWPE-1 cells stably expressing an exogenous human androgen receptor, using RNA-microarrays and validation by qRT-PCR. Expression of 48 preselected genes was quantified in tissue samples (seminal vesicles, prostate transitional zones and prostate cancers, benign prostatic hypertrophy obtained from surgical specimens using TaqMan® low-density arrays. The diagnostic performances of these potential biomarkers were compared to that of genes known to be associated with PCa (i.e. PCA3 and DLX1. RESULTS AND DISCUSSION: By crossing expression studies in 26 matched PCa and normal prostate transitional zone samples, and 35 matched seminal vesicle and PCa samples, 14 genes were identified. Similarly, 9 genes were overexpressed in 15 benign prostatic hypertrophy samples, as compared to PCa samples. Overall, we selected 8 genes of interest to evaluate their diagnostic performances in comparison with that of PCA3 and DLX1. Among them, 3 genes: CRYAB, KCNMA1 and SDPR, were overexpressed in all 3 reference non-cancerous tissues. The areas under ROC curves of these genes reached those of PCA3 (0.91 and DLX1 (0.94. CONCLUSIONS: We identified ARG with reduced expression in PCa and with significant diagnostic values for discriminating between cancerous and non-cancerous prostatic tissues, similar that of PCA3. Given their expression pattern, they could be considered as potentially protective against prostate cancer. Moreover, they could

  19. Quantitative RT-PCR analysis of estrogen receptor gene expression in laser microdissected prostate cancer tissue.

    Science.gov (United States)

    Walton, Thomas J; Li, Geng; McCulloch, Thomas A; Seth, Rashmi; Powe, Desmond G; Bishop, Michael C; Rees, Robert C

    2009-06-01

    Real-time quantitative RT-PCR analysis of laser microdissected tissue is considered the most accurate technique for determining tissue gene expression. The discovery of estrogen receptor beta (ERbeta) has focussed renewed interest on the role of estrogen receptors in prostate cancer, yet few studies have utilized the technique to analyze estrogen receptor gene expression in prostate cancer. Fresh tissue was obtained from 11 radical prostatectomy specimens and from 6 patients with benign prostate hyperplasia. Pure populations of benign and malignant prostate epithelium were laser microdissected, followed by RNA isolation and electrophoresis. Quantitative RT-PCR was performed using primers for androgen receptor (AR), estrogen receptor beta (ERbeta), estrogen receptor alpha (ERalpha), progesterone receptor (PGR) and prostate specific antigen (PSA), with normalization to two housekeeping genes. Differences in gene expression were analyzed using the Mann-Whitney U-test. Correlation coefficients were analyzed using Spearman's test. Significant positive correlations were seen when AR and AR-dependent PSA, and ERalpha and ERalpha-dependent PGR were compared, indicating a representative population of RNA transcripts. ERbeta gene expression was significantly over-expressed in the cancer group compared with benign controls (P cancer group (P prostate cancer specimens. In concert with recent studies the findings suggest differential production of ERbeta splice variants, which may play important roles in the genesis of prostate cancer. (c) 2009 Wiley-Liss, Inc.

  20. Gene expression variation to predict 10-year survival in lymph-node-negative breast cancer

    International Nuclear Information System (INIS)

    Karlsson, Elin; Delle, Ulla; Danielsson, Anna; Olsson, Björn; Abel, Frida; Karlsson, Per; Helou, Khalil

    2008-01-01

    It is of great significance to find better markers to correctly distinguish between high-risk and low-risk breast cancer patients since the majority of breast cancer cases are at present being overtreated. 46 tumours from node-negative breast cancer patients were studied with gene expression microarrays. A t-test was carried out in order to find a set of genes where the expression might predict clinical outcome. Two classifiers were used for evaluation of the gene lists, a correlation-based classifier and a Voting Features Interval (VFI) classifier. We then evaluated the predictive accuracy of this expression signature on tumour sets from two similar studies on lymph-node negative patients. They had both developed gene expression signatures superior to current methods in classifying node-negative breast tumours. These two signatures were also tested on our material. A list of 51 genes whose expression profiles could predict clinical outcome with high accuracy in our material (96% or 89% accuracy in cross-validation, depending on type of classifier) was developed. When tested on two independent data sets, the expression signature based on the 51 identified genes had good predictive qualities in one of the data sets (74% accuracy), whereas their predictive value on the other data set were poor, presumably due to the fact that only 23 of the 51 genes were found in that material. We also found that previously developed expression signatures could predict clinical outcome well to moderately well in our material (72% and 61%, respectively). The list of 51 genes derived in this study might have potential for clinical utility as a prognostic gene set, and may include candidate genes of potential relevance for clinical outcome in breast cancer. According to the predictions by this expression signature, 30 of the 46 patients may have benefited from different adjuvant treatment than they recieved. The research on these tumours was approved by the Medical Faculty Research

  1. Integrative analysis of gene expression and DNA methylation using unsupervised feature extraction for detecting candidate cancer biomarkers.

    Science.gov (United States)

    Moon, Myungjin; Nakai, Kenta

    2018-04-01

    Currently, cancer biomarker discovery is one of the important research topics worldwide. In particular, detecting significant genes related to cancer is an important task for early diagnosis and treatment of cancer. Conventional studies mostly focus on genes that are differentially expressed in different states of cancer; however, noise in gene expression datasets and insufficient information in limited datasets impede precise analysis of novel candidate biomarkers. In this study, we propose an integrative analysis of gene expression and DNA methylation using normalization and unsupervised feature extractions to identify candidate biomarkers of cancer using renal cell carcinoma RNA-seq datasets. Gene expression and DNA methylation datasets are normalized by Box-Cox transformation and integrated into a one-dimensional dataset that retains the major characteristics of the original datasets by unsupervised feature extraction methods, and differentially expressed genes are selected from the integrated dataset. Use of the integrated dataset demonstrated improved performance as compared with conventional approaches that utilize gene expression or DNA methylation datasets alone. Validation based on the literature showed that a considerable number of top-ranked genes from the integrated dataset have known relationships with cancer, implying that novel candidate biomarkers can also be acquired from the proposed analysis method. Furthermore, we expect that the proposed method can be expanded for applications involving various types of multi-omics datasets.

  2. Efficacy of laser capture microdissection plus RT-PCR technique in analyzing gene expression levels in human gastric cancer and colon cancer

    International Nuclear Information System (INIS)

    Makino, Hiroshi; Uetake, Hiroyuki; Danenberg, Kathleen; Danenberg, Peter V; Sugihara, Kenichi

    2008-01-01

    Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase gene expressions are reported to be valid predictive markers for 5-fluorouracil sensitivity to gastrointestinal cancer. For more reliable predictability, their expressions in cancer cells and stromal cells in the cancerous tissue (cancerous stroma) have been separately investigated using laser capture microdissection. Thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase mRNA in cancer cells and cancerous stroma from samples of 47 gastric and 43 colon cancers were separately quantified by reverse transcription polymerase chain reaction after laser capture microdissection. In both gastric and colon cancers, thymidylate synthase and orotate phosphoribosyltransferase mRNA expressions were higher (p < 0.0001, p <0.0001 respectively in gastric cancer and P = 0.0002, p < 0.0001 respectively in colon cancer) and dihydropyrimidine dehydrogenase mRNA expressions were lower in cancer cells than in cancerous stroma (P = 0.0136 in gastric cancer and p < 0.0001 in colon cancer). In contrast, thymidine phosphorylase mRNA was higher in cancer cells than in cancerous stroma in gastric cancer (p < 0.0001) and lower in cancer cells than in cancerous stroma in colon cancer (P = 0.0055). By using this method, we could estimate gene expressions separately in cancer cells and stromal cells from colon and gastric cancers, in spite of the amount of stromal tissue. Our method is thought to be useful for accurately evaluating intratumoral gene expressions

  3. Gene expression of circulating tumour cells in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Bölke E

    2009-09-01

    Full Text Available Abstract Background The diagnostic tools to predict the prognosis in patients suffering from breast cancer (BC need further improvements. New technological achievements like the gene profiling of circulating tumour cells (CTC could help identify new prognostic markers in the clinical setting. Furthermore, gene expression patterns of CTC might provide important informations on the mechanisms of tumour cell metastasation. Materials and methods We performed realtime-PCR and multiplex-PCR analyses following immunomagnetic separation of CTC. Peripheral blood (PB samples of 63 patients with breast cancer of various stages were analyzed and compared to a control group of 14 healthy individuals. After reverse-transcription, we performed multiplex PCR using primers for the genes ga733.3, muc-1 and c-erbB2. Mammaglobin1, spdef and c-erbB2 were analyzed applying realtime-PCR. Results ga733.2 overexpression was found in 12.7% of breast cancer cases, muc-1 in 15.9%, mgb1 in 9.1% and spdef in 12.1%. In this study, c-erbB2 did not show any significant correlation to BC, possibly due to a highly ambient expression. Besides single gene analyses, gene profiles were additionally evaluated. Highly significant correlations to BC were found in single gene analyses of ga733.2 and muc-1 and in gene profile analyses of ga733.3*muc-1 and GA7 ga733.3*muc-1*mgb1*spdef. Conclusion Our study reveals that the single genes ga733.3, muc-1 and the gene profiles ga733.3*muc-1 and ga733.3*3muc-1*mgb1*spdef can serve as markers for the detection of CTC in BC. The multigene analyses found highly positive levels in BC patients. Our study indicates that not single gene analyses but subtle patterns of multiple genes lead to rising accuracy and low loss of specificity in detection of breast cancer cases.

  4. Dynamic changes of tumor gene expression during repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal cancer

    International Nuclear Information System (INIS)

    Rezniczek, Günther A.; Jüngst, Friederike; Jütte, Hendrik; Tannapfel, Andrea; Hilal, Ziad; Hefler, Lukas A.; Reymond, Marc-André; Tempfer, Clemens B.

    2016-01-01

    Intraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel. Total RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes. Gene expression profiles differed significantly between peritoneal cancer and non- peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival. In summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations. The online version of this article (doi:10.1186/s12885-016-2668-4) contains supplementary material, which is available to authorized users

  5. BRCA1 gene expression in relation to prognostic parameters of breast cancer

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    Manal Kamal

    2011-09-01

    Full Text Available The tumor suppressor gene, BRCA1 has been conferred to increase the susceptibility to breast cancer in younger women. This work studied the expression of BRCA1 (mRNA in women with breast cancer in relation to other prognostic parameters such as histological type and grade of cancer, hormone receptor status, human epidermal growth factor receptor 2 (HER2/neu and CA15-3. Thirty patients with positive family history of breast cancer and a control group of 20 healthy subjects were also included for the study. Ribonucleic acid (RNA extraction from breast cancer tissues was done (considered suitable for RNA extraction if 70% or more of the tissue section contained tumor and was followed by real-time reverse transcription polymerase chain reaction. BRCA1 expression was assessed and correlated with age, histological type and grade of breast cancer, estrogen and progesterone receptor (ER, PR status, HER2/neu expression and CA15-3 levels. The mean age of patients was 54.8 ± 10.49 years. Of the 30 breast cancer cases studied, the majority (77% was of high histological grade and the most common histological type was infiltrating ductal carcinoma (20 cases. ER expression was positive in 53.3% of breast cancers, while PR expression was positive in 50% of cancers. BRCA1 mRNA was found in 6 patient samples (20% of the breast cancer patients while the remaining 24 patients (80% showed negative BRCA1 mRNA expression as well as the control group. A positive significant relationship was demonstrated between BRCA1 (mRNA expression and high histological grade, negative estrogen and progesterone receptor status, and high levels of serum CA15-3. A significant negative correlation was found between BRCA1 mRNA expression and age (r = −0.683; p < 0.01. The study demonstrated lack of BRCA1 gene expression (mRNA in the majority of breast cancer cases and confirmed the relationship between BRCA1 expression and parameters that determine poor prognosis in breast cancer. The

  6. Identification of upstream transcription factors (TFs) for expression signature genes in breast cancer.

    Science.gov (United States)

    Zang, Hongyan; Li, Ning; Pan, Yuling; Hao, Jingguang

    2017-03-01

    Breast cancer is a common malignancy among women with a rising incidence. Our intention was to detect transcription factors (TFs) for deeper understanding of the underlying mechanisms of breast cancer. Integrated analysis of gene expression datasets of breast cancer was performed. Then, functional annotation of differentially expressed genes (DEGs) was conducted, including Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Furthermore, TFs were identified and a global transcriptional regulatory network was constructed. Seven publically available GEO datasets were obtained, and a set of 1196 DEGs were identified (460 up-regulated and 736 down-regulated). Functional annotation results showed that cell cycle was the most significantly enriched pathway, which was consistent with the fact that cell cycle is closely related to various tumors. Fifty-three differentially expressed TFs were identified, and the regulatory networks consisted of 817 TF-target interactions between 46 TFs and 602 DEGs in the context of breast cancer. Top 10 TFs covering the most downstream DEGs were SOX10, NFATC2, ZNF354C, ARID3A, BRCA1, FOXO3, GATA3, ZEB1, HOXA5 and EGR1. The transcriptional regulatory networks could enable a better understanding of regulatory mechanisms of breast cancer pathology and provide an opportunity for the development of potential therapy.

  7. Gene expression profiling demonstrates WNT/β-catenin pathway genes alteration in Mexican patients with colorectal cancer and diabetes mellitus.

    Science.gov (United States)

    Ivonne Wence-Chavez, Laura; Palomares-Chacon, Ulises; Pablo Flores-Gutierrez, Juan; Felipe Jave-Suarez, Luis; Del Carmen Aguilar-Lemarroy, Adriana; Barros-Nunez, Patricio; Esperanza Flores-Martinez, Silvia; Sanchez-Corona, Jose; Alejandra Rosales-Reynoso, Monica

    2017-01-01

    Several studies have shown a strong association between diabetes mellitus (DM) and increased risk of colorectal cancer (CRC). The fundamental mechanisms that support this association are not entirely understood; however, it is believed that hyperinsulinemia and hyperglycemia may be involved. Some proposed mechanisms include upregulation of mitogenic signaling pathways like MAPK, PI3K, mTOR, and WNT, which are involved in cell proliferation, growth, and cancer cell survival. The purpose of this study was to evaluate the gene expression profile and identify differently expressed genes involved in mitogenic pathways in CRC patients with and without DM. In this study, microarray analysis of gene expression followed by quantitative PCR (qPCR) was performed in cancer tissue from CRC patients with and without DM to identify the gene expression profiles and validate the differently expressed genes. Among the study groups, some differently expressed genes were identified. However, when bioinformatics clustering tools were used, a significant modulation of genes involved in the WNT pathway was evident. Therefore, we focused on genes participating in this pathway, such as WNT3A, LRP6, TCF7L2, and FRA-1. Validation of the expression levels of those genes by qPCR showed that CRC patients without type 2 diabetes mellitus (T2DM) expressed significantly more WNT3Ay LRP6, but less TCF7L2 and FRA-1 compared to controls, while in CRC patients with DM the expression levels of WNT3A, LRP6, TCF7L2, and FRA-1 were significantly higher compared to controls. Our results suggest that WNT/β-catenin pathway is upregulated in patients with CRC and DM, demonstrating its importance and involvement in both pathologies.

  8. Clinical Omics Analysis of Colorectal Cancer Incorporating Copy Number Aberrations and Gene Expression Data

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    Tsuyoshi Yoshida

    2010-07-01

    Full Text Available Background: Colorectal cancer (CRC is one of the most frequently occurring cancers in Japan, and thus a wide range of methods have been deployed to study the molecular mechanisms of CRC. In this study, we performed a comprehensive analysis of CRC, incorporating copy number aberration (CRC and gene expression data. For the last four years, we have been collecting data from CRC cases and organizing the information as an “omics” study by integrating many kinds of analysis into a single comprehensive investigation. In our previous studies, we had experienced difficulty in finding genes related to CRC, as we observed higher noise levels in the expression data than in the data for other cancers. Because chromosomal aberrations are often observed in CRC, here, we have performed a combination of CNA analysis and expression analysis in order to identify some new genes responsible for CRC. This study was performed as part of the Clinical Omics Database Project at Tokyo Medical and Dental University. The purpose of this study was to investigate the mechanism of genetic instability in CRC by this combination of expression analysis and CNA, and to establish a new method for the diagnosis and treatment of CRC. Materials and methods: Comprehensive gene expression analysis was performed on 79 CRC cases using an Affymetrix Gene Chip, and comprehensive CNA analysis was performed using an Affymetrix DNA Sty array. To avoid the contamination of cancer tissue with normal cells, laser micro-dissection was performed before DNA/RNA extraction. Data analysis was performed using original software written in the R language. Result: We observed a high percentage of CNA in colorectal cancer, including copy number gains at 7, 8q, 13 and 20q, and copy number losses at 8p, 17p and 18. Gene expression analysis provided many candidates for CRC-related genes, but their association with CRC did not reach the level of statistical significance. The combination of CNA and gene

  9. Gene Expression Profiling of Peripheral Blood From Kidney Transplant Recipients for the Early Detection of Digestive System Cancer.

    Science.gov (United States)

    Kusaka, M; Okamoto, M; Takenaka, M; Sasaki, H; Fukami, N; Kataoka, K; Ito, T; Kenmochi, T; Hoshinaga, K; Shiroki, R

    2017-06-01

    Kidney transplant recipients are at increased risk of developing cancer in comparison with the general population. To effectively manage post-transplantation malignancies, it is essential to proactively monitor patients. A long-term intensive screening program was associated with a reduced incidence of cancer after transplantation. This study evaluated the usefulness of the gene expression profiling of peripheral blood samples obtained from kidney transplant patients and adopted a screening test for detecting cancer of the digestive system (gastric, colon, pancreas, and biliary tract). Nineteen patients were included in this study and a total of 53 gene expression screening tests were performed. The gene expression profiles of blood-delivered total RNA and whole genome human gene expression profiles were obtained. We investigated the expression levels of 2665 genes associated with digestive cancers and counted the number of genes in which expression was altered. A hierarchical clustering analysis was also performed. The final prediction of the cancer possibility was determined according to an algorithm. The number of genes in which expression was altered was significantly increased in the kidney transplant recipients in comparison with the general population (1091 ± 63 vs 823 ± 94; P = .0024). The number of genes with altered expression decreased after the induction of mechanistic target of rapamycin (mTOR) inhibitor (1484 ± 227 vs 883 ± 154; P = .0439). No cases of possible digestive cancer were detected in this study period. The gene expression profiling of peripheral blood samples may be a useful and noninvasive diagnostic tool that allows for the early detection of cancer of the digestive system. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Gene expression profiling in woman with women with breast cancer in a Saudi population

    International Nuclear Information System (INIS)

    Amer, Saud M. Bin; Maqbool, Z.; Nirmal, Maimoona S.; Hussain, Syed S.; Jeprel, Hatim A.; Qattan, Amal T.; Tulbah, Asma M.; Malik, Osama A.; Al-Tweigeri, Taher A.

    2008-01-01

    Objective was to generate consensus gene expression profiles of invasive breast tumors from a small cohort of Saudi females and to explore the possibility that they may be broadly conserved between Caucasian and Middle Eastern populations. This study was performed at King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia, from January 2005 to January 2007. Gene expression profiles were generated from 38 invasive breast tumors and 8 tumor adjacent tissues (TATs) using BD Atlas cDNA expression arrays containing 1176 genes. Results were confirmed by reverse transcriptase polymerase chain reaction and analyzed by 2-dimensional unsupervised hierarchical clustering. The analysis identified 48 differentially expressed genes in tumors from which 25 are already reported by various western studies. Forty-three of these genes were also differentially expressed in TATs. The same data set has been able to distinguish between tumors and the TAT's, interestingly by using only 4 of the differentially expressed genes. Moreover, we were able to group the patients according to prognosis to an extent by hierarchical clustering. Our results indicate that expression profiles between Saudi females with breast cancer and the Caucasian population are conserved to some extent, and can be used to classify patients according to prognostic groups. We also suggest 3 differentially expressed genes (IGHG3, CDK3 and RPS9) in tumors may have a novel role in breast cancer. In addition, the role of TATs is much more essential in breast cancer and needs to be explored thoroughly. (author)

  11. Establishment of a 12-gene expression signature to predict colon cancer prognosis

    Directory of Open Access Journals (Sweden)

    Dalong Sun

    2018-06-01

    Full Text Available A robust and accurate gene expression signature is essential to assist oncologists to determine which subset of patients at similar Tumor-Lymph Node-Metastasis (TNM stage has high recurrence risk and could benefit from adjuvant therapies. Here we applied a two-step supervised machine-learning method and established a 12-gene expression signature to precisely predict colon adenocarcinoma (COAD prognosis by using COAD RNA-seq transcriptome data from The Cancer Genome Atlas (TCGA. The predictive performance of the 12-gene signature was validated with two independent gene expression microarray datasets: GSE39582 includes 566 COAD cases for the development of six molecular subtypes with distinct clinical, molecular and survival characteristics; GSE17538 is a dataset containing 232 colon cancer patients for the generation of a metastasis gene expression profile to predict recurrence and death in COAD patients. The signature could effectively separate the poor prognosis patients from good prognosis group (disease specific survival (DSS: Kaplan Meier (KM Log Rank p = 0.0034; overall survival (OS: KM Log Rank p = 0.0336 in GSE17538. For patients with proficient mismatch repair system (pMMR in GSE39582, the signature could also effectively distinguish high risk group from low risk group (OS: KM Log Rank p = 0.005; Relapse free survival (RFS: KM Log Rank p = 0.022. Interestingly, advanced stage patients were significantly enriched in high 12-gene score group (Fisher’s exact test p = 0.0003. After stage stratification, the signature could still distinguish poor prognosis patients in GSE17538 from good prognosis within stage II (Log Rank p = 0.01 and stage II & III (Log Rank p = 0.017 in the outcome of DFS. Within stage III or II/III pMMR patients treated with Adjuvant Chemotherapies (ACT and patients with higher 12-gene score showed poorer prognosis (III, OS: KM Log Rank p = 0.046; III & II, OS: KM Log Rank p = 0.041. Among stage II/III pMMR patients

  12. Gene expression in triple-negative breast cancer in relation to survival.

    Science.gov (United States)

    Wang, Shuyang; Beeghly-Fadiel, Alicia; Cai, Qiuyin; Cai, Hui; Guo, Xingyi; Shi, Liang; Wu, Jie; Ye, Fei; Qiu, Qingchao; Zheng, Ying; Zheng, Wei; Bao, Ping-Ping; Shu, Xiao-Ou

    2018-05-10

    The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression. We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources. Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS. We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.

  13. Changes in gene expression and cellular architecture in an ovarian cancer progression model.

    Directory of Open Access Journals (Sweden)

    Amy L Creekmore

    Full Text Available BACKGROUND: Ovarian cancer is the fifth leading cause of cancer deaths among women. Early stage disease often remains undetected due the lack of symptoms and reliable biomarkers. The identification of early genetic changes could provide insights into novel signaling pathways that may be exploited for early detection and treatment. METHODOLOGY/PRINCIPAL FINDINGS: Mouse ovarian surface epithelial (MOSE cells were used to identify stage-dependent changes in gene expression levels and signal transduction pathways by mouse whole genome microarray analyses and gene ontology. These cells have undergone spontaneous transformation in cell culture and transitioned from non-tumorigenic to intermediate and aggressive, malignant phenotypes. Significantly changed genes were overrepresented in a number of pathways, most notably the cytoskeleton functional category. Concurrent with gene expression changes, the cytoskeletal architecture became progressively disorganized, resulting in aberrant expression or subcellular distribution of key cytoskeletal regulatory proteins (focal adhesion kinase, α-actinin, and vinculin. The cytoskeletal disorganization was accompanied by altered patterns of serine and tyrosine phosphorylation as well as changed expression and subcellular localization of integral signaling intermediates APC and PKCβII. CONCLUSIONS/SIGNIFICANCE: Our studies have identified genes that are aberrantly expressed during MOSE cell neoplastic progression. We show that early stage dysregulation of actin microfilaments is followed by progressive disorganization of microtubules and intermediate filaments at later stages. These stage-specific, step-wise changes provide further insights into the time and spatial sequence of events that lead to the fully transformed state since these changes are also observed in aggressive human ovarian cancer cell lines independent of their histological type. Moreover, our studies support a link between aberrant cytoskeleton

  14. HAP1 gene expression is associated with radiosensitivity in breast cancer cells

    International Nuclear Information System (INIS)

    Wu, Jing; Zhang, Jun-ying; Yin, Li; Wu, Jian-zhong; Guo, Wen-jie; Wu, Jian-feng; Chen, Meng; Xia, You-you; Tang, Jin-hai; Ma, Yong-chao; He, Xia

    2015-01-01

    Highlights: • Overexpression of HAP1 gene promotes apoptosis in MCF-7 cells after irradiation. • HAP1 reduces tumor volume in nude mice xenograft models after irradiation. • HAP1 increases radiosensitivity of breast cancer cells in vitro and vivo. - Abstract: Objectives: The purpose of this study was to investigate the relationship between huntingtin-associated protein1 (HAP1) gene and radiation therapy of breast cancer cells. Methods: HAP1 gene was transfected into breast cancer MCF-7 cells, which was confirmed by quantitative reverse transcription-polymerase chain reaction analysis (qRT-PCR) and Western blot in vitro. The changes of cell radiosensitivity were assessed by colony formation assay. Apoptosis were examined by flow cytometry. The expressions of two radiation-induced genes were evaluated by Western blot. Tumor growth was investigated in nude mice xenograft models in vivo. Results: Our data showed that HAP1 gene expression was significantly increased in HAP1-transfected MCF-7 cells in comparison with the parental cells or negative control cells. The survival rate in MCF-7/HAP1 cells was significantly decreased after irradiation (0, 2, 4, 6, 8 Gy), compared to cells in MCF-7 and MCF-7/Pb groups in vitro. HAP1 gene increased apoptosis in MCF-7 cells after irradiation. Additionally, the tumor volume and weight in MCF-7/HAP1 + RT group were observably lower than in MCF-7/HAP1 group and MCF-7/Pb + RT group. Conclusion: The present study indicated that HAP1 gene expression was related to the radiosensitivity of breast cancer cells and may play an important role in the regulation of cellular radiosensitivity

  15. Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature.

    Science.gov (United States)

    Herrera, Mercedes; Islam, Abul B M M K; Herrera, Alberto; Martín, Paloma; García, Vanesa; Silva, Javier; Garcia, Jose M; Salas, Clara; Casal, Ignacio; de Herreros, Antonio García; Bonilla, Félix; Peña, Cristina

    2013-11-01

    Cancer-associated fibroblasts (CAF) actively participate in reciprocal communication with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive neighborhood and promoting tumor progression. The aim of this study is the characterization of how CAFs from primary human colon tumors promote migration of colon cancer cells. Primary CAF cultures from 15 primary human colon tumors were established. Their enrichment in CAFs was evaluated by the expression of various epithelial and myofibroblast specific markers. Coculture assays of primary CAFs with different colon tumor cells were performed to evaluate promigratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics. Coculture assays showed significant differences in fibroblast-derived paracrine promigratory effects on cancer cells. Moreover, the association between CAFs' promigratory effects on cancer cells and classic fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs. The gene expression signature, derived from the most protumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. Moreover, this prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR (qRT-PCR), with a set of four genes included in the "CAF signature." In summary, these studies show for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high- and low-risk groups was identified.

  16. Comparative effects of DHEA and DHT on gene expression in human LNCaP prostate cancer cells.

    Science.gov (United States)

    Steele, Vernon E; Arnold, Julia T; Lei, Hanh; Izmirlian, Grant; Blackman, Marc R

    2006-01-01

    DHEA is widely used as a dietary supplement in older men. Because DHEA can be converted to androgens or estrogens, such use may promote prostate cancer. In this study, the effects of DHEA were compared with those of DHT using gene expression array profiles in human LNCaP prostate cancer cells. LNCaP cells were exposed to DHEA (300 nM), DHT (300 nM), or vehicle for 48 h, and mRNA expression was measured using Affymetrix HU-95 gene chips. Gene expression values were sorted in ascending order on the p-values corresponding to the extent of differential RNA expression between control and either hormone treatment. S100 calcium binding protein, neurotensin, 24-dehydrocholesterol reductase, and anterior-gradient 2 homologue were the four most differentially expressed genes (p-values all DHT treatment (p DHT were used for pathway analysis. DHT decreased expression of more genes involved in intercellular communication, signal transduction, nucleic acid binding and transport, and in structural components, such as myosin and golgin, than DHEA. These data revealed consistent, measurable changes in gene expression patterns following treatment of LNCaP prostate cancer cells with DHEA and DHT. Understanding the mechanisms of DHEA versus DHT actions in the prostate may help clarify the separate and interactive effects of androgenic and estrogenic actions in prostate cancer progression.

  17. Effect of Twist, Snail and YB-1 gene expression in cervical cancer tissue on cell invasion and epithelial-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Xin-Qin Kang1

    2017-05-01

    Full Text Available Objective: To study the effect of Twist, Snail and YB-1 gene expression in cervical cancer tissue on cell invasion and epithelial-mesenchymal transition. Methods: Cervical cancer tissue samples and tissue samples adjacent to carcinoma were collected from 138 patients with radical operation for cervical cancer, fluorescence quantitative PCR method was used to detect the mRNA expression of Twist, Snail and YB-1 genes, cell invasion-related genes and epithelial-mesenchymal transition marker genes, the Pearson test was used to analyze the correlation of Twist, Snail and YB-1 gene mRNA expression in cervical cancer tissue with cell invasion and epithelial-mesenchymal transition. Results: Twist, Snail and YB-1 gene mRNA expression in cervical cancer tissue were higher than those in tissue adjacent to carcinoma, the invasion genes STAT3, YAP1, TUG1, FoxM1 and Rab11 mRNA expression were higher than those in tissue adjacent to carcinoma, and the epithelial-mesenchymal transition markers E-cadherin and β-catenin gene mRNA expression were lower than those in tissue adjacent to carcinoma while vimentin gene mRNA expression was higher than that in tissue adjacent to carcinoma. Pearson test showed that Twist, Snail and YB-1 gene mRNA expression in cervical cancer tissue were directly correlated with cell invasion and epithelial-mesenchymal transition. Conclusion: Twist, Snail and YB-1 genes are highly expressed in cervical cancer tissue, and their abnormal expression directly leads to the increased tumor cell invasion activity and the aggravated epithelial-mesenchymal transition.

  18. Hormonal Modulation of Breast Cancer Gene Expression: Implications for Intrinsic Subtyping in Premenopausal Women

    OpenAIRE

    Bernhardt, Sarah M.; Dasari, Pallave; Walsh, David; Townsend, Amanda R.; Price, Timothy J.; Ingman, Wendy V.

    2016-01-01

    Clinics are increasingly adopting gene-expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumor. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and vali...

  19. Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs

    International Nuclear Information System (INIS)

    Kurayoshi, Kenta; Ozono, Eiko; Iwanaga, Ritsuko; Bradford, Andrew P.; Komori, Hideyuki; Ohtani, Kiyoshi

    2014-01-01

    Highlights: • ARF promoter showed higher responsiveness to deregulated E2F activity than the E2F1 promoter. • ARF promoter showed higher cancer cell-specificity than E2F1 promoter to drive gene expression. • HSV-TK driven by ARF promoter showed higher cancer cell-specific cytotoxicity than that driven by E2F1 promoter. - Abstract: In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicide gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter

  20. Cancer cell specific cytotoxic gene expression mediated by ARF tumor suppressor promoter constructs

    Energy Technology Data Exchange (ETDEWEB)

    Kurayoshi, Kenta [Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan); Ozono, Eiko [Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ (United Kingdom); Iwanaga, Ritsuko; Bradford, Andrew P. [Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, CO 80045 (United States); Komori, Hideyuki [Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109 (United States); Ohtani, Kiyoshi, E-mail: btm88939@kwansei.ac.jp [Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan)

    2014-07-18

    Highlights: • ARF promoter showed higher responsiveness to deregulated E2F activity than the E2F1 promoter. • ARF promoter showed higher cancer cell-specificity than E2F1 promoter to drive gene expression. • HSV-TK driven by ARF promoter showed higher cancer cell-specific cytotoxicity than that driven by E2F1 promoter. - Abstract: In current cancer treatment protocols, such as radiation and chemotherapy, side effects on normal cells are major obstacles to radical therapy. To avoid these side effects, a cancer cell-specific approach is needed. One way to specifically target cancer cells is to utilize a cancer specific promoter to express a cytotoxic gene (suicide gene therapy) or a viral gene required for viral replication (oncolytic virotherapy). For this purpose, the selected promoter should have minimal activity in normal cells to avoid side effects, and high activity in a wide variety of cancers to obtain optimal therapeutic efficacy. In contrast to the AFP, CEA and PSA promoters, which have high activity only in a limited spectrum of tumors, the E2F1 promoter exhibits high activity in wide variety of cancers. This is based on the mechanism of carcinogenesis. Defects in the RB pathway and activation of the transcription factor E2F, the main target of the RB pathway, are observed in almost all cancers. Consequently, the E2F1 promoter, which is mainly regulated by E2F, has high activity in wide variety of cancers. However, E2F is also activated by growth stimulation in normal growing cells, suggesting that the E2F1 promoter may also be highly active in normal growing cells. In contrast, we found that the tumor suppressor ARF promoter is activated by deregulated E2F activity, induced by forced inactivation of pRB, but does not respond to physiological E2F activity induced by growth stimulation. We also found that the deregulated E2F activity, which activates the ARF promoter, is detected only in cancer cell lines. These observations suggest that ARF promoter

  1. Effect of MLH1 -93G>A on gene expression in patients with colorectal cancer.

    Science.gov (United States)

    Funck, Alexandre; Santos, Juliana C; Silva-Fernandes, Isabelle J L; Rabenhorst, Silvia H B; Martinez, Carlos A R; Ribeiro, Marcelo L

    2014-09-01

    The DNA repair machinery plays a key role in maintaining genomic stability by preventing the emergence of mutations. Furthermore, the -93G>A polymorphism in the MLH1 gene has been associated with an increased risk of developing colorectal cancer. Therefore, the aim of this study was to examine the expression pattern and effect of this polymorphism in normal and tumour samples from patients with colorectal cancer. The MLH1 -93G>A (rs1800734) polymorphism was detected by PCR-RFLP in 49 cases of colorectal cancer. MLH1 expression was investigated using real-time quantitative PCR. The results indicate a significant decrease in MLH1 expression in tumour samples compared to their normal counterparts. The MLH1 gene was also significantly repressed in samples from patients who had some degree of tumour invasion into other organs. Similarly, those patients who were in a more advanced tumour stage (TNM III and IV) exhibited a significant reduction in MLH1 gene expression. Finally, the mutant genotype AA of MLH1 was associated with a significant decrease in the expression of this gene. This finding suggests that this polymorphism could increase the risk of developing colorectal cancer by a defective mismatch repair system, particularly through the loss of MLH1 expression in an allele-specific manner.

  2. Low expression of a few genes indicates good prognosis in estrogen receptor positive breast cancer

    Directory of Open Access Journals (Sweden)

    Buechler Steven

    2009-07-01

    Full Text Available Abstract Background Many breast cancer patients remain free of distant metastasis even without adjuvant chemotherapy. While standard histopathological tests fail to identify these good prognosis patients with adequate precision, analyses of gene expression patterns in primary tumors have resulted in more successful diagnostic tests. These tests use continuous measurements of the mRNA concentrations of numerous genes to determine a risk of metastasis in lymph node negative breast cancer patients with other clinical traits. Methods A survival model is constructed from genes that are both connected with relapse and have expression patterns that define distinct subtypes, suggestive of different cellular states. This in silico study uses publicly available microarray databases generated with Affymetrix GeneChip technology. The genes in our model, as represented by array probes, have distinctive distributions in a patient cohort, consisting of a large normal component of low expression values; and a long right tail of high expression values. The cutoff between low and high expression of a probe is determined from the distribution using the theory of mixture models. The good prognosis group in our model consists of the samples in the low expression component of multiple genes. Results Here, we define a novel test for risk of metastasis in estrogen receptor positive (ER+ breast cancer patients, using four probes that determine distinct subtypes. The good prognosis group in this test, denoted AP4-, consists of the samples with low expression of each of the four probes. Two probes target MKI67, antigen identified by monoclonal antibody Ki-67, one targets CDC6, cell division cycle 6 homolog (S. cerevisiae, and a fourth targets SPAG5, sperm associated antigen 5. The long-term metastasis-free survival probability for samples in AP4- is sufficiently high to render chemotherapy of questionable benefit. Conclusion A breast cancer subtype defined by low

  3. Using gene expression in patients with endometrial intraepithelial neoplasia to assess the risk of cancer

    Directory of Open Access Journals (Sweden)

    Koah Vierkoetter

    2018-05-01

    Full Text Available Patients diagnosed with an endometrial cancer precursor lesion on biopsy may be found to have endometrial cancer at the time of subsequent surgery. The current study seeks to identify patients with endometrial intraepithelial neoplasia (EIN on biopsy that may be harboring an occult carcinoma. Immunohistochemical stains for gene loss of expression (LOE for 6 genes, PTEN, ARID1A, MSH6, MSH2, MLH1, and PMS2, were performed on 113 biopsy specimens with EIN. For the 95 patients with follow-up histology, 40 patients had cancer, 41 had EIN, and 14 had normal endometrium. PTEN LOE was found frequently in both EIN and endometrial cancer, and therefore had low positive predictive value. All specimens with ARID1A, MSH6, MSH2, MLH1, or PMS2 LOE on biopsy were subsequently found to have cancer. LOE of any gene was associated with modest sensitivity (0.78 in identifying patients with endometrial cancer who had EIN on biopsy. Further investigation is warranted to determine if gene LOE is a useful clinical tool when evaluating patients with EIN on biopsy. Keywords: Endometrial intraepithelial neoplasia, Endometrial cancer, Gene expression, PTEN, ARID1A, Mismatch repair genes

  4. Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target.

    Directory of Open Access Journals (Sweden)

    Mariëlle I Gallegos Ruiz

    Full Text Available BACKGROUND: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC is essential to improve early diagnosis and treatment for this disease. METHODOLOGY AND PRINCIPAL FINDINGS: In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%, which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008, survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04. Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. CONCLUSIONS: We suggest that targeting HSP90 will have clinical impact for NSCLC patients.

  5. Inferring gene dependency network specific to phenotypic alteration based on gene expression data and clinical information of breast cancer.

    Science.gov (United States)

    Zhou, Xionghui; Liu, Juan

    2014-01-01

    Although many methods have been proposed to reconstruct gene regulatory network, most of them, when applied in the sample-based data, can not reveal the gene regulatory relations underlying the phenotypic change (e.g. normal versus cancer). In this paper, we adopt phenotype as a variable when constructing the gene regulatory network, while former researches either neglected it or only used it to select the differentially expressed genes as the inputs to construct the gene regulatory network. To be specific, we integrate phenotype information with gene expression data to identify the gene dependency pairs by using the method of conditional mutual information. A gene dependency pair (A,B) means that the influence of gene A on the phenotype depends on gene B. All identified gene dependency pairs constitute a directed network underlying the phenotype, namely gene dependency network. By this way, we have constructed gene dependency network of breast cancer from gene expression data along with two different phenotype states (metastasis and non-metastasis). Moreover, we have found the network scale free, indicating that its hub genes with high out-degrees may play critical roles in the network. After functional investigation, these hub genes are found to be biologically significant and specially related to breast cancer, which suggests that our gene dependency network is meaningful. The validity has also been justified by literature investigation. From the network, we have selected 43 discriminative hubs as signature to build the classification model for distinguishing the distant metastasis risks of breast cancer patients, and the result outperforms those classification models with published signatures. In conclusion, we have proposed a promising way to construct the gene regulatory network by using sample-based data, which has been shown to be effective and accurate in uncovering the hidden mechanism of the biological process and identifying the gene signature for

  6. Comparison of miRNA and gene expression profiles between metastatic and primary prostate cancer.

    Science.gov (United States)

    Guo, Kaimin; Liang, Zuowen; Li, Fubiao; Wang, Hongliang

    2017-11-01

    The present study aimed to identify the regulatory mechanisms associated with the metastasis of prostate cancer (PC). The microRNA (miRNA/miR) microarray dataset GSE21036 and gene transcript dataset GSE21034 were downloaded from the Gene Expression Omnibus database. Following pre-processing, differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) between samples from patients with primary prostate cancer (PPC) and metastatic prostate cancer (MPC) with |log 2 fold change (FC)| >1 and a false discovery rate terms (36 terms), followed by miR-494 (24 terms), miR-30d (18 terms), miR-181a (15 terms), hsa-miR-196a (8 terms), miR-708 (7 terms) and miR-486-5p (2 terms). Therefore, these miRNAs may serve roles in the metastasis of PC cells via downregulation of their corresponding target DEGs.

  7. Expression and clinical significance of ATM and PUMA gene in patients with colorectal cancer.

    Science.gov (United States)

    Xiong, Hui; Zhang, Jiangnan

    2017-12-01

    The expression of ataxia-telangiectasia mutated (ATM) and p53 upregulated modulator of apoptosis (PUMA) genes in patients with colorectal cancer were investigated, to explore the correlation between the expression of ATM and PUMA and tumor development, to evaluate the clinical significance of ATM and PUMA in the treatment of colorectal cancer. Quantitative real-time PCR was used to detect the expression of ATM and PUMA in tumor tissue and adjacent healthy tissue of 67 patients with colorectal cancer and in normal colorectal tissue of 33 patients with colorectal polyps at mRNA level. The expression level of ATM mRNA in colorectal cancer tissues was significantly higher than that in normal mucosa tissues and adjacent non-cancerous tissue (P≤0.05), while no significant differences in expression level of ATM mRNA were found between normal mucosa tissues and adjacent noncancerous tissue (P=0.07). There was a negative correlation between the expression of ATM mRNA and the degree of differentiation of colorectal cancer (r= -0.312, P=0.013), while expression level of ATM mRNA was not significantly correlated with the age, sex, tumor invasion, lymph node metastasis or clinical stage (P>0.05). Expression levels of PUMA mRNA in colorectal cancer tissues, adjacent noncancerous tissue and normal tissues were 0.68±0.07, 0.88±0.04 and 1.76±0.06, respectively. Expression level of PUMA mRNA in colorectal cancer tissues and adjacent noncancerous tissue was significantly lower than that in normal colorectal tissues (PATM mRNA is expressed abnormally in colorectal cancer tissues. Expression of PUMA gene in colorectal carcinoma is downregulated, and is negatively correlated with the occurrence of cancer.

  8. Over-expression of Eph and ephrin genes in advanced ovarian cancer: ephrin gene expression correlates with shortened survival

    Directory of Open Access Journals (Sweden)

    Lincoln Douglas

    2006-06-01

    Full Text Available Abstract Background Increased expression of Eph receptor tyrosine kinases and their ephrin ligands has been implicated in tumor progression in a number of malignancies. This report describes aberrant expression of these genes in ovarian cancer, the commonest cause of death amongst gynaecological malignancies. Methods Eph and ephrin expression was determined using quantitative real time RT-PCR. Correlation of gene expression was measured using Spearman's rho statistic. Survival was analysed using log-rank analysis and (was visualised by Kaplan-Meier survival curves. Results Greater than 10 fold over-expression of EphA1 and a more modest over-expression of EphA2 were observed in partially overlapping subsets of tumors. Over-expression of EphA1 strongly correlated (r = 0.801; p Conclusion These data imply that increased levels of ephrins A1 and A5 in the presence of high expression of Ephs A1 and A2 lead to a more aggressive tumor phenotype. The known functions of Eph/ephrin signalling in cell de-adhesion and movement may explain the observed correlation of ephrin expression with poor prognosis.

  9. Expression profiling identifies genes involved in neoplastic transformation of serous ovarian cancer

    International Nuclear Information System (INIS)

    Merritt, Melissa A; Parsons, Peter G; Newton, Tanya R; Martyn, Adam C; Webb, Penelope M; Green, Adèle C; Papadimos, David J; Boyle, Glen M

    2009-01-01

    The malignant potential of serous ovarian tumors, the most common ovarian tumor subtype, varies from benign to low malignant potential (LMP) tumors to frankly invasive cancers. Given the uncertainty about the relationship between these different forms, we compared their patterns of gene expression. Expression profiling was carried out on samples of 7 benign, 7 LMP and 28 invasive (moderate and poorly differentiated) serous tumors and four whole normal ovaries using oligonucleotide microarrays representing over 21,000 genes. We identified 311 transcripts that distinguished invasive from benign tumors, and 20 transcripts that were significantly differentially expressed between invasive and LMP tumors at p < 0.01 (with multiple testing correction). Five genes that were differentially expressed between invasive and either benign or normal tissues were validated by real time PCR in an independent panel of 46 serous tumors (4 benign, 7 LMP, 35 invasive). Overexpression of SLPI and WNT7A and down-regulation of C6orf31, PDGFRA and GLTSCR2 were measured in invasive and LMP compared with benign and normal tissues. Over-expression of WNT7A in an ovarian cancer cell line led to increased migration and invasive capacity. These results highlight several genes that may play an important role across the spectrum of serous ovarian tumorigenesis

  10. 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.

  11. Gene expression profiling in cervical cancer: identification of novel markers for disease diagnosis and therapy.

    LENUS (Irish Health Repository)

    Martin, Cara M

    2012-02-01

    Cervical cancer, a potentially preventable disease, remains the second most common malignancy in women worldwide. Human papillomavirus is the single most important etiological agent in cervical cancer. HPV contributes to neoplastic progression through the action of two viral oncoproteins E6 and E7, which interfere with critical cell cycle pathways, p53, and retinoblastoma. However, evidence suggests that HPV infection alone is insufficient to induce malignant changes and other host genetic variations are important in the development of cervical cancer. Advances in molecular biology and high throughput gene expression profiling technologies have heralded a new era in biomarker discovery and identification of molecular targets related to carcinogenesis. These advancements have improved our understanding of carcinogenesis and will facilitate screening, early detection, management, and personalised targeted therapy. In this chapter, we have described the use of high density microarrays to assess gene expression profiles in cervical cancer. Using this approach we have identified a number of novel genes which are differentially expressed in cervical cancer, including several genes involved in cell cycle regulation. These include p16ink4a, MCM 3 and 5, CDC6, Geminin, Cyclins A-D, TOPO2A, CDCA1, and BIRC5. We have validated expression of mRNA using real-time PCR and protein by immunohistochemistry.

  12. Effect of hrHPV infection on anti-apoptotic gene and pro-apoptotic gene expression in cervical cancer tissue

    Directory of Open Access Journals (Sweden)

    Min-Er Tang

    2016-09-01

    Full Text Available Objective: To study the effect of hrHPV infection on anti-apoptotic gene and pro-apoptotic gene expression in cervical cancer tissue. Methods: A total of 56 patients with cervical cancer, 94 cases of patients with cervical intraepithelial neoplasia and 48 cases of patients with chronic cervicitis who were treated in our hospital from May 2013 to December 2015 were selected for study and included in malignant group, precancerous lesion group and benign group respectively. hrHPV infection as well as the expression of anti-apoptotic genes and proapoptotic genes in cervical tissue were detected. Results: hrHPV infection rate and viral load in cervical tissue of malignant group were significantly higher than those of precancerous lesion group and benign group; P27 and p16 levels in cervical tissue of malignant group were significantly lower than those of precancerous lesion group and benign group, and K-ras, c-myc, Prdx4 and TNFAIP8 levels were significantly higher than those of precancerous lesion group and benign group; the greater the HPV virus load, the lower the p27 and p16 levels and the higher the K-ras, c-myc, Prdx4 and TNFAIP8 levels in cervical tissue. Conclusions: hrHPV infection can result in tumor suppressor genes p27 and p16 expression deletion and increase the expression of proto-oncogene and apoptosis-inhibiting genes, and it is associated with the occurrence and development of cervical cancer.

  13. Hormonal modulation of breast cancer gene expression: implications for intrinsic subtyping in pre-menopausal women

    Directory of Open Access Journals (Sweden)

    Sarah M Bernhardt

    2016-11-01

    Full Text Available Clinics are increasingly adopting gene expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumour. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and validated using breast cancer samples from post-menopausal women. Thus, the accuracy of such tests has not been explored in the context of the hormonal fluctuations in estrogen and progesterone that occur during the menstrual cycle in pre-menopausal women. Concordance between traditional methods of subtyping and the new tests in pre-menopausal women is likely to depend on the stage of the menstrual cycle at which the tissue sample is taken, and the relative effect of hormones on expression of genes versus proteins. The lack of knowledge around the effect of fluctuating estrogen and progesterone on gene expression in breast cancer patients raises serious concerns for intrinsic subtyping in pre-menopausal women, which comprise about 25% of breast cancer diagnoses. Further research on the impact of the menstrual cycle on intrinsic breast cancer profiling is required if pre-menopausal women are to benefit from the new technology of intrinsic subtyping.

  14. Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Verena Jabs

    Full Text Available Non-small cell lung cancer (NSCLC represents a genomically unstable cancer type with extensive copy number aberrations. The relationship of gene copy number alterations and subsequent mRNA levels has only fragmentarily been described. The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190 and their association with survival. While more than half of all analyzed gene copy number-gene expression pairs showed statistically significant correlations (10,296 of 18,756 genes, high correlations, with a correlation coefficient >0.7, were obtained only in a subset of 301 genes (1.6%, including KRAS, EGFR and MDM2. Higher correlation coefficients were associated with higher copy number and expression levels. Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression. Among the highly correlating genes, GO groups associated with posttranslational protein modifications were particularly frequent, including ubiquitination and neddylation. In a meta-analysis including 1,779 patients we found that survival associated genes were overrepresented among highly correlating genes (61 of the 301 highly correlating genes, FDR adjusted p<0.05. Among them are the chaperone CCT2, the core complex protein NUP107 and the ubiquitination and neddylation associated protein CAND1. In conclusion, in a comprehensive analysis we described a distinct set of highly correlating genes. These genes were found to be overrepresented among survival-associated genes based on gene expression in a large collection of publicly available datasets.

  15. Songs about Cancer, Gene Expression, and the Biochemistry of Photosynthesis

    Science.gov (United States)

    Heineman, Richard H.

    2018-01-01

    These three biology songs can be used for educational purposes to teach about biochemical concepts. They touch on three different topics: (1) cancer progression and germ cells, (2) gene expression, promoters, and repressors, and (3) electronegativity and the biochemical basis of photosynthesis.

  16. Recovery of NIS expression in thyroid cancer cells by overexpression of Pax8 gene

    International Nuclear Information System (INIS)

    Presta, Ivan; Filetti, Sebastiano; Russo, Diego; Arturi, Franco; Ferretti, Elisabetta; Mattei, Tiziana; Scarpelli, Daniela; Tosi, Emanuele; Scipioni, Angela; Celano, Marilena; Gulino, Alberto

    2005-01-01

    Recovery of iodide uptake in thyroid cancer cells by means of obtaining the functional expression of the sodium/iodide symporter (NIS) represents an innovative strategy for the treatment of poorly differentiated thyroid cancer. However, the NIS gene expression alone is not always sufficient to restore radioiodine concentration ability in these tumour cells. In this study, the anaplastic thyroid carcinoma ARO cells were stably transfected with a Pax8 gene expression vector. A quantitative RT-PCR was performed to assess the thyroid specific gene expression in selected clones. The presence of NIS protein was detected by Western blot and localized by immunofluorescence. A iodide uptake assay was also performed to verify the functional effect of NIS induction and differentiation switch. The clones overexpressing Pax8 showed the re-activation of several thyroid specific genes including NIS, Pendrin, Thyroglobulin, TPO and TTF1. In ARO-Pax8 clones NIS protein was also localized both in cell cytoplasm and membrane. Thus, the ability to uptake the radioiodine was partially restored, associated to a high rate of efflux. In addition, ARO cells expressing Pax8 presented a lower rate of cell growth. These finding demonstrate that induction of Pax8 expression may determine a re-differentiation of thyroid cancer cells, including a partial recovery of iodide uptake, fundamental requisite for a radioiodine-based therapeutic approach for thyroid tumours

  17. Gene-expression patterns in peripheral blood classify familial breast cancer susceptibility.

    Science.gov (United States)

    Piccolo, Stephen R; Andrulis, Irene L; Cohen, Adam L; Conner, Thomas; Moos, Philip J; Spira, Avrum E; Buys, Saundra S; Johnson, W Evan; Bild, Andrea H

    2015-11-04

    Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk variants have a relatively modest effect on risk and show limited potential for predicting FBC development. As an alternative, we hypothesized that additional genomic data types, such as gene-expression levels, which can reflect genetic and epigenetic variation, could contribute to classifying a person's risk status. Specifically, we aimed to identify common patterns in gene-expression levels across individuals who develop FBC. We profiled peripheral blood mononuclear cells from women with a family history of breast cancer (with or without a germline BRCA1/2 variant) and from controls. We used the support vector machines algorithm to differentiate between patients who developed FBC and those who did not. Our study used two independent datasets, a training set of 124 women from Utah (USA) and an external validation (test) set from Ontario (Canada) of 73 women (197 total). We controlled for expression variation associated with clinical, demographic, and treatment variables as well as lymphocyte markers. Our multigene biomarker provided accurate, individual-level estimates of FBC occurrence for the Utah cohort (AUC = 0.76 [0.67-84]) . Even at their lower confidence bounds, these accuracy estimates meet or exceed estimates from alternative approaches. Our Ontario cohort resulted in similarly high levels of accuracy (AUC = 0.73 [0.59-0.86]), thus providing external validation of our findings. Individuals deemed to have "high" risk by our model would have an estimated 2.4 times greater odds of

  18. The effects of timing of fine needle aspiration biopsies on gene expression profiles in breast cancers

    International Nuclear Information System (INIS)

    Wong, Vietty; Wang, Dong-Yu; Warren, Keisha; Kulkarni, Supriya; Boerner, Scott; Done, Susan Jane; Leong, Wey Liang

    2008-01-01

    DNA microarray analysis has great potential to become an important clinical tool to individualize prognostication and treatment for breast cancer patients. However, with any emerging technology, there are many variables one must consider before bringing the technology to the bedside. There are already concerted efforts to standardize protocols and to improve reproducibility of DNA microarray. Our study examines one variable that is often overlooked, the timing of tissue acquisition, which may have a significant impact on the outcomes of DNA microarray analyses especially in studies that compare microarray data based on biospecimens taken in vivo and ex vivo. From 16 patients, we obtained paired fine needle aspiration biopsies (FNABs) of breast cancers taken before (PRE) and after (POST) their surgeries and compared the microarray data to determine the genes that were differentially expressed between the FNABs taken at the two time points. qRT-PCR was used to validate our findings. To examine effects of longer exposure to hypoxia on gene expression, we also compared the gene expression profiles of 10 breast cancers from clinical tissue bank. Using hierarchical clustering analysis, 12 genes were found to be differentially expressed between the FNABs taken before and after surgical removal. Remarkably, most of the genes were linked to FOS in an early hypoxia pathway. The gene expression of FOS also increased with longer exposure to hypoxia. Our study demonstrated that the timing of fine needle aspiration biopsies can be a confounding factor in microarray data analyses in breast cancer. We have shown that FOS-related genes, which have been implicated in early hypoxia as well as the development of breast cancers, were differentially expressed before and after surgery. Therefore, it is important that future studies take timing of tissue acquisition into account

  19. Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.

    LENUS (Irish Health Repository)

    Perry, Antoinette S

    2013-04-15

    Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2\\/20) (SFRP1), 64.86% (48\\/74) (SFRP2), 0% (0\\/20) (SFRP4) and 60% (12\\/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6\\/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7\\/69), p < 0.0001) and BPH (11.43% (4\\/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.

  20. Twist and YB-1 gene expression in cervical cancer and precancerous tissue and their correlation with cell invasion

    Directory of Open Access Journals (Sweden)

    Qin Tian

    2017-04-01

    Full Text Available Objective: To study the correlation of Twist and YB-1 gene expression in cervical cancer and precancerous tissue with cell invasion. Methods: Cervical cancer tissue, precancerous tissue and normal cervical tissue surgically removed in our hospital between May 2013 and April 2015 were collected; immunohistochemical staining kits were used to detect the positive protein expression rate of Twist and YB-1 gene; fluorescence quantitative PCR kits were used to detect Twist, YB-1 and invasion gene mRNA expression. Results: Twist and YB-1 mRNA expression and positive protein expression rate as well as USP22, Rab11, Rac1 and ANXA5 mRNA expression in cervical cancer tissue and precancerous tissue were significantly higher than those in normal cervical tissue, Twist and YB-1 mRNA expression and positive protein expression rate as well as USP22, Rab11, Rac1 and ANXA5 mRNA expression in cervical cancer tissue were significantly higher than those in precancerous tissue; USP22, Rab11, Rac1 and ANXA5 mRNA expression in cervical cancer tissue and precancerous tissue with positive Twist and YB-1 expression were significantly higher than those in cervical cancer tissue and precancerous tissue with negative Twist and YB-1 expression. Conclusion: Highly expressed Twist and YB-1 in cervical cancer and precancerous tissue can promote cell invasion.

  1. Hormonal modulation of breast cancer gene expression: implications for intrinsic subtyping in pre-menopausal women

    OpenAIRE

    Sarah M Bernhardt; Pallave Dasari; David Walsh; Amanda R Townsend; Amanda R Townsend; Timothy J Price; Timothy J Price; Wendy V Ingman

    2016-01-01

    Clinics are increasingly adopting gene expression profiling to diagnose breast cancer subtype, providing an intrinsic, molecular portrait of the tumour. For example, the PAM50-based Prosigna test quantifies expression of 50 key genes to classify breast cancer subtype, and this method of classification has been demonstrated to be superior over traditional immunohistochemical methods that detect proteins, to predict risk of disease recurrence. However, these tests were largely developed and val...

  2. Tumor-specific expression of shVEGF and suicide gene as a novel strategy for esophageal cancer therapy.

    Science.gov (United States)

    Liu, Ting; Wu, Hai-Jun; Liang, Yu; Liang, Xu-Jun; Huang, Hui-Chao; Zhao, Yan-Zhong; Liao, Qing-Chuan; Chen, Ya-Qi; Leng, Ai-Min; Yuan, Wei-Jian; Zhang, Gui-Ying; Peng, Jie; Chen, Yong-Heng

    2016-06-21

    To develop a potent and safe gene therapy for esophageal cancer. An expression vector carrying fusion suicide gene (yCDglyTK) and shRNA against vascular endothelial growth factor (VEGF) was constructed and delivered into EC9706 esophageal cancer cells by calcium phosphate nanoparticles (CPNP). To achieve tumor selectivity, expression of the fusion suicide gene was driven by a tumor-specific human telomerase reverse transcriptase (hTERT) promoter. The biologic properties and therapeutic efficiency of the vector, in the presence of prodrug 5-fluorocytosine (5-FC), were evaluated in vitro and in vivo. Both in vitro and in vivo testing showed that the expression vector was efficiently introduced by CPNP into tumor cells, leading to cellular expression of yCDglyTK and decreased VEGF level. With exposure to 5-FC, it exhibited strong anti-tumor effects against esophageal cancer. Combination of VEGF shRNA with the fusion suicide gene demonstrated strong anti-tumor activity. The shVEGF-hTERT-yCDglyTK/5-FC system provided a novel approach for esophageal cancer-targeted gene therapy.

  3. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process

    International Nuclear Information System (INIS)

    Chandran, Uma R; Ma, Changqing; Dhir, Rajiv; Bisceglia, Michelle; Lyons-Weiler, Maureen; Liang, Wenjing; Michalopoulos, George; Becich, Michael; Monzon, Federico A

    2007-01-01

    Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. The metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer

  4. Gene expression signature in organized and growth arrested mammaryacini predicts good outcome in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Fournier, Marcia V.; Martin, Katherine J.; Kenny, Paraic A.; Xhaja, Kris; Bosch, Irene; Yaswen, Paul; Bissell, Mina J.

    2006-02-08

    To understand how non-malignant human mammary epithelial cells (HMEC) transit from a disorganized proliferating to an organized growth arrested state, and to relate this process to the changes that occur in breast cancer, we studied gene expression changes in non-malignant HMEC grown in three-dimensional cultures, and in a previously published panel of microarray data for 295 breast cancer samples. We hypothesized that the gene expression pattern of organized and growth arrested mammary acini would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in two HMEC cell lines, 184 (finite life span) and HMT3522 S1 (immortal non-malignant), on successive days post-seeding in a laminin-rich extracellular matrix assay. Both HMECs underwent growth arrest in G0/G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines. We show that genes that are significantly lower in the organized, growth arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of use clinically.

  5. ABC gene expression profiles have clinical importance and possibly form a new hallmark of cancer.

    Science.gov (United States)

    Dvorak, Pavel; Pesta, Martin; Soucek, Pavel

    2017-05-01

    Adenosine triphosphate-binding cassette proteins constitute a large family of active transporters through extracellular and intracellular membranes. Increased drug efflux based on adenosine triphosphate-binding cassette protein activity is related to the development of cancer cell chemoresistance. Several articles have focused on adenosine triphosphate-binding cassette gene expression profiles (signatures), based on the expression of all 49 human adenosine triphosphate-binding cassette genes, in individual tumor types and reported connections to established clinicopathological features. The aim of this study was to test our theory about the existence of adenosine triphosphate-binding cassette gene expression profiles common to multiple types of tumors, which may modify tumor progression and provide clinically relevant information. Such general adenosine triphosphate-binding cassette profiles could constitute a new attribute of carcinogenesis. Our combined cohort consisted of tissues from 151 cancer patients-breast, colorectal, and pancreatic carcinomas. Standard protocols for RNA isolation and quantitative real-time polymerase chain reaction were followed. Gene expression data from individual tumor types as well as a merged tumor dataset were analyzed by bioinformatics tools. Several general adenosine triphosphate-binding cassette profiles, with differences in gene functions, were established and shown to have significant relations to clinicopathological features such as tumor size, histological grade, or clinical stage. Genes ABCC7, A3, A8, A12, and C8 prevailed among the most upregulated or downregulated ones. In conclusion, the results supported our theory about general adenosine triphosphate-binding cassette gene expression profiles and their importance for cancer on clinical as well as research levels. The presence of ABCC7 (official symbol CFTR) among the genes with key roles in the profiles supports the emerging evidence about its crucial role in various

  6. Identification of differentially expressed genes and signaling pathways in ovarian cancer by integrated bioinformatics analysis

    Directory of Open Access Journals (Sweden)

    Yang X

    2018-03-01

    Full Text Available Xiao Yang,1 Shaoming Zhu,2 Li Li,3 Li Zhang,1 Shu Xian,1 Yanqing Wang,1 Yanxiang Cheng1 1Department of Obstetrics and Gynecology, 2Department of Urology, Renmin Hospital of Wuhan University, 3Department of Pharmacology, Wuhan University Health Science Center, Wuhan, Hubei, People’s Republic of China Background: The mortality rate associated with ovarian cancer ranks the highest among gynecological malignancies. However, the cause and underlying molecular events of ovarian cancer are not clear. Here, we applied integrated bioinformatics to identify key pathogenic genes involved in ovarian cancer and reveal potential molecular mechanisms. Results: The expression profiles of GDS3592, GSE54388, and GSE66957 were downloaded from the Gene Expression Omnibus (GEO database, which contained 115 samples, including 85 cases of ovarian cancer samples and 30 cases of normal ovarian samples. The three microarray datasets were integrated to obtain differentially expressed genes (DEGs and were deeply analyzed by bioinformatics methods. The gene ontology (GO and Kyoto Encyclopedia of Genes and Genomes (KEGG pathway enrichments of DEGs were performed by DAVID and KOBAS online analyses, respectively. The protein–protein interaction (PPI networks of the DEGs were constructed from the STRING database. A total of 190 DEGs were identified in the three GEO datasets, of which 99 genes were upregulated and 91 genes were downregulated. GO analysis showed that the biological functions of DEGs focused primarily on regulating cell proliferation, adhesion, and differentiation and intracellular signal cascades. The main cellular components include cell membranes, exosomes, the cytoskeleton, and the extracellular matrix. The molecular functions include growth factor activity, protein kinase regulation, DNA binding, and oxygen transport activity. KEGG pathway analysis showed that these DEGs were mainly involved in the Wnt signaling pathway, amino acid metabolism, and the

  7. Identification of Differentially Expressed IGFBP5-Related Genes in Breast Cancer Tumor Tissues Using cDNA Microarray Experiments.

    Science.gov (United States)

    Akkiprik, Mustafa; Peker, İrem; Özmen, Tolga; Amuran, Gökçe Güllü; Güllüoğlu, Bahadır M; Kaya, Handan; Özer, Ayşe

    2015-11-10

    IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs) between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were used to determine IGFBP5 expression by qPCR. cDNA microarrays were applied to the highest IGFBP5 overexpressed tumor samples compared to their adjacent normal breast tissue. Microarray analysis revealed that a total of 186 genes were differentially expressed in breast cancer compared with normal breast tissues. Of the 186 genes, 169 genes were downregulated and 17 genes were upregulated in the tumor samples. KEGG pathway analyses showed that protein digestion and absorption, focal adhesion, salivary secretion, drug metabolism-cytochrome P450, and phenylalanine metabolism pathways are involved. Among these DEGs, the prominent top two genes (MMP11 and COL1A1) which potentially correlated with IGFBP5 were selected for validation using real time RT-qPCR. Only COL1A1 expression showed a consistent upregulation with IGFBP5 expression and COL1A1 and MMP11 were significantly positively correlated. We concluded that the discovery of coordinately expressed genes related with IGFBP5 might contribute to understanding of the molecular mechanism of the function of IGFBP5 in breast cancer. Further functional studies on DEGs and association with IGFBP5 may identify novel biomarkers for clinical applications in breast cancer.

  8. Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

    DEFF Research Database (Denmark)

    Gravgaard Thomsen, Karina Hedelund; Lyng, Maria Bibi; Elias, Daniel

    2015-01-01

    predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated...... by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ≥1.5, p ....05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen...

  9. Gene expression profiles in cervical cancer with radiation therapy alone and chemo-radiation therapy

    International Nuclear Information System (INIS)

    Lee, Kyu Chan; Kim, Joo Young; Hwang, You Jin; Kim, Meyoung Kon; Choi, Myung Sun; Kim, Chul Young

    2003-01-01

    To analyze the gene expression profiles of uterine cervical cancer, and its variation after radiation therapy, with or without concurrent chemotherapy, using a cDNA microarray. Sixteen patients, 8 with squamous cell carcinomas of the uterine cervix, who were treated with radiation alone, and the other 8 treated with concurrent chemo-radiation, were included in the study. Before the starting of the treatment, tumor biopsies were carried out, and the second time biopsies were performed after a radiation dose of 16.2-27 Gy. Three normal cervix tissues were used as a control group. The microarray experiments were performed with 5 groups of the total RNAs extracted individually and then admixed as control, pre-radiation therapy alone, during-radiation therapy alone, pre-chemoradiation therapy, and during chemoradiation therapy. The 33P-labeled cDNAs were synthesized from the total RNAs of each group, by reverse transcription, and then they were hybridized to the cDNA microarray membrane. The gene expression of each microarrays was captured by the intensity of each spot produced by the radioactive isotopes. The pixels per spot were counted with an Arrayguage, and were exported to Microsoft Excel. The data were normalized by the Z transformation, and the comparisons were performed on the Z-ratio values calculated. The expressions of 15 genes, including integrin linked kinase (ILK), CDC28 protein kinase 2, Spry 2, and ERK 3, were increased with the Z-ratio values of over 2.0 for the cervix cancer tissues compared to those for the normal controls. Those genes were involved in cell growth and proliferation, cell cycle control, or signal transduction. The expressions of the other 6 genes, including G protein coupled receptor kinase 6, were decreased with the Z-ratio values of below -2.0. After the radiation therapy, most of the genes, with a previously increase expressions, represented the decreased expression profiles, and the genes, with the Z-ratio values of over 2.0, were

  10. Leucine zipper, down regulated in cancer-1 gene expression in prostate cancer

    Science.gov (United States)

    Salemi, Michele; Barone, Nunziata; La Vignera, Sandro; Condorelli, Rosita A.; Recupero, Domenico; Galia, Antonio; Fraggetta, Filippo; Aiello, Anna Maria; Pepe, Pietro; Castiglione, Roberto; Vicari, Enzo; Calogero, Aldo E.

    2016-01-01

    Numerous genetic alterations have been implicated in the development of prostate cancer (PCa). DNA and protein microarrays have enabled the identification of genes associated with apoptosis, which is important in PCa development. Despite the molecular mechanisms are not entirely understood, inhibition of apoptosis is a critical pathophysiological factor that contributes to the onset and progression of PCa. Leucine zipper, down-regulated in cancer 1 (LDOC-1) is a known regulator of the nuclear factor (NF)-mediated pathway of apoptosis through the inhibition of NF-κB. The present study investigated the expression of the LDOC-1 gene in LNCaP, PC-3, PNT1A and PNT2 prostate cell lines by reverse transcription-quantitative polymerase chain reaction. In addition LDOC-1 protein expression in normal prostate tissues and PCa was studied by immunohistochemistry. LDOC-1 messenger RNA resulted overexpressed in LNCaP and PC-3 PCa cell lines compared with the two normal prostate cell lines PNT1A and PNT2. The results of immunohistochemistry demonstrated a positive cytoplasmic LDOC-1 staining in all PCa and normal prostate samples, whereas no nuclear staining was observed in any sample. Furthermore, a more intense signal was evidenced in PCa samples. LDOC-1 gene overexpression in PCa suggests an activity of LDOC-1 in PCa cell lines. PMID:27698860

  11. RNA-seq reveals more consistent reference genes for gene expression studies in human non-melanoma skin cancers

    Directory of Open Access Journals (Sweden)

    Van L.T. Hoang

    2017-08-01

    Full Text Available Identification of appropriate reference genes (RGs is critical to accurate data interpretation in quantitative real-time PCR (qPCR experiments. In this study, we have utilised next generation RNA sequencing (RNA-seq to analyse the transcriptome of a panel of non-melanoma skin cancer lesions, identifying genes that are consistently expressed across all samples. Genes encoding ribosomal proteins were amongst the most stable in this dataset. Validation of this RNA-seq data was examined using qPCR to confirm the suitability of a set of highly stable genes for use as qPCR RGs. These genes will provide a valuable resource for the normalisation of qPCR data for the analysis of non-melanoma skin cancer.

  12. The clinical impact of hypoxia-regulated gene expression in loco-regional gastroesophageal cancer

    DEFF Research Database (Denmark)

    Winther, M.; Alsner, J.; Tramm, T.

    2015-01-01

    Purpose/Objective: In a former study (1), the hypoxia gene expression classifier, developed in head and neck squamous cell carcinomas, was applied in 89 patients with loco-regional gastroesophageal cancer (GC). Analysis of the 15 genes was indicative of hypoxia being more profound in esophagus...... and display greater heterogeneity compared to AC. However, previous indications that the hypoxia classifier might hold prognostic significance in ESCC patients could not be confirmed. Ongoing work includes in vitro studies of esophageal cancer cell lines in order to identify alternative hypoxia induced genes...... and to further explore the prognostic value of hypoxia in patients with loco-regional gastroesophageal cancer. (Figure Presented)....

  13. Evaluation of the effect of Fennel extract on TERT gene expression changes in mouse liver tumors induced with cancer

    Directory of Open Access Journals (Sweden)

    Zeinab Mousaee

    2018-01-01

    Full Text Available Background: The use of plants for therapeutic purposes is the source of many modern medical treatments. In this study, at first, the cytotoxicity of the Foeniculum vulgare (Fennel extract on cancer cells was studied. Then, TERT gene expression changes were estimated via induction of cancer and extract treatment. Materials and Methods: At first, different concentrations of the Fennel extract were obtained for cell morphology and the MTT assay. Afterwards, cancer in mice was induced. Sampling was performed to determine changes in gene expression after 7, 14, 21 and 28 days. After that, RNA was extracted, cDNA was synthesized, and gene expression changes were studied. Results: Results showed an inhibitory effect on both cell lines at 50% inhibition (IC50 of proliferation at 200 µg/ml after 72 hours using the MTT assay. The morphology results in the third day in 100 and 200 concentrations showed that the extract caused complete degeneration and destruction of cancer cells. The results of analysis of the graphs revealed that the expression of TERT gene in treated cancer samples decreased on days 7, 14 and 28 compared with the control. Conclusion: The Fennel extract has dual effects on cancer cells through initiating intracellular events. In high concentrations, the extract stimulates proliferative growth in cancer cells and in low concentrations it has inhibitory effects on cell growth and proliferation. In the evaluation of the extract on TERT gene expression, a reduction was observed in gene expression on days 7, 14 and 28. Therefore, the Fennel extract can affect the gene expression through its effect on molecular pathways.

  14. Gene expression patterns combined with network analysis identify hub genes associated with bladder cancer.

    Science.gov (United States)

    Bi, Dongbin; Ning, Hao; Liu, Shuai; Que, Xinxiang; Ding, Kejia

    2015-06-01

    To explore molecular mechanisms of bladder cancer (BC), network strategy was used to find biomarkers for early detection and diagnosis. The differentially expressed genes (DEGs) between bladder carcinoma patients and normal subjects were screened using empirical Bayes method of the linear models for microarray data package. Co-expression networks were constructed by differentially co-expressed genes and links. Regulatory impact factors (RIF) metric was used to identify critical transcription factors (TFs). The protein-protein interaction (PPI) networks were constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and clusters were obtained through molecular complex detection (MCODE) algorithm. Centralities analyses for complex networks were performed based on degree, stress and betweenness. Enrichment analyses were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Co-expression networks and TFs (based on expression data of global DEGs and DEGs in different stages and grades) were identified. Hub genes of complex networks, such as UBE2C, ACTA2, FABP4, CKS2, FN1 and TOP2A, were also obtained according to analysis of degree. In gene enrichment analyses of global DEGs, cell adhesion, proteinaceous extracellular matrix and extracellular matrix structural constituent were top three GO terms. ECM-receptor interaction, focal adhesion, and cell cycle were significant pathways. Our results provide some potential underlying biomarkers of BC. However, further validation is required and deep studies are needed to elucidate the pathogenesis of BC. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Expression of multi-drug resistance-related genes MDR3 and MRP as prognostic factors in clinical liver cancer patients.

    Science.gov (United States)

    Yu, Zheng; Peng, Sun; Hong-Ming, Pan; Kai-Feng, Wang

    2012-01-01

    To investigate the expression of multi-drug resistance-related genes, MDR3 and MRP, in clinical specimens of primary liver cancer and their potential as prognostic factors in liver cancer patients. A total of 26 patients with primary liver cancer were enrolled. The expression of MDR3 and MRP genes was measured by real-time PCR and the association between gene expression and the prognosis of patients was analyzed by the Kaplan-Meier method and COX regression model. This study showed that increases in MDR3 gene expression were identified in cholangiocellular carcinoma, cirrhosis and HBsAg-positive patients, while MRP expression increased in hepatocellular carcinoma, non-cirrhosis and HBsAg-negative patients. Moreover, conjugated bilirubin and total bile acid in the serum were significantly reduced in patients with high MRP expression compared to patients with low expression. The overall survival tended to be longer in patients with high MDR3 and MRP expression compared to the control group. MRP might be an independent prognostic factor in patients with liver cancer by COX regression analysis. MDR3 and MRP may play important roles in liver cancer patients as prognostic factors and their underlying mechanisms in liver cancer are worthy of further investigation.

  16. Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data.

    Science.gov (United States)

    Ren, Zhonglu; Wang, Wenhui; Li, Jinming

    2016-02-01

    Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristics of each subtype. Clustering analysis and discriminant analysis were utilized to discover the subtypes in two different molecular levels on 153 colon cancer samples from The Cancer Genome Atlas (TCGA) Data Portal. At gene expression level, we identified two major subtypes, ECL1 (expression cluster 1) and ECL2 (expression cluster 2) and a list of signature genes. Due to the heterogeneity of colon cancer, the subtype ECL1 can be further subdivided into three nested subclasses, and HOTAIR were found upregulated in subclass 2. At DNA methylation level, we uncovered three major subtypes, MCL1 (methylation cluster 1), MCL2 (methylation cluster 2) and MCL3 (methylation cluster 3). We found only three subtypes of CpG island methylator phenotype (CIMP) in colon cancer instead of the four subtypes in the previous reports, and we found no sufficient evidence to subdivide MCL3 into two distinct subgroups.

  17. [Effect of cisplatin on the expression of Pokemon gene: experiment with different human lung cancer cells].

    Science.gov (United States)

    Zhao, Zhi-Hong; Wang, Sheng-Fa; Yu, Liang; Wang, Ju; Cong, De-Gang; Chang, Hao; Wang, Xue-Feng; Zhang, Tie-Wa; Zhang, Jian; Fu, Kai; Jiang, Jiu-Yang

    2008-04-29

    To investigate the correlation between Pokemon gene and cisplatin mechanism. Human lung adenocarcinoma cells of the lines A549 and AGZY83-a, human lung squamous carcinoma cells of the line HE-99, and human giant cell lung cancer cells of the line 95D were cultured and cisplatin was added into the medium. Other lung cancer cells of the above mentioned lines were cultured in the medium without cisplatin and were used as control groups. RT-PCR and Western blotting were used to detect the mRNA and protein expression of Pokemon. Pokemon mRNA and protein were expressed highly in all the 4 cell lines. The Pokemon gene expression did not changed significantly after cisplatin treatment groups. There were not significant differences in the mRNA and protein expression of Pokemon among the 4 experiment groups and the control groups (all P > 0.05). Cisplatin has no effect on the Pokemon gene expression of the human lung cancer cells.

  18. 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

    to both immunological and endogenous cellular factors, although little is known about the distinct biology of MCB that may contribute to the improved outcome of MCB patients. To identify candidate genes, we performed gene array expression analysis of cell lines of MCB, ductal breast cancer and normal......Medullary breast cancer (MCB) is a morphologically and biologically distinct subtype that, despite cytologically highly malignant characteristics, has a favorable prognosis compared to the more common infiltrating ductal breast carcinoma. MCB metastasizes less frequently, which has been attributed...... breast epithelia, and the differential expression of a panel of candidate genes was further validated by quantitative PCR and immunohistochemical analysis of cell lines and tumor biopsies. A limited number of genes, including several members of the GAGE and insulin growth factor binding protein (IGFBP...

  19. A systematic study on drug-response associated genes using baseline gene expressions of the Cancer Cell Line Encyclopedia

    Science.gov (United States)

    Liu, Xiaoming; Yang, Jiasheng; Zhang, Yi; Fang, Yun; Wang, Fayou; Wang, Jun; Zheng, Xiaoqi; Yang, Jialiang

    2016-03-01

    We have studied drug-response associated (DRA) gene expressions by applying a systems biology framework to the Cancer Cell Line Encyclopedia data. More than 4,000 genes are inferred to be DRA for at least one drug, while the number of DRA genes for each drug varies dramatically from almost 0 to 1,226. Functional enrichment analysis shows that the DRA genes are significantly enriched in genes associated with cell cycle and plasma membrane. Moreover, there might be two patterns of DRA genes between genders. There are significantly shared DRA genes between male and female for most drugs, while very little DRA genes tend to be shared between the two genders for a few drugs targeting sex-specific cancers (e.g., PD-0332991 for breast cancer and ovarian cancer). Our analyses also show substantial difference for DRA genes between young and old samples, suggesting the necessity of considering the age effects for personalized medicine in cancers. Lastly, differential module and key driver analyses confirm cell cycle related modules as top differential ones for drug sensitivity. The analyses also reveal the role of TSPO, TP53, and many other immune or cell cycle related genes as important key drivers for DRA network modules. These key drivers provide new drug targets to improve the sensitivity of cancer therapy.

  20. Bridging cancer biology with the clinic: relative expression of a GRHL2-mediated gene-set pair predicts breast cancer metastasis.

    Directory of Open Access Journals (Sweden)

    Xinan Yang

    Full Text Available Identification and characterization of crucial gene target(s that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2, a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP, is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3 from all 2717 possible gene-set pairs (GSPs. The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035. It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e-6. This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017, a GRHL2-associated clinical character (p = 6.8e-6, Spearman correlation, suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic

  1. Automated Detection of Cancer Associated Genes Using a Combined Fuzzy-Rough-Set-Based F-Information and Water Swirl Algorithm of Human Gene Expression Data.

    Directory of Open Access Journals (Sweden)

    Pugalendhi Ganesh Kumar

    Full Text Available This study describes a novel approach to reducing the challenges of highly nonlinear multiclass gene expression values for cancer diagnosis. To build a fruitful system for cancer diagnosis, in this study, we introduced two levels of gene selection such as filtering and embedding for selection of potential genes and the most relevant genes associated with cancer, respectively. The filter procedure was implemented by developing a fuzzy rough set (FR-based method for redefining the criterion function of f-information (FI to identify the potential genes without discretizing the continuous gene expression values. The embedded procedure is implemented by means of a water swirl algorithm (WSA, which attempts to optimize the rule set and membership function required to classify samples using a fuzzy-rule-based multiclassification system (FRBMS. Two novel update equations are proposed in WSA, which have better exploration and exploitation abilities while designing a self-learning FRBMS. The efficiency of our new approach was evaluated on 13 multicategory and 9 binary datasets of cancer gene expression. Additionally, the performance of the proposed FRFI-WSA method in designing an FRBMS was compared with existing methods for gene selection and optimization such as genetic algorithm (GA, particle swarm optimization (PSO, and artificial bee colony algorithm (ABC on all the datasets. In the global cancer map with repeated measurements (GCM_RM dataset, the FRFI-WSA showed the smallest number of 16 most relevant genes associated with cancer using a minimal number of 26 compact rules with the highest classification accuracy (96.45%. In addition, the statistical validation used in this study revealed that the biological relevance of the most relevant genes associated with cancer and their linguistics detected by the proposed FRFI-WSA approach are better than those in the other methods. The simple interpretable rules with most relevant genes and effectively

  2. In silico analysis of stomach lineage specific gene set expression pattern in gastric cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pandi, Narayanan Sathiya, E-mail: sathiyapandi@gmail.com; Suganya, Sivagurunathan; Rajendran, Suriliyandi

    2013-10-04

    Highlights: •Identified stomach lineage specific gene set (SLSGS) was found to be under expressed in gastric tumors. •Elevated expression of SLSGS in gastric tumor is a molecular predictor of metabolic type gastric cancer. •In silico pathway scanning identified estrogen-α signaling is a putative regulator of SLSGS in gastric cancer. •Elevated expression of SLSGS in GC is associated with an overall increase in the survival of GC patients. -- Abstract: Stomach lineage specific gene products act as a protective barrier in the normal stomach and their expression maintains the normal physiological processes, cellular integrity and morphology of the gastric wall. However, the regulation of stomach lineage specific genes in gastric cancer (GC) is far less clear. In the present study, we sought to investigate the role and regulation of stomach lineage specific gene set (SLSGS) in GC. SLSGS was identified by comparing the mRNA expression profiles of normal stomach tissue with other organ tissue. The obtained SLSGS was found to be under expressed in gastric tumors. Functional annotation analysis revealed that the SLSGS was enriched for digestive function and gastric epithelial maintenance. Employing a single sample prediction method across GC mRNA expression profiles identified the under expression of SLSGS in proliferative type and invasive type gastric tumors compared to the metabolic type gastric tumors. Integrative pathway activation prediction analysis revealed a close association between estrogen-α signaling and SLSGS expression pattern in GC. Elevated expression of SLSGS in GC is associated with an overall increase in the survival of GC patients. In conclusion, our results highlight that estrogen mediated regulation of SLSGS in gastric tumor is a molecular predictor of metabolic type GC and prognostic factor in GC.

  3. In silico analysis of stomach lineage specific gene set expression pattern in gastric cancer

    International Nuclear Information System (INIS)

    Pandi, Narayanan Sathiya; Suganya, Sivagurunathan; Rajendran, Suriliyandi

    2013-01-01

    Highlights: •Identified stomach lineage specific gene set (SLSGS) was found to be under expressed in gastric tumors. •Elevated expression of SLSGS in gastric tumor is a molecular predictor of metabolic type gastric cancer. •In silico pathway scanning identified estrogen-α signaling is a putative regulator of SLSGS in gastric cancer. •Elevated expression of SLSGS in GC is associated with an overall increase in the survival of GC patients. -- Abstract: Stomach lineage specific gene products act as a protective barrier in the normal stomach and their expression maintains the normal physiological processes, cellular integrity and morphology of the gastric wall. However, the regulation of stomach lineage specific genes in gastric cancer (GC) is far less clear. In the present study, we sought to investigate the role and regulation of stomach lineage specific gene set (SLSGS) in GC. SLSGS was identified by comparing the mRNA expression profiles of normal stomach tissue with other organ tissue. The obtained SLSGS was found to be under expressed in gastric tumors. Functional annotation analysis revealed that the SLSGS was enriched for digestive function and gastric epithelial maintenance. Employing a single sample prediction method across GC mRNA expression profiles identified the under expression of SLSGS in proliferative type and invasive type gastric tumors compared to the metabolic type gastric tumors. Integrative pathway activation prediction analysis revealed a close association between estrogen-α signaling and SLSGS expression pattern in GC. Elevated expression of SLSGS in GC is associated with an overall increase in the survival of GC patients. In conclusion, our results highlight that estrogen mediated regulation of SLSGS in gastric tumor is a molecular predictor of metabolic type GC and prognostic factor in GC

  4. Potential in a single cancer cell to produce heterogeneous morphology, radiosensitivity and gene expression

    International Nuclear Information System (INIS)

    Ban, Sadayuki; Ishikawa, Ken-ichi; Kawai, Seiko; Koyama-Saegusa, Kumiko; Ishikawa, Atsuko; Imai, Takashi; Shimada, Yutaka; Inazawa, Johji

    2005-01-01

    Morphologically heterogeneous colonies were formed from a cultured cell line (KYSE70) established from one human esophageal carcinoma tissue. Two subclones were separated from a single clone (clone 13) of KYSE70 cells. One subclone (clone 13-3G) formed mainly mounding colonies and the other (clone 13-6G) formed flat, diffusive colonies. X-irradiation stimulated the cells to dedifferentiate from the mounding state to the flat, diffusive state. Clone 13-6G cells were more radiosensitive than the other 3 cell lines. Clustering analysis for gene expression level by oligonucleotide microarray demonstrated that in the radiosensitive clone 13-6G cells, expression of genes involved in cell adhesion was upregulated, but genes involved in the response to DNA damage stimulus were downregulated. The data demonstrated that a single cancer cell had the potential to produce progeny heterogeneous in terms of morphology, radiation sensitivity and gene expression, and irradiation enhanced the dedifferentiation of cancer cells. (author)

  5. Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array

    Directory of Open Access Journals (Sweden)

    Sugnet Charles

    2006-12-01

    Full Text Available Abstract Background Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. Results We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic

  6. Cancer-Predicting Gene Expression Changes in Colonic Mucosa of Western Diet Fed Mlh1 +/- Mice

    Science.gov (United States)

    Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi; Peltomäki, Päivi; Mutanen, Marja; Nyström, Minna

    2013-01-01

    Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1 +/- mice, an animal model for human Lynch syndrome (LS), and wild type Mlh1 +/+ littermates, fed by either Western-style (WD) or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1 +/- mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold) together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1 +/- and Mlh1 +/+ mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis. PMID:24204690

  7. Cancer-predicting gene expression changes in colonic mucosa of Western diet fed Mlh1+/- mice.

    Directory of Open Access Journals (Sweden)

    Marjaana Pussila

    Full Text Available Colorectal cancer (CRC is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age in the heterozygote Mlh1(+/- mice, an animal model for human Lynch syndrome (LS, and wild type Mlh1(+/+ littermates, fed by either Western-style (WD or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1(+/- mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1(+/- and Mlh1(+/+ mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis.

  8. Operator dependent choice of prostate cancer biopsy has limited impact on a gene signature analysis for the highly expressed genes IGFBP3 and F3 in prostate cancer epithelial cells.

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    Zhuochun Peng

    Full Text Available BACKGROUND: Predicting the prognosis of prostate cancer disease through gene expression analysis is receiving increasing interest. In many cases, such analyses are based on formalin-fixed, paraffin embedded (FFPE core needle biopsy material on which Gleason grading for diagnosis has been conducted. Since each patient typically has multiple biopsy samples, and since Gleason grading is an operator dependent procedure known to be difficult, the impact of the operator's choice of biopsy was evaluated. METHODS: Multiple biopsy samples from 43 patients were evaluated using a previously reported gene signature of IGFBP3, F3 and VGLL3 with potential prognostic value in estimating overall survival at diagnosis of prostate cancer. A four multiplex one-step qRT-PCR test kit, designed and optimized for measuring the signature in FFPE core needle biopsy samples was used. Concordance of gene expression levels between primary and secondary Gleason tumor patterns, as well as benign tissue specimens, was analyzed. RESULTS: The gene expression levels of IGFBP3 and F3 in prostate cancer epithelial cell-containing tissue representing the primary and secondary Gleason patterns were high and consistent, while the low expressed VGLL3 showed more variation in its expression levels. CONCLUSION: The assessment of IGFBP3 and F3 gene expression levels in prostate cancer tissue is independent of Gleason patterns, meaning that the impact of operator's choice of biopsy is low.

  9. Quantitative gene expression underlying 18f-fluorodeoxyglucose uptake in colon cancer

    DEFF Research Database (Denmark)

    Engelmann, Bodil E.; Binderup, Tina; Kjær, Andreas

    2015-01-01

    Background: Positron emission tomography (PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples....... Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUVmax with gene expression levels showed significant correlations between SUVmax and HK2, ki67...

  10. Gene Expression Profiling of Early Stage Non-Small Cell Lung Cancer

    NARCIS (Netherlands)

    J. Hou (Jun)

    2010-01-01

    textabstractNSCLC is a highly heterogeneous malignancy with a poor prognosis. Treatment for NSCLC is currently based on a combination of pathological staging and histological classification. Recently, gene expression-based NSCLC profiling is proven a superior approach to stratify cancer cases with

  11. The Relationship between TP53 Gene Status and Carboxylesterase 2 Expression in Human Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Momoko Ishimine

    2018-01-01

    Full Text Available Irinotecan (CPT-11 is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between TP53 gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37 showed lower CES2 mRNA levels (≥1.5-fold lower than the adjacent normal tissue, and only 30% (12 of 37 showed similar (<1.5-fold lower or higher CES2 mRNA levels. However, TP53 gene sequencing revealed no relationship between CES2 downregulation and TP53 mutational status. Moreover, while colorectal cancer cells expressing wild-type p53 exhibited p53-dependent upregulation of CES2, PRIMA-1MET, a drug that restores the transcriptional activity of mutant p53, failed to upregulate CES2 expression in cells with TP53 missense mutations. These results, taken together, suggest that CES2 mRNA expression is decreased in human colorectal cancer independently of p53.

  12. Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression

    International Nuclear Information System (INIS)

    Abba, Martin C; Aldaz, C Marcelo; Drake, Jeffrey A; Hawkins, Kathleen A; Hu, Yuhui; Sun, Hongxia; Notcovich, Cintia; Gaddis, Sally; Sahin, Aysegul; Baggerly, Keith

    2004-01-01

    Genomic and transcriptomic alterations affecting key cellular processes such us cell proliferation, differentiation and genomic stability are considered crucial for the development and progression of cancer. Most invasive breast carcinomas are known to derive from precursor in situ lesions. It is proposed that major global expression abnormalities occur in the transition from normal to premalignant stages and further progression to invasive stages. Serial analysis of gene expression (SAGE) was employed to generate a comprehensive global gene expression profile of the major changes occurring during breast cancer malignant evolution. In the present study we combined various normal and tumor SAGE libraries available in the public domain with sets of breast cancer SAGE libraries recently generated and sequenced in our laboratory. A recently developed modified t test was used to detect the genes differentially expressed. We accumulated a total of approximately 1.7 million breast tissue-specific SAGE tags and monitored the behavior of more than 25,157 genes during early breast carcinogenesis. We detected 52 transcripts commonly deregulated across the board when comparing normal tissue with ductal carcinoma in situ, and 149 transcripts when comparing ductal carcinoma in situ with invasive ductal carcinoma (P < 0.01). A major novelty of our study was the use of a statistical method that correctly accounts for the intra-SAGE and inter-SAGE library sources of variation. The most useful result of applying this modified t statistics beta binomial test is the identification of genes and gene families commonly deregulated across samples within each specific stage in the transition from normal to preinvasive and invasive stages of breast cancer development. Most of the gene expression abnormalities detected at the in situ stage were related to specific genes in charge of regulating the proper homeostasis between cell death and cell proliferation. The comparison of in situ lesions

  13. Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

    International Nuclear Information System (INIS)

    Klopfleisch, Robert; Lenze, Dido; Hummel, Michael; Gruber, Achim D

    2010-01-01

    Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs are in some aspects suitable as a

  14. Prediction of drug efficacy for cancer treatment based on comparative analysis of chemosensitivity and gene expression data

    DEFF Research Database (Denmark)

    Wan, Peng; Li, Qiyuan; Larsen, Jens Erik Pontoppidan

    2012-01-01

    The NCI60 database is the largest available collection of compounds with measured anti-cancer activity. The strengths and limitations for using the NCI60 database as a source of new anti-cancer agents are explored and discussed in relation to previous studies. We selected a sub-set of 2333...... and in a data set of expression profiles of 1901 genes for the corresponding tumor cell lines. Five clusters were identified based on the gene expression data using self-organizing maps (SOM), comprising leukemia, melanoma, ovarian and prostate, basal breast, and luminal breast cancer cells, respectively....... The strong difference in gene expression between basal and luminal breast cancer cells was reflected clearly in the chemosensitivity data. Although most compounds in the data set were of low potency, high efficacy compounds that showed specificity with respect to tissue of origin could be found. Furthermore...

  15. Gene Expression Profile of Proton Beam Irradiated Breast Cancer Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Myung Hwan; Park, Jeong Chan [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-05-15

    Cancer stem cells (CSCs) possess characteristics associated with normal stem cells. The mechanisms regulating CSC radio-resistance, including to proton beam, remain unclear. They showed that a subset of cells expressing CD44 with weak or no CD24 expression could establish new tumors in xenograft mice. Recently, BCSC-targeting therapies have been evaluated by numerous groups. Strategies include targeting BCSC self-renewal, indirectly targeting the microenvironment, and directly killing BCSCs by chemical agents that induce differentiation, immunotherapy, and oncolytic viruses. However, the mechanisms regulating CSC radio-resistance, particularly proton beam resistance, remain unclear. The identification of CSC-related gene expression patterns would make up offer data for better understanding CSCs properties. In this study we investigated the gene expression profile of BCSCs isolation from MCF-7 cell line. Reducing BCSC resistance to pulsed proton beams is essential to improve therapeutic efficacy and decrease the 5-year recurrence rate. In this respect, the information of the level of gene expression patterns in BCSCs is attractive for understanding molecular mechanisms of radio-resistance of BCSCs.

  16. Multiclass classification for skin cancer profiling based on the integration of heterogeneous gene expression series.

    Science.gov (United States)

    Gálvez, Juan Manuel; Castillo, Daniel; Herrera, Luis Javier; San Román, Belén; Valenzuela, Olga; Ortuño, Francisco Manuel; Rojas, Ignacio

    2018-01-01

    Most of the research studies developed applying microarray technology to the characterization of different pathological states of any disease may fail in reaching statistically significant results. This is largely due to the small repertoire of analysed samples, and to the limitation in the number of states or pathologies usually addressed. Moreover, the influence of potential deviations on the gene expression quantification is usually disregarded. In spite of the continuous changes in omic sciences, reflected for instance in the emergence of new Next-Generation Sequencing-related technologies, the existing availability of a vast amount of gene expression microarray datasets should be properly exploited. Therefore, this work proposes a novel methodological approach involving the integration of several heterogeneous skin cancer series, and a later multiclass classifier design. This approach is thus a way to provide the clinicians with an intelligent diagnosis support tool based on the use of a robust set of selected biomarkers, which simultaneously distinguishes among different cancer-related skin states. To achieve this, a multi-platform combination of microarray datasets from Affymetrix and Illumina manufacturers was carried out. This integration is expected to strengthen the statistical robustness of the study as well as the finding of highly-reliable skin cancer biomarkers. Specifically, the designed operation pipeline has allowed the identification of a small subset of 17 differentially expressed genes (DEGs) from which to distinguish among 7 involved skin states. These genes were obtained from the assessment of a number of potential batch effects on the gene expression data. The biological interpretation of these genes was inspected in the specific literature to understand their underlying information in relation to skin cancer. Finally, in order to assess their possible effectiveness in cancer diagnosis, a cross-validation Support Vector Machines (SVM

  17. Expression of estrogen-related gene markers in breast cancer tissue predicts aromatase inhibitor responsiveness.

    Directory of Open Access Journals (Sweden)

    Irene Moy

    Full Text Available Aromatase inhibitors (AIs are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC. Messenger RNA (mRNA levels of 5 estrogen-related genes-AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR-were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy-defined as the combined complete response, partial response, and stable disease rates for at least 6 months-was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36% and identical sensitivity (96% to the current clinical practice (ERα/PR-IHC. In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection.

  18. IGF-Regulated Genes in Prostate Cancer

    National Research Council Canada - National Science Library

    Roberts, Charles

    2003-01-01

    We hypothesized that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression...

  19. IGF-Regulated Genes in Prostate Cancer

    National Research Council Canada - National Science Library

    Roberts, Charles T., Jr

    2005-01-01

    We hypothesized that genes that are differentially expressed as a result of the decreased IGF-I receptor gene expression seen in metastatic prostate cancer contribute to prostate cancer progression...

  20. Effects of Smac gene over-expression on radiotherapeutic sensitivity of cervical cancer cell line HeLa

    International Nuclear Information System (INIS)

    Zheng Liduan; Wang Liang; Tong Qiangsong; Fei Shihong; Xiong Yufang; Wu Gang

    2005-01-01

    Objective: To study the effects of extrinsic Smac gene transfection and its over-expression on radiotherapeutic sensitivity of cervical cancer cells, in order to explore a novel strategy for ameliorating radiotherapy of cervical cancer. Methods: After Smac gene was transferred into cells of cervical cancer cell line HeLa, the subclone cells were obtained by persistent G 418 selection. Cellular Smac gene expression was determined by RT-PCR and Western blot. After treatment with X-ray irradiation, cellular growth activity in vitro was investigated by MTT colorimetry. Cellular apoptosis and its rate were determined by electron microscopy, Annexin V-FITC and propidium iodide staining flow cytometry. Cellular Caspase-3 protein expression and its activity were assayed by Western blot and colorimetry. Results: RT-PCR and Western blot demonstrated that Smac mRNA and protein levels of HeLa/Smac cells, the selected subclone cells of cervical cancer cell line, were significantly higher than those of HeLa cells (P<0.01). After treated with 8 Gy X-ray irradiation, growth activity of HeLa/Smac cells reduced by 10.19%(P<0.01), as compared with that of HeLa cells. Partial HeLa/Smac cancer cells presented characteristic morphological changes of apoptosis under electron microscope, with an apoptosis rate of 16.4%, which was significantly higher than that of HeLa cells(6.2%, P<0.01). Compared with HeLa cells, Caspase-3 expression level in HeLa/Smac was improved significantly (P<0.01), while its activity was 3.42 times as much as that of HeLa cells (P<0.01). Conclusion: Stable transfection of extrinsic Smac gene and its over-expression in cervical cancer cell line could significantly enhance cellular caspase-3 expression and activity, ameliorate apoptosis-inducing effects of radiation on cancer cells, which would be a novel strategy to improve radiotherapeutic effects for cervical cancer. (authors)

  1. Pancreatic cancer circulating tumour cells express a cell motility gene signature that predicts survival after surgery

    International Nuclear Information System (INIS)

    Sergeant, Gregory; Eijsden, Rudy van; Roskams, Tania; Van Duppen, Victor; Topal, Baki

    2012-01-01

    Most cancer deaths are caused by metastases, resulting from circulating tumor cells (CTC) that detach from the primary cancer and survive in distant organs. The aim of the present study was to develop a CTC gene signature and to assess its prognostic relevance after surgery for pancreatic ductal adenocarcinoma (PDAC). Negative depletion fluorescence activated cell sorting (FACS) was developed and validated with spiking experiments using cancer cell lines in whole human blood samples. This FACS-based method was used to enrich for CTC from the blood of 10 patients who underwent surgery for PDAC. Total RNA was isolated from 4 subgroup samples, i.e. CTC, haematological cells (G), original tumour (T), and non-tumoural pancreatic control tissue (P). After RNA quality control, samples of 6 patients were eligible for further analysis. Whole genome microarray analysis was performed after double linear amplification of RNA. ‘Ingenuity Pathway Analysis’ software and AmiGO were used for functional data analyses. A CTC gene signature was developed and validated with the nCounter system on expression data of 78 primary PDAC using Cox regression analysis for disease-free (DFS) and overall survival (OS). Using stringent statistical analysis, we retained 8,152 genes to compare expression profiles of CTC vs. other subgroups, and found 1,059 genes to be differentially expressed. The pathway with the highest expression ratio in CTC was p38 mitogen-activated protein kinase (p38 MAPK) signaling, known to be involved in cancer cell migration. In the p38 MAPK pathway, TGF-β1, cPLA2, and MAX were significantly upregulated. In addition, 9 other genes associated with both p38 MAPK signaling and cell motility were overexpressed in CTC. High co-expression of TGF-β1 and our cell motility panel (≥ 4 out of 9 genes for DFS and ≥ 6 out of 9 genes for OS) in primary PDAC was identified as an independent predictor of DFS (p=0.041, HR (95% CI) = 1.885 (1.025 – 3.559)) and OS (p=0.047, HR

  2. Advanced colorectal adenoma related gene expression signature may predict prognostic for colorectal cancer patients with adenoma-carcinoma sequence.

    Science.gov (United States)

    Li, Bing; Shi, Xiao-Yu; Liao, Dai-Xiang; Cao, Bang-Rong; Luo, Cheng-Hua; Cheng, Shu-Jun

    2015-01-01

    There are still no absolute parameters predicting progression of adenoma into cancer. The present study aimed to characterize functional differences on the multistep carcinogenetic process from the adenoma-carcinoma sequence. All samples were collected and mRNA expression profiling was performed by using Agilent Microarray high-throughput gene-chip technology. Then, the characteristics of mRNA expression profiles of adenoma-carcinoma sequence were described with bioinformatics software, and we analyzed the relationship between gene expression profiles of adenoma-adenocarcinoma sequence and clinical prognosis of colorectal cancer. The mRNA expressions of adenoma-carcinoma sequence were significantly different between high-grade intraepithelial neoplasia group and adenocarcinoma group. The biological process of gene ontology function enrichment analysis on differentially expressed genes between high-grade intraepithelial neoplasia group and adenocarcinoma group showed that genes enriched in the extracellular structure organization, skeletal system development, biological adhesion and itself regulated growth regulation, with the P value after FDR correction of less than 0.05. In addition, IPR-related protein mainly focused on the insulin-like growth factor binding proteins. The variable trends of gene expression profiles for adenoma-carcinoma sequence were mainly concentrated in high-grade intraepithelial neoplasia and adenocarcinoma. The differentially expressed genes are significantly correlated between high-grade intraepithelial neoplasia group and adenocarcinoma group. Bioinformatics analysis is an effective way to study the gene expression profiles in the adenoma-carcinoma sequence, and may provide an effective tool to involve colorectal cancer research strategy into colorectal adenoma or advanced adenoma.

  3. Building prognostic models for breast cancer patients using clinical variables and hundreds of gene expression signatures

    Directory of Open Access Journals (Sweden)

    Liu Yufeng

    2011-01-01

    Full Text Available Abstract Background Multiple breast cancer gene expression profiles have been developed that appear to provide similar abilities to predict outcome and may outperform clinical-pathologic criteria; however, the extent to which seemingly disparate profiles provide additive prognostic information is not known, nor do we know whether prognostic profiles perform equally across clinically defined breast cancer subtypes. We evaluated whether combining the prognostic powers of standard breast cancer clinical variables with a large set of gene expression signatures could improve on our ability to predict patient outcomes. Methods Using clinical-pathological variables and a collection of 323 gene expression "modules", including 115 previously published signatures, we build multivariate Cox proportional hazards models using a dataset of 550 node-negative systemically untreated breast cancer patients. Models predictive of pathological complete response (pCR to neoadjuvant chemotherapy were also built using this approach. Results We identified statistically significant prognostic models for relapse-free survival (RFS at 7 years for the entire population, and for the subgroups of patients with ER-positive, or Luminal tumors. Furthermore, we found that combined models that included both clinical and genomic parameters improved prognostication compared with models with either clinical or genomic variables alone. Finally, we were able to build statistically significant combined models for pathological complete response (pCR predictions for the entire population. Conclusions Integration of gene expression signatures and clinical-pathological factors is an improved method over either variable type alone. Highly prognostic models could be created when using all patients, and for the subset of patients with lymph node-negative and ER-positive breast cancers. Other variables beyond gene expression and clinical-pathological variables, like gene mutation status or DNA

  4. Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

    Science.gov (United States)

    Ebot, Ericka M; Gerke, Travis; Labbé, David P; Sinnott, Jennifer A; Zadra, Giorgia; Rider, Jennifer R; Tyekucheva, Svitlana; Wilson, Kathryn M; Kelly, Rachel S; Shui, Irene M; Loda, Massimo; Kantoff, Philip W; Finn, Stephen; Vander Heiden, Matthew G; Brown, Myles; Giovannucci, Edward L; Mucci, Lorelei A

    2017-11-01

    Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate 7, 41% vs 17%; P = 2 × 10 -4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society. © 2017 American Cancer Society.

  5. Identification of Differentially Expressed Genes between Original Breast Cancer and Xenograft Using Machine Learning Algorithms

    Directory of Open Access Journals (Sweden)

    Deling Wang

    2018-03-01

    Full Text Available Breast cancer is one of the most common malignancies in women. Patient-derived tumor xenograft (PDX model is a cutting-edge approach for drug research on breast cancer. However, PDX still exhibits differences from original human tumors, thereby challenging the molecular understanding of tumorigenesis. In particular, gene expression changes after tissues are transplanted from human to mouse model. In this study, we propose a novel computational method by incorporating several machine learning algorithms, including Monte Carlo feature selection (MCFS, random forest (RF, and rough set-based rule learning, to identify genes with significant expression differences between PDX and original human tumors. First, 831 breast tumors, including 657 PDX and 174 human tumors, were collected. Based on MCFS and RF, 32 genes were then identified to be informative for the prediction of PDX and human tumors and can be used to construct a prediction model. The prediction model exhibits a Matthews coefficient correlation value of 0.777. Seven interpretable interactions within the informative gene were detected based on the rough set-based rule learning. Furthermore, the seven interpretable interactions can be well supported by previous experimental studies. Our study not only presents a method for identifying informative genes with differential expression but also provides insights into the mechanism through which gene expression changes after being transplanted from human tumor into mouse model. This work would be helpful for research and drug development for breast cancer.

  6. Identification of Differentially Expressed Genes between Original Breast Cancer and Xenograft Using Machine Learning Algorithms.

    Science.gov (United States)

    Wang, Deling; Li, Jia-Rui; Zhang, Yu-Hang; Chen, Lei; Huang, Tao; Cai, Yu-Dong

    2018-03-12

    Breast cancer is one of the most common malignancies in women. Patient-derived tumor xenograft (PDX) model is a cutting-edge approach for drug research on breast cancer. However, PDX still exhibits differences from original human tumors, thereby challenging the molecular understanding of tumorigenesis. In particular, gene expression changes after tissues are transplanted from human to mouse model. In this study, we propose a novel computational method by incorporating several machine learning algorithms, including Monte Carlo feature selection (MCFS), random forest (RF), and rough set-based rule learning, to identify genes with significant expression differences between PDX and original human tumors. First, 831 breast tumors, including 657 PDX and 174 human tumors, were collected. Based on MCFS and RF, 32 genes were then identified to be informative for the prediction of PDX and human tumors and can be used to construct a prediction model. The prediction model exhibits a Matthews coefficient correlation value of 0.777. Seven interpretable interactions within the informative gene were detected based on the rough set-based rule learning. Furthermore, the seven interpretable interactions can be well supported by previous experimental studies. Our study not only presents a method for identifying informative genes with differential expression but also provides insights into the mechanism through which gene expression changes after being transplanted from human tumor into mouse model. This work would be helpful for research and drug development for breast cancer.

  7. Investigating a multigene prognostic assay based on significant pathways for Luminal A breast cancer through gene expression profile analysis.

    Science.gov (United States)

    Gao, Haiyan; Yang, Mei; Zhang, Xiaolan

    2018-04-01

    The present study aimed to investigate potential recurrence-risk biomarkers based on significant pathways for Luminal A breast cancer through gene expression profile analysis. Initially, the gene expression profiles of Luminal A breast cancer patients were downloaded from The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were identified using a Limma package and the hierarchical clustering analysis was conducted for the DEGs. In addition, the functional pathways were screened using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and rank ratio calculation. The multigene prognostic assay was exploited based on the statistically significant pathways and its prognostic function was tested using train set and verified using the gene expression data and survival data of Luminal A breast cancer patients downloaded from the Gene Expression Omnibus. A total of 300 DEGs were identified between good and poor outcome groups, including 176 upregulated genes and 124 downregulated genes. The DEGs may be used to effectively distinguish Luminal A samples with different prognoses verified by hierarchical clustering analysis. There were 9 pathways screened as significant pathways and a total of 18 DEGs involved in these 9 pathways were identified as prognostic biomarkers. According to the survival analysis and receiver operating characteristic curve, the obtained 18-gene prognostic assay exhibited good prognostic function with high sensitivity and specificity to both the train and test samples. In conclusion the 18-gene prognostic assay including the key genes, transcription factor 7-like 2, anterior parietal cortex and lymphocyte enhancer factor-1 may provide a new method for predicting outcomes and may be conducive to the promotion of precision medicine for Luminal A breast cancer.

  8. Integrative Analysis of Gene Expression Data Including an Assessment of Pathway Enrichment for Predicting Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Pingzhao Hu

    2006-01-01

    Full Text Available Background: Microarray technology has been previously used to identify genes that are differentially expressed between tumour and normal samples in a single study, as well as in syntheses involving multiple studies. When integrating results from several Affymetrix microarray datasets, previous studies summarized probeset-level data, which may potentially lead to a loss of information available at the probe-level. In this paper, we present an approach for integrating results across studies while taking probe-level data into account. Additionally, we follow a new direction in the analysis of microarray expression data, namely to focus on the variation of expression phenotypes in predefined gene sets, such as pathways. This targeted approach can be helpful for revealing information that is not easily visible from the changes in the individual genes. Results: We used a recently developed method to integrate Affymetrix expression data across studies. The idea is based on a probe-level based test statistic developed for testing for differentially expressed genes in individual studies. We incorporated this test statistic into a classic random-effects model for integrating data across studies. Subsequently, we used a gene set enrichment test to evaluate the significance of enriched biological pathways in the differentially expressed genes identified from the integrative analysis. We compared statistical and biological significance of the prognostic gene expression signatures and pathways identified in the probe-level model (PLM with those in the probeset-level model (PSLM. Our integrative analysis of Affymetrix microarray data from 110 prostate cancer samples obtained from three studies reveals thousands of genes significantly correlated with tumour cell differentiation. The bioinformatics analysis, mapping these genes to the publicly available KEGG database, reveals evidence that tumour cell differentiation is significantly associated with many

  9. Gene expression disorders of innate antibacterial signaling pathway in pancreatic cancer patients: implications for leukocyte dysfunction and tumor progression

    Science.gov (United States)

    Dąbrowska, Aleksandra; Lech, Gustaw; Słodkowski, Maciej; Słotwińska, Sylwia M.

    2014-01-01

    The study was carried out to investigate changes in gene expression of innate antibacterial signaling pathways in patients with pancreatic cancer. Expression of the following genes was measured in peripheral blood leukocytes of 55 patients with pancreatic adenocarcinoma using real-time polymerase chain reaction (RT-PCR): TLR4, NOD1, MyD88, TRAF6 and HMGB1. The levels of expression of TLR4, NOD1 and TRAF6 genes were significantly elevated (p = 0.007; p = 0.001 and p = 0.01, respectively), while MyD88 expression was markedly reduced (p = 0.0002), as compared to controls. Expression of TLR4 and NOD1 exceeded the normal level more than 3.5-fold and there was a significant correlation found between the expression of these genes (r = 0.558, p < 0.001). TLR4, NOD1 and MyD88 genes were expressed at a similar level both before and after surgery. No significant changes in the expression of HMGB1 gene were observed. The results of the study clearly indicate abnormal expression of genes belonging to innate antibacterial signaling pathways in peripheral blood leukocytes of patients with pancreatic cancer, which may lead to leukocyte dysfunction. Overexpression of TLR4, NOD1 and TRAF6 genes, and decreased MyD88 gene expression may contribute to chronic inflammation and tumor progression by up-regulation of the innate antibacterial response. The parameters tested are useful for monitoring innate immunity gene disorders and pancreatic cancer progression. PMID:26155170

  10. Gene expression profiles in prostate cancer: identification of candidate non-invasive diagnostic markers.

    Science.gov (United States)

    Mengual, L; Ars, E; Lozano, J J; Burset, M; Izquierdo, L; Ingelmo-Torres, M; Gaya, J M; Algaba, F; Villavicencio, H; Ribal, M J; Alcaraz, A

    2014-04-01

    To analyze gene expression profiles of prostate cancer (PCa) with the aim of determining the relevant differentially expressed genes and subsequently ascertain whether this differential expression is maintained in post-prostatic massage (PPM) urine samples. Forty-six tissue specimens (36 from PCa patients and 10 controls) and 158 urine PPM-urines (113 from PCa patients and 45 controls) were collected between December 2003 and May 2007. DNA microarrays were used to identify genes differentially expressed between tumour and control samples. Ten genes were technically validated in the same tissue samples by quantitative RT-PCR (RT-qPCR). Forty two selected differentially expressed genes were validated in an independent set of PPM-urines by qRT-PCR. Multidimensional scaling plot according to the expression of all the microarray genes showed a clear distinction between control and tumour samples. A total of 1047 differentially expressed genes (FDR≤.1) were indentified between both groups of samples. We found a high correlation in the comparison of microarray and RT-qPCR gene expression levels (r=.928, P<.001). Thirteen genes maintained the same fold change direction when analyzed in PPM-urine samples and in four of them (HOXC6, PCA3, PDK4 and TMPRSS2-ERG), these differences were statistically significant (P<.05). The analysis of PCa by DNA microarrays provides new putative mRNA markers for PCa diagnosis that, with caution, can be extrapolated to PPM-urines. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

  11. Identifying miRNA and gene modules of colon cancer associated with pathological stage by weighted gene co-expression network analysis

    Directory of Open Access Journals (Sweden)

    Zhou X

    2018-05-01

    Full Text Available Xian-guo Zhou,1,2,* Xiao-liang Huang,1,2,* Si-yuan Liang,1–3 Shao-mei Tang,1,2 Si-kao Wu,1,2 Tong-tong Huang,1,2 Zeng-nan Mo,1,2,4 Qiu-yan Wang1,2,5 1Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3Department of Colorectal Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 4Department of Urology and Nephrology, The First Affiliated Hospital of Guangxi, Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 5Guangxi Colleges and Universities Key Laboratory of Biological Molecular Medicine Research, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China *These authors contributed equally to this work Introduction: Colorectal cancer (CRC is the fourth most common cause of cancer-related mortality worldwide. The tumor, node, metastasis (TNM stage remains the standard for CRC prognostication. Identification of meaningful microRNA (miRNA and gene modules or representative biomarkers related to the pathological stage of colon cancer helps to predict prognosis and reveal the mechanisms behind cancer progression.Materials and methods: We applied a systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA to detect the pathological stage-related miRNA and gene modules and construct a miRNA–gene network. The Cancer Genome Atlas (TCGA colon adenocarcinoma (CAC RNA-sequencing data and miRNA-sequencing data were subjected to WGCNA analysis, and the GSE29623, GSE35602 and GSE39396 were utilized to validate and

  12. Comparing cancer vs normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients

    DEFF Research Database (Denmark)

    Rapin, Nicolas; Bagger, Frederik Otzen; Jendholm, Johan

    2014-01-01

    Gene expression profiling has been used extensively to characterize cancer, identify novel subtypes, and improve patient stratification. However, it has largely failed to identify transcriptional programs that differ between cancer and corresponding normal cells and has not been efficient in iden......-karyotype AML, which allowed for the generation of a highly prognostic survival signature. Collectively, our CvN method holds great potential as a tool for the analysis of gene expression profiles of cancer patients....

  13. Profile of differentially expressed genes mediated by the type III epidermal growth factor receptor mutation expressed in a small-cell lung cancer cell line

    DEFF Research Database (Denmark)

    Pedersen, M.W.; Andersen, Thomas Thykjær; Ørntoft, Torben Falck

    2001-01-01

    Previous studies have shown a correlation between expression of the EGF receptor type III mutation (EGFRvIII) and a more malignant phenotype of various cancers including: non-small-cell lung cancer, glioblastoma multiforme, prostate cancer and breast cancer. Thus, a detailed molecular genetic...... understanding of how the EGFRvIII contributes to the malignant phenotype is of major importance for future therapy. The GeneChip Hu6800Set developed by Affymetrix was used to identify changes in gene expression caused by the expression of EGFRvIII. The cell line selected for the study was an EGF receptor...... negative small-cell-lung cancer cell line, GLC3, stably transfected with the EGFRvIII gene in a Tet-On system. By comparison of mRNA levels in EGFRvIII-GLC3 with those of Tet-On-GLC3, it was found that the levels of mRNAs encoding several transcription factors (ATF-3, JunD, and c-Myb), cell adhesion...

  14. Comparison of global gene expression of gastric cardia and noncardia cancers from a high-risk population in china.

    Directory of Open Access Journals (Sweden)

    Gangshi Wang

    Full Text Available To profile RNA expression in gastric cancer by anatomic subsites as an initial step in identifying molecular subtypes and providing targets for early detection and therapy.We performed transcriptome analysis using the Affymetrix GeneChip U133A in gastric cardia adenocarcinomas (n = 62 and gastric noncardia adenocarcinomas (n = 72 and their matched normal tissues from patients in Shanxi Province, and validated selected dysregulated genes with additional RNA studies. Expression of dysregulated genes was also related to survival of cases.Principal Component Analysis showed that samples clustered by tumor vs. normal, anatomic location, and histopathologic features. Paired t-tests of tumor/normal tissues identified 511 genes whose expression was dysregulated (P<4.7E-07 and at least two-fold difference in magnitude in cardia or noncardia gastric cancers, including nearly one-half (n = 239, 47% dysregulated in both cardia and noncardia, one-fourth dysregulated in cardia only (n = 128, 25%, and about one-fourth in noncardia only (n = 144, 28%. Additional RNA studies confirmed profiling results. Expression was associated with case survival for 20 genes in cardia and 36 genes in noncardia gastric cancers.The dysregulated genes identified here represent a comprehensive starting point for future efforts to understand etiologic heterogeneity, develop diagnostic biomarkers for early detection, and test molecularly-targeted therapies for gastric cancer.

  15. Hormone replacement therapy dependent changes in breast cancer-related gene expression in breast tissue of healthy postmenopausal women.

    Science.gov (United States)

    Sieuwerts, Anieta M; De Napoli, Giuseppina; van Galen, Anne; Kloosterboer, Helenius J; de Weerd, Vanja; Zhang, Hong; Martens, John W M; Foekens, John A; De Geyter, Christian

    2011-12-01

    Risk assessment of future breast cancer risk through exposure to sex steroids currently relies on clinical scorings such as mammographic density. Knowledge about the gene expression patterns in existing breast cancer tumors may be used to identify risk factors in the breast tissue of women still free of cancer. The differential effects of estradiol, estradiol together with gestagens, or tibolone on breast cancer-related gene expression in normal breast tissue samples taken from postmenopausal women may be used to identify gene expression profiles associated with a higher breast cancer risk. Breast tissue samples were taken from 33 healthy postmenopausal women both before and after a six month treatment with either 2mg micronized estradiol [E2], 2mg micronized estradiol and 1mg norethisterone acetate [E2+NETA], 2.5mg tibolone [T] or [no HRT]. Except for [E2], which was only given to women after hysterectomy, the allocation to each of the three groups was randomized. The expression of 102 mRNAs and 46 microRNAs putatively involved in breast cancer was prospectively determined in the biopsies of 6 women receiving [no HRT], 5 women receiving [E2], 5 women receiving [E2+NETA], and 6 receiving [T]. Using epithelial and endothelial markers genes, non-representative biopsies from 11 women were eliminated. Treatment of postmenopausal women with [E2+NETA] resulted in the highest number of differentially (pbreast tissue with a change in the expression of genes putatively involved in breast cancer. Our data suggest that normal mammary cells triggered by [E2+NETA] adjust for steroidogenic up-regulation through down-regulation of the estrogen-receptor pathway. This feasibility study provides the basis for whole genome analyses to identify novel markers involved in increased breast cancer risk. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  16. Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 1

    NARCIS (Netherlands)

    Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske

    2013-01-01

    Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have

  17. Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 2

    NARCIS (Netherlands)

    Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van Klaske

    2013-01-01

    Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have

  18. Predictive value of MSH2 gene expression in colorectal cancer treated with capecitabine

    DEFF Research Database (Denmark)

    Jensen, Lars H; Danenberg, Kathleen D; Danenberg, Peter V

    2007-01-01

    was associated with a hazard ratio of 0.5 (95% confidence interval, 0.23-1.11; P = 0.083) in survival analysis. CONCLUSION: The higher gene expression of MSH2 in responders and the trend for predicting overall survival indicates a predictive value of this marker in the treatment of advanced CRC with capecitabine.......PURPOSE: The objective of the present study was to evaluate the gene expression of the DNA mismatch repair gene MSH2 as a predictive marker in advanced colorectal cancer (CRC) treated with first-line capecitabine. PATIENTS AND METHODS: Microdissection of paraffin-embedded tumor tissue, RNA...

  19. Decreased expression of cell adhesion genes in cancer stem-like cells isolated from primary oral squamous cell carcinomas.

    Science.gov (United States)

    Mishra, Amrendra; Sriram, Harshini; Chandarana, Pinal; Tanavde, Vivek; Kumar, Rekha V; Gopinath, Ashok; Govindarajan, Raman; Ramaswamy, S; Sadasivam, Subhashini

    2018-05-01

    The goal of this study was to isolate cancer stem-like cells marked by high expression of CD44, a putative cancer stem cell marker, from primary oral squamous cell carcinomas and identify distinctive gene expression patterns in these cells. From 1 October 2013 to 4 September 2015, 76 stage III-IV primary oral squamous cell carcinoma of the gingivobuccal sulcus were resected. In all, 13 tumours were analysed by immunohistochemistry to visualise CD44-expressing cells. Expression of CD44 within The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma RNA-sequencing data was also assessed. Seventy resected tumours were dissociated into single cells and stained with antibodies to CD44 as well as CD45 and CD31 (together referred as Lineage/Lin). From 45 of these, CD44 + Lin - and CD44 - Lin - subpopulations were successfully isolated using fluorescence-activated cell sorting, and good-quality RNA was obtained from 14 such sorted pairs. Libraries from five pairs were sequenced and the results analysed using bioinformatics tools. Reverse transcription quantitative polymerase chain reaction was performed to experimentally validate the differential expression of selected candidate genes identified from the transcriptome sequencing in the same 5 and an additional 9 tumours. CD44 was expressed on the surface of poorly differentiated tumour cells, and within the The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma samples, its messenger RNA levels were higher in tumours compared to normal. Transcriptomics revealed that 102 genes were upregulated and 85 genes were downregulated in CD44 + Lin - compared to CD44 - Lin - cells in at least 3 of the 5 tumours sequenced. The upregulated genes included those involved in immune regulation, while the downregulated genes were enriched for genes involved in cell adhesion. Decreased expression of PCDH18, MGP, SPARCL1 and KRTDAP was confirmed by reverse transcription quantitative polymerase chain reaction. Lower expression of

  20. Multi-platform whole-genome microarray analyses refine the epigenetic signature of breast cancer metastasis with gene expression and copy number.

    Directory of Open Access Journals (Sweden)

    Joseph Andrews

    2010-01-01

    Full Text Available We have previously identified genome-wide DNA methylation changes in a cell line model of breast cancer metastasis. These complex epigenetic changes that we observed, along with concurrent karyotype analyses, have led us to hypothesize that complex genomic alterations in cancer cells (deletions, translocations and ploidy are superimposed over promoter-specific methylation events that are responsible for gene-specific expression changes observed in breast cancer metastasis.We undertook simultaneous high-resolution, whole-genome analyses of MDA-MB-468GFP and MDA-MB-468GFP-LN human breast cancer cell lines (an isogenic, paired lymphatic metastasis cell line model using Affymetrix gene expression (U133, promoter (1.0R, and SNP/CNV (SNP 6.0 microarray platforms to correlate data from gene expression, epigenetic (DNA methylation, and combination copy number variant/single nucleotide polymorphism microarrays. Using Partek Software and Ingenuity Pathway Analysis we integrated datasets from these three platforms and detected multiple hypomethylation and hypermethylation events. Many of these epigenetic alterations correlated with gene expression changes. In addition, gene dosage events correlated with the karyotypic differences observed between the cell lines and were reflected in specific promoter methylation patterns. Gene subsets were identified that correlated hyper (and hypo methylation with the loss (or gain of gene expression and in parallel, with gene dosage losses and gains, respectively. Individual gene targets from these subsets were also validated for their methylation, expression and copy number status, and susceptible gene pathways were identified that may indicate how selective advantage drives the processes of tumourigenesis and metastasis.Our approach allows more precisely profiling of functionally relevant epigenetic signatures that are associated with cancer progression and metastasis.

  1. Prioritizing genes associated with prostate cancer development

    International Nuclear Information System (INIS)

    Gorlov, Ivan P; Logothetis, Christopher J; Sircar, Kanishka; Zhao, Hongya; Maity, Sankar N; Navone, Nora M; Gorlova, Olga Y; Troncoso, Patricia; Pettaway, Curtis A; Byun, Jin Young

    2010-01-01

    The genetic control of prostate cancer development is poorly understood. Large numbers of gene-expression datasets on different aspects of prostate tumorigenesis are available. We used these data to identify and prioritize candidate genes associated with the development of prostate cancer and bone metastases. Our working hypothesis was that combining meta-analyses on different but overlapping steps of prostate tumorigenesis will improve identification of genes associated with prostate cancer development. A Z score-based meta-analysis of gene-expression data was used to identify candidate genes associated with prostate cancer development. To put together different datasets, we conducted a meta-analysis on 3 levels that follow the natural history of prostate cancer development. For experimental verification of candidates, we used in silico validation as well as in-house gene-expression data. Genes with experimental evidence of an association with prostate cancer development were overrepresented among our top candidates. The meta-analysis also identified a considerable number of novel candidate genes with no published evidence of a role in prostate cancer development. Functional annotation identified cytoskeleton, cell adhesion, extracellular matrix, and cell motility as the top functions associated with prostate cancer development. We identified 10 genes--CDC2, CCNA2, IGF1, EGR1, SRF, CTGF, CCL2, CAV1, SMAD4, and AURKA--that form hubs of the interaction network and therefore are likely to be primary drivers of prostate cancer development. By using this large 3-level meta-analysis of the gene-expression data to identify candidate genes associated with prostate cancer development, we have generated a list of candidate genes that may be a useful resource for researchers studying the molecular mechanisms underlying prostate cancer development

  2. Differential gene expression between African American and European American colorectal cancer patients.

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    Biljana Jovov

    Full Text Available The incidence and mortality of colorectal cancer (CRC is higher in African Americans (AAs than other ethnic groups in the U. S., but reasons for the disparities are unknown. We performed gene expression profiling of sporadic CRCs from AAs vs. European Americans (EAs to assess the contribution to CRC disparities. We evaluated the gene expression of 43 AA and 43 EA CRC tumors matched by stage and 40 matching normal colorectal tissues using the Agilent human whole genome 4x44K cDNA arrays. Gene and pathway analyses were performed using Significance Analysis of Microarrays (SAM, Ten-fold cross validation, and Ingenuity Pathway Analysis (IPA. SAM revealed that 95 genes were differentially expressed between AA and EA patients at a false discovery rate of ≤5%. Using IPA we determined that most prominent disease and pathway associations of differentially expressed genes were related to inflammation and immune response. Ten-fold cross validation demonstrated that following 10 genes can predict ethnicity with an accuracy of 94%: CRYBB2, PSPH, ADAL, VSIG10L, C17orf81, ANKRD36B, ZNF835, ARHGAP6, TRNT1 and WDR8. Expression of these 10 genes was validated by qRT-PCR in an independent test set of 28 patients (10 AA, 18 EA. Our results are the first to implicate differential gene expression in CRC racial disparities and indicate prominent difference in CRC inflammation between AA and EA patients. Differences in susceptibility to inflammation support the existence of distinct tumor microenvironments in these two patient populations.

  3. Sterol regulatory element binding protein-1 (SREBP1) gene expression is similarly increased in polycystic ovary syndrome and endometrial cancer.

    Science.gov (United States)

    Shafiee, Mohamad N; Mongan, Nigel; Seedhouse, Claire; Chapman, Caroline; Deen, Suha; Abu, Jafaru; Atiomo, William

    2017-05-01

    Women with polycystic ovary syndrome have a three-fold higher risk of endometrial cancer. Insulin resistance and hyperlipidemia may be pertinent factors in the pathogenesis of both conditions. The aim of this study was to investigate endometrial sterol regulatory element binding protein-1 gene expression in polycystic ovary syndrome and endometrial cancer endometrium, and to correlate endometrial sterol regulatory element binding protein-1 gene expression with serum lipid profiles. A cross-sectional study was performed at Nottingham University Hospital, UK. A total of 102 women (polycystic ovary syndrome, endometrial cancer and controls; 34 participants in each group) were recruited. Clinical and biochemical assessments were performed before endometrial biopsies were obtained from all participants. Taqman real-time polymerase chain reaction for endometrial sterol regulatory element binding protein-1 gene and its systemic protein expression were analyzed. The body mass indices of women with polycystic ovary syndrome (29.28 ± 2.91 kg/m 2 ) and controls (28.58 ± 2.62 kg/m 2 ) were not significantly different. Women with endometrial cancer had a higher mean body mass index (32.22 ± 5.70 kg/m 2 ). Sterol regulatory element binding protein-1 gene expression was significantly increased in polycystic ovary syndrome and endometrial cancer endometrium compared with controls (p ovary syndrome, but this was not statistically significant. Similarly, statistically insignificant positive correlations were found between endometrial sterol regulatory element binding protein-1 gene expression and body mass index in endometrial cancer (r = 0.643, p = 0.06) and waist-hip ratio (r = 0.096, p = 0.073). Sterol regulatory element binding protein-1 gene expression was significantly positively correlated with triglyceride in both polycystic ovary syndrome and endometrial cancer (p = 0.028 and p = 0.027, respectively). Quantitative serum sterol regulatory element

  4. Cyclophilin B as a co-regulator of prolactin-induced gene expression and function in breast cancer cells.

    Science.gov (United States)

    Fang, Feng; Zheng, Jiamao; Galbaugh, Traci L; Fiorillo, Alyson A; Hjort, Elizabeth E; Zeng, Xianke; Clevenger, Charles V

    2010-06-01

    The effects of prolactin (PRL) during the pathogenesis of breast cancer are mediated in part though Stat5 activity enhanced by its interaction with its transcriptional inducer, the prolyl isomerase cyclophilin B (CypB). We have demonstrated that knockdown of CypB decreases cell growth, proliferation, and migration, and CypB expression is associated with malignant progression of breast cancer. In this study, we examined the effect of CypB knockdown on PRL signaling in breast cancer cells. CypB knockdown with two independent siRNAs was shown to impair PRL-induced reporter expression in breast cancer cell line. cDNA microarray analysis was performed on these cells to assess the effect of CypB reduction, and revealed a significant decrease in PRL-induced endogenous gene expression in two breast cancer cell lines. Parallel functional assays revealed corresponding alterations of both anchorage-independent cell growth and cell motility of breast cancer cells. Our results demonstrate that CypB expression levels significantly modulate PRL-induced function in breast cancer cells ultimately resulting in enhanced levels of PRL-responsive gene expression, cell growth, and migration. Given the increasingly appreciated role of PRL in the pathogenesis of breast cancer, the actions of CypB detailed here are of biological significance.

  5. The Y-located gonadoblastoma gene TSPY amplifies its own expression through a positive feedback loop in prostate cancer cells

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    Kido, Tatsuo; Lau, Yun-Fai Chris, E-mail: Chris.Lau@UCSF.edu

    2014-03-28

    Highlights: • Y-encoded proto-oncoprotein TSPY amplifies its expression level via a positive feedback loop. • TSPY binds to the chromatin/DNA at exon 1 of TSPY gene. • TSPY enhances the gene expression in a TSPY exon 1 sequence dependent manner. • The conserved SET/NAP-domain is essential for TSPY transactivation. • Insights on probable mechanisms on TSPY exacerbation on cancer development in men. - Abstract: The testis-specific protein Y-encoded (TSPY) is a repetitive gene located on the gonadoblastoma region of the Y chromosome, and has been considered to be the putative gene for this oncogenic locus on the male-only chromosome. It is expressed in spermatogonial cells and spermatocytes in normal human testis, but abundantly in gonadoblastoma, testicular germ cell tumors and a variety of somatic cancers, including melanoma, hepatocellular carcinoma and prostate cancer. Various studies suggest that TSPY accelerates cell proliferation and growth, and promotes tumorigenesis. In this report, we show that TSPY could bind directly to the chromatin/DNA at exon 1 of its own gene, and greatly enhance the transcriptional activities of the endogenous gene in the LNCaP prostate cancer cells. Domain mapping analyses of TSPY have localized the critical and sufficient domain to the SET/NAP-domain. These results suggest that TSPY could efficiently amplify its expression and oncogenic functions through a positive feedback loop, and contribute to the overall tumorigenic processes when it is expressed in various human cancers.

  6. Decreased expression of the ARID1A gene is associated with poor prognosis in primary gastric cancer.

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    Dan-dan Wang

    Full Text Available BACKGROUND: The ARID1A gene encodes adenine-thymine (AT-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. ARID1A has been showed to function as a tumor suppressor in various cancer types. In the current study, we investigated the expression and prognosis value of ARID1A in primary gastric cancer. Meanwhile, the biological role of ARID1A was further investigated using cell model in vitro. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of ARID1A gene in primary gastric cancer pathogenesis, real-time quantitative PCR and western blotting were used to examine the ARID1A expression in paired cancerous and noncancerous tissues. Results revealed decreased ARID1A mRNA (P = 0.0029 and protein (P = 0.0015 expression in most tumor-bearing tissues compared with the matched adjacent non-tumor tissues, and in gastric cancer cell lines. To further investigate the clinicopathological and prognostic roles of ARID1A expression, we performed immunohistochemical analyses of the 224 paraffin-embedded gastric cancer tissue blocks. Data revealed that the loss of ARID1A expression was significantly correlated with T stage (P = 0.001 and grade (P = 0.006. Consistent with these results, we found that loss of ARID1A expression was significantly correlated with poor survival in gastric cancer patients (P = 0.003. Cox regression analyses showed that ARID1A expression was an independent predictor of overall survival (P = 0.029. Furthermore, the functions of ARID1A in the proliferation and colony formation of gastric cell lines were analyzed by transfecting cells with full-length ARID1A expression vector or siRNA targeting ARID1A. Restoring ARID1A expression in gastric cancer cells significantly inhibited cell proliferation and colony formation. Silencing ARID1A expression in gastric epithelial cell line significantly enhanced cell growth rate. CONCLUSIONS/SIGNIFICANCE: Our data suggest that ARID1A may play an important role

  7. Epigenetics-related genes in prostate cancer: expression profile in prostate cancer tissues, androgen-sensitive and -insensitive cell lines.

    Science.gov (United States)

    Shaikhibrahim, Zaki; Lindstrot, Andreas; Ochsenfahrt, Jacqueline; Fuchs, Kerstin; Wernert, Nicolas

    2013-01-01

    Epigenetic changes have been suggested to drive prostate cancer (PCa) development and progression. Therefore, in this study, we aimed to identify novel epigenetics-related genes in PCa tissues, and to examine their expression in metastatic PCa cell lines. We analyzed the expression of epigenetics-related genes via a clustering analysis based on gene function in moderately and poorly differentiated PCa glands compared to normal glands of the peripheral zone (prostate proper) from PCa patients using Whole Human Genome Oligo Microarrays. Our analysis identified 12 epigenetics-related genes with a more than 2-fold increase or decrease in expression and a p-value epigenetics-related genes that we identified in primary PCa tissues may provide further insight into the role that epigenetic changes play in PCa. Moreover, some of the genes that we identified may play important roles in primary PCa and metastasis, in primary PCa only, or in metastasis only. Follow-up studies are required to investigate the functional role and the role that the expression of these genes play in the outcome and progression of PCa using tissue microarrays.

  8. Identification of differentially expressed genes and biological pathways in bladder cancer

    Science.gov (United States)

    Tang, Fucai; He, Zhaohui; Lei, Hanqi; Chen, Yuehan; Lu, Zechao; Zeng, Guohua; Wang, Hangtao

    2018-01-01

    The purpose of the present study was to identify key genes and investigate the related molecular mechanisms of bladder cancer (BC) progression. From the Gene Expression Omnibus database, the gene expression dataset GSE7476 was downloaded, which contained 43 BC samples and 12 normal bladder tissues. GSE7476 was analyzed to screen the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for the DEGs using the DAVID database, and a protein-protein interaction (PPI) network was then constructed using Cytoscape software. The results of the GO analysis showed that the upregulated DEGs were significantly enriched in cell division, nucleoplasm and protein binding, while the downregulated DEGs were significantly enriched in ‘extracellular matrix organization’, ‘proteinaceous extracellular matrix’ and ‘heparin binding’. The results of the KEGG pathway analysis showed that the upregulated DEGs were significantly enriched in the ‘cell cycle’, whereas the downregulated DEGs were significantly enriched in ‘complement and coagulation cascades’. JUN, cyclin-dependent kinase 1, FOS, PCNA, TOP2A, CCND1 and CDH1 were found to be hub genes in the PPI network. Sub-networks revealed that these gene were enriched in significant pathways, including the ‘cell cycle’ signaling pathway and ‘PI3K-Akt signaling pathway’. In summary, the present study identified DEGs and key target genes in the progression of BC, providing potential molecular targets and diagnostic biomarkers for the treatment of BC. PMID:29532898

  9. Cross-platform analysis of cancer microarray data improves gene expression based classification of phenotypes

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    Eils Roland

    2005-11-01

    Full Text Available Abstract Background The extensive use of DNA microarray technology in the characterization of the cell transcriptome is leading to an ever increasing amount of microarray data from cancer studies. Although similar questions for the same type of cancer are addressed in these different studies, a comparative analysis of their results is hampered by the use of heterogeneous microarray platforms and analysis methods. Results In contrast to a meta-analysis approach where results of different studies are combined on an interpretative level, we investigate here how to directly integrate raw microarray data from different studies for the purpose of supervised classification analysis. We use median rank scores and quantile discretization to derive numerically comparable measures of gene expression from different platforms. These transformed data are then used for training of classifiers based on support vector machines. We apply this approach to six publicly available cancer microarray gene expression data sets, which consist of three pairs of studies, each examining the same type of cancer, i.e. breast cancer, prostate cancer or acute myeloid leukemia. For each pair, one study was performed by means of cDNA microarrays and the other by means of oligonucleotide microarrays. In each pair, high classification accuracies (> 85% were achieved with training and testing on data instances randomly chosen from both data sets in a cross-validation analysis. To exemplify the potential of this cross-platform classification analysis, we use two leukemia microarray data sets to show that important genes with regard to the biology of leukemia are selected in an integrated analysis, which are missed in either single-set analysis. Conclusion Cross-platform classification of multiple cancer microarray data sets yields discriminative gene expression signatures that are found and validated on a large number of microarray samples, generated by different laboratories and

  10. Gradient phenomenon of multidrug resistance gene expression in breast cancer during neoadjuvant chemotherapy is related to disease progression

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    N. V. Litviakov

    2013-01-01

    Full Text Available The paper examined 106 patients with breast cancer (BC treated with neoadjuvant chemotherapy (NАС. In the biopsy material, derived from primary tumor before NAC and surgical samples after chemotherapy the expression of 8 multidrug resistance genes (MDR ABCB1, АВСВ2, ABCC1, ABCC2, АВСС5, ABCG1, ABCG2 и MVP was evaluated using quantitative RT-PCR. During the NAC course 75 % of patients manifested gradient phenomenon for gene expression that means a unidirectional change in the expression of all five MDR genes ABCB1, ABCC1, ABCC2, ABCG1 и ABCG2 closely associated with the NAC efficacy: the reduction in MDR gene expression was related to good response to NAC while the expression increase associated with poor response to NAC. In 25% of patients there was no such change in studied gene expression that means the lack of a gradient phenomenon. The objective was to study whether gradient phenomenon for MDR gene expression during NAC is related to disease free survival in breast cancer patients. Five-year metastasis-free survival in patients having a gradient phenomenon was 73 % versus 39 % in patients who lack a gradient phenomenon (log-rank test p=0,0018. So, the presence of a gradient phenomenon in patients is appeared to be associated with a good disease prognosis. It is assumed that the gradiThe paper examined 106 patients with breast cancer (BC treated with neoadjuvant chemotherapy (NАС. In the biopsy material, derived from primary tumor before NAC and surgical samples after chemotherapy the expression of 8 multidrug resistance genes (MDR ABCB1, АВСВ2, ABCC1, ABCC2, АВСС5, ABCG1, ABCG2 и MVP was evaluated using quantitative RT-PCR. During the NAC course 75 % of patients manifested gradient phenomenon for gene expression that means a unidirectional change in the expression of all five MDR genes ABCB1, ABCC1, ABCC2, ABCG1 и ABCG2 closely associated with the NAC efficacy: the reduction in MDR gene expression was related to good

  11. Gene expression meta-analysis identifies chromosomal regions involved in ovarian cancer survival

    DEFF Research Database (Denmark)

    Thomassen, Mads; Jochumsen, Kirsten M; Mogensen, Ole

    2009-01-01

    the relation of gene expression and chromosomal position to identify chromosomal regions of importance for early recurrence of ovarian cancer. By use of *Gene Set Enrichment Analysis*, we have ranked chromosomal regions according to their association to survival. Over-representation analysis including 1...... using death (P = 0.015) and recurrence (P = 0.002) as outcome. The combined mutation score is strongly associated to upregulation of several growth factor pathways....

  12. The action of a dietary retinoid on gene expression and cancer induction in electron-irradiated rat skin

    International Nuclear Information System (INIS)

    Burns, F.J.; Chen, S.; Xu, G.; Wu, F.; Tang, M.S.

    2002-01-01

    Current models of radiation carcinogenesis generally assume that the DNA is damaged in a variety of ways by the radiation and that subsequent cell divisions contribute to the conversion of the damage to heritable mutations. Cancer may seem complex and intractable, but its complexity provides multiple opportunities for preventive interventions. Mitotic inhibitors are among the strongest cancer preventive agents, not only slowing the growth rate of preneoplasias but also increasing the fidelity of DNA repair processes. Ionizing radiation, including electrons, is a strong inducer of cancer in rat skin, and dietary retinoids have shown potent cancer preventive activity in the same system. A non-toxic dietary dose of retinyl acetate altered gene expression levels 24 hours after electron irradiation of rat skin. Of the 8740 genes on an Affymetrix rat expression array, the radiation significantly (5 fold or higher) altered 188, while the retinoid altered 231, including 16 radiation-altered genes that were reversely altered. While radiation strongly affected the expression of stress response, immune/inflammation and nucleic acid metabolism genes, the retinoid most strongly affected proliferation-related genes, including some significant reversals, such as, keratin 14, retinol binding protein, and calcium binding proteins. These results point to reversal of proliferation-relevant genes as a likely basis for the anti-radiogenic effects of dietary retinyl acetate. (author)

  13. Dissecting Time- from Tumor-Related Gene Expression Variability in Bilateral Breast Cancer

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    Maurizio Callari

    2018-01-01

    Full Text Available Metachronous (MBC and synchronous bilateral breast tumors (SBC are mostly distinct primaries, whereas paired primaries and their local recurrences (LRC share a common origin. Intra-pair gene expression variability in MBC, SBC, and LRC derives from time/tumor microenvironment-related and tumor genetic background-related factors and pairs represents an ideal model for trying to dissect tumor-related from microenvironment-related variability. Pairs of tumors derived from women with SBC (n = 18, MBC (n = 11, and LRC (n = 10 undergoing local-regional treatment were profiled for gene expression; similarity between pairs was measured using an intraclass correlation coefficient (ICC computed for each gene and compared using analysis of variance (ANOVA. When considering biologically unselected genes, the highest correlations were found for primaries and paired LRC, and the lowest for MBC pairs. By instead limiting the analysis to the breast cancer intrinsic genes, correlations between primaries and paired LRC were enhanced, while lower similarities were observed for SBC and MBC. Focusing on stromal-related genes, the ICC values decreased for MBC and were significantly different from SBC. These findings indicate that it is possible to dissect intra-pair gene expression variability into components that are associated with genetic origin or with time and microenvironment by using specific gene subsets.

  14. Gene Expression Analyses of HER-2/neu and ESR1 in Patients with Breast Cancer

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    Omid Kheyri Nadergoli

    2017-10-01

    Full Text Available ABSTRACT Background: Her-2 and ESR1 genes, that interact in the cell signaling pathway, are the most important molecular markers of breast cancer, which have been amplified or overexpressed in 30% and 70%, respectively. This study was performed to evaluate the gene expression levels of Her-2 and ESR1 genes in tumor cells and its adjacent normal tissue of breast cancer patients and compared them whit clinical-pathological features. Methods: In total, 80 tissue specimens from 40 patients, with an average age of 48.47 years, were examined by Real-time PCR technique, and ultimately evaluated the expression level of Her-2 and ESR1genes. The data were analyzed by REST 2009 V2.0.13 statistical software. Results: HER2 and ESR1 overexpression was identified in 19 (48% and 12 (30% of 40 patients respectively, which was higher and lower than that recorded in international statistics, respectively. ESR1 overexpression was associated with Stage 3A and lymph node involvement 2 (N2 (P = 0.04 and P = 0.047, respectively. No significant correlation was observed between the expression of HER2 and ESR1 and other clinical-pathological features, however, the relative differences were identified in the expression levels of genes between main group and groups that were classified according to the clinical-pathological features and age. Conclusions: Overexpression of Her-2 and ESR1 genes in the patients of our study are higher and lower than international statistics, respectively, indicating the differences in genetic, environmental and ethnic factors that involved in the developing of breast cancer.

  15. A sparse regulatory network of copy-number driven gene expression reveals putative breast cancer oncogenes.

    Science.gov (United States)

    Yuan, Yinyin; Curtis, Christina; Caldas, Carlos; Markowetz, Florian

    2012-01-01

    Copy number aberrations are recognized to be important in cancer as they may localize to regions harboring oncogenes or tumor suppressors. Such genomic alterations mediate phenotypic changes through their impact on expression. Both cis- and transacting alterations are important since they may help to elucidate putative cancer genes. However, amidst numerous passenger genes, trans-effects are less well studied due to the computational difficulty in detecting weak and sparse signals in the data, and yet may influence multiple genes on a global scale. We propose an integrative approach to learn a sparse interaction network of DNA copy-number regions with their downstream transcriptional targets in breast cancer. With respect to goodness of fit on both simulated and real data, the performance of sparse network inference is no worse than other state-of-the-art models but with the advantage of simultaneous feature selection and efficiency. The DNA-RNA interaction network helps to distinguish copy-number driven expression alterations from those that are copy-number independent. Further, our approach yields a quantitative copy-number dependency score, which distinguishes cis- versus trans-effects. When applied to a breast cancer data set, numerous expression profiles were impacted by cis-acting copy-number alterations, including several known oncogenes such as GRB7, ERBB2, and LSM1. Several trans-acting alterations were also identified, impacting genes such as ADAM2 and BAGE, which warrant further investigation. An R package named lol is available from www.markowetzlab.org/software/lol.html.

  16. The gene expression profiles of canine mammary cancer cells grown with carcinoma-associated fibroblasts (CAFs as a co-culture in vitro

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    Król Magdalena

    2012-03-01

    Full Text Available Abstract Background It is supposed that fibroblasts present in tumour microenvironment increase cancer invasiveness and its ability to metastasize but the mechanisms have not been clearly defined yet. Thus, the current study was designed to assess changes in gene expression in five various cancer cell lines grown as a co-culture with the carcinoma-associated fibroblasts (CAFs in vitro. Results A carcinoma-associated fibroblast cell line was isolated from a canine mammary cancer. Then, a co-culture of cancer cells with the CAFs was established and maintained for 72 hrs. Having sorted the cells, a global gene expression in cancer cells using DNA microarrays was examined. The analysis revealed an up-regulation of 100 genes and a down-regulation of 106 genes in the cancer cells grown as a co-culture with the CAFs in comparison to control conditions. The PANTHER binomial statistics tool was applied to determine statistically over-manifested pathways (p Conclusion The results of the current study showed that the co-culturing of cancer cells and the CAFs caused significant changes to the cancer gene expression. The presence of the CAFs in a microenvironment of cancer cells promotes adhesion, angiogenesis and EMT.

  17. Gene expression profile of colon cancer cell lines treated with SN-38

    DEFF Research Database (Denmark)

    Wallin, A; Francis, P; Nilbert, M

    2010-01-01

    the incidence in fact has increased. To improve chemotherapy and enable personalised treatment, the need of biomarkers is of great significance. In this study, we evaluated the gene expression profiles of the colon cancer cell lines treated with SN-38, the active metabolite of topoisomerase-1 inhibitor......Colorectal cancer is the third most common form of cancer in the industrial countries. Due to advances regarding the treatments, primarily development of improved surgical methods and the ability to make the earlier diagnosis, the mortality has remained constant during the past decades even though...

  18. A network-based gene expression signature informs prognosis and treatment for colorectal cancer patients.

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    Mingguang Shi

    Full Text Available Several studies have reported gene expression signatures that predict recurrence risk in stage II and III colorectal cancer (CRC patients with minimal gene membership overlap and undefined biological relevance. The goal of this study was to investigate biological themes underlying these signatures, to infer genes of potential mechanistic importance to the CRC recurrence phenotype and to test whether accurate prognostic models can be developed using mechanistically important genes.We investigated eight published CRC gene expression signatures and found no functional convergence in Gene Ontology enrichment analysis. Using a random walk-based approach, we integrated these signatures and publicly available somatic mutation data on a protein-protein interaction network and inferred 487 genes that were plausible candidate molecular underpinnings for the CRC recurrence phenotype. We named the list of 487 genes a NEM signature because it integrated information from Network, Expression, and Mutation. The signature showed significant enrichment in four biological processes closely related to cancer pathophysiology and provided good coverage of known oncogenes, tumor suppressors, and CRC-related signaling pathways. A NEM signature-based Survival Support Vector Machine prognostic model was trained using a microarray gene expression dataset and tested on an independent dataset. The model-based scores showed a 75.7% concordance with the real survival data and separated patients into two groups with significantly different relapse-free survival (p = 0.002. Similar results were obtained with reversed training and testing datasets (p = 0.007. Furthermore, adjuvant chemotherapy was significantly associated with prolonged survival of the high-risk patients (p = 0.006, but not beneficial to the low-risk patients (p = 0.491.The NEM signature not only reflects CRC biology but also informs patient prognosis and treatment response. Thus, the network

  19. EMX2 gene expression predicts liver metastasis and survival in colorectal cancer.

    Science.gov (United States)

    Aykut, Berk; Ochs, Markus; Radhakrishnan, Praveen; Brill, Adrian; Höcker, Hermine; Schwarz, Sandra; Weissinger, Daniel; Kehm, Roland; Kulu, Yakup; Ulrich, Alexis; Schneider, Martin

    2017-08-22

    The Empty Spiracles Homeobox (EMX-) 2 gene has been associated with regulation of growth and differentiation in neuronal development. While recent studies provide evidence that EMX2 regulates tumorigenesis of various solid tumors, its role in colorectal cancer remains unknown. We aimed to assess the prognostic significance of EMX2 expression in stage III colorectal adenocarcinoma. Expression levels of EMX2 in human colorectal cancer and adjacent mucosa were assessed by qRT-PCR technology, and results were correlated with clinical and survival data. siRNA-mediated knockdown and adenoviral delivery-mediated overexpression of EMX2 were performed in order to investigate its effects on the migration of colorectal cancer cells in vitro. Compared to corresponding healthy mucosa, colorectal tumor samples had decreased EMX2 expression levels. Furthermore, EMX2 down-regulation in colorectal cancer tissue was associated with distant metastasis (M1) and impaired overall patient survival. In vitro knockdown of EMX2 resulted in increased tumor cell migration. Conversely, overexpression of EMX2 led to an inhibition of tumor cell migration. EMX2 is frequently down-regulated in human colorectal cancer, and down-regulation of EMX2 is a prognostic marker for disease-free and overall survival. EMX2 might thus represent a promising therapeutic target in colorectal cancer.

  20. Differential expression of the klf6 tumor suppressor gene upon cell damaging treatments in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Gehrau, Ricardo C.; D' Astolfo, Diego S.; Andreoli, Veronica [Centro de Investigaciones en Bioquimica Clinica e Inmunologia (CIBICI-CONICET), Departamento de Bioquimica Clinica, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5000 Cordoba (Argentina); Bocco, Jose L., E-mail: jbocco@fcq.unc.edu.ar [Centro de Investigaciones en Bioquimica Clinica e Inmunologia (CIBICI-CONICET), Departamento de Bioquimica Clinica, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5000 Cordoba (Argentina); Koritschoner, Nicolas P. [Centro de Investigaciones en Bioquimica Clinica e Inmunologia (CIBICI-CONICET), Departamento de Bioquimica Clinica, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5000 Cordoba (Argentina)

    2011-02-10

    The mammalian Krueppel-like factor 6 (KLF6) is involved in critical roles such as growth-related signal transduction, cell proliferation and differentiation, development, apoptosis and angiogenesis. Also, KLF6 appears to be an emerging key factor during cancer development and progression. Its expression is thoroughly regulated by several cell-damaging stimuli. DNA damaging agents at lethal concentrations induce a p53-independent down-regulation of the klf6 gene. To investigate the impact of external stimuli on human klf6 gene expression, its mRNA level was analyzed using a cancer cell line profiling array system, consisting in an assortment of immobilized cDNAs from multiple cell lines treated with several cell-damaging agents at growth inhibitory concentrations (IC{sub 50}). Cell-damaging agents affected the klf6 expression in 62% of the cDNA samples, though the expression pattern was not dependent on the cell origin type. Interestingly, significant differences (p < 0.0001) in KLF6 mRNA levels were observed depending on the cellular p53 status upon cell damage. KLF6 expression was significantly increased in 63% of p53-deficient cells (122/195). Conversely, KLF6 mRNA level decreased nearly 4 fold in more than 70% of p53+/+ cells. In addition, klf6 gene promoter activity was down-regulated by DNA damaging agents in cells expressing the functional p53 protein whereas it was moderately increased in the absence of functional p53. Consistent results were obtained for the endogenous KLF6 protein level. Results indicate that human klf6 gene expression is responsive to external cell damage mediated by IC{sub 50} concentrations of physical and chemical stimuli in a p53-dependent manner. Most of these agents are frequently used in cancer therapy. Induction of klf6 expression in the absence of functional p53 directly correlates with cell death triggered by these compounds, whereas it is down-regulated in p53+/+ cells. Hence, klf6 expression level could represent a valuable

  1. Integrated analysis of gene expression, CpG island methylation, and gene copy number in breast cancer cells by deep sequencing.

    Directory of Open Access Journals (Sweden)

    Zhifu Sun

    Full Text Available We used deep sequencing technology to profile the transcriptome, gene copy number, and CpG island methylation status simultaneously in eight commonly used breast cell lines to develop a model for how these genomic features are integrated in estrogen receptor positive (ER+ and negative breast cancer. Total mRNA sequence, gene copy number, and genomic CpG island methylation were carried out using the Illumina Genome Analyzer. Sequences were mapped to the human genome to obtain digitized gene expression data, DNA copy number in reference to the non-tumor cell line (MCF10A, and methylation status of 21,570 CpG islands to identify differentially expressed genes that were correlated with methylation or copy number changes. These were evaluated in a dataset from 129 primary breast tumors. Gene expression in cell lines was dominated by ER-associated genes. ER+ and ER- cell lines formed two distinct, stable clusters, and 1,873 genes were differentially expressed in the two groups. Part of chromosome 8 was deleted in all ER- cells and part of chromosome 17 amplified in all ER+ cells. These loci encoded 30 genes that were overexpressed in ER+ cells; 9 of these genes were overexpressed in ER+ tumors. We identified 149 differentially expressed genes that exhibited differential methylation of one or more CpG islands within 5 kb of the 5' end of the gene and for which mRNA abundance was inversely correlated with CpG island methylation status. In primary tumors we identified 84 genes that appear to be robust components of the methylation signature that we identified in ER+ cell lines. Our analyses reveal a global pattern of differential CpG island methylation that contributes to the transcriptome landscape of ER+ and ER- breast cancer cells and tumors. The role of gene amplification/deletion appears to more modest, although several potentially significant genes appear to be regulated by copy number aberrations.

  2. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks | Center for Cancer Research

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    The purpose of this study was to develop a method of classifying cancers to specific diagnostic categories based on their gene expression signatures using artificial neural networks (ANNs). We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancers belong to four distinct diagnostic categories and often present diagnostic dilemmas in

  3. Imaging gene expression in gene therapy

    International Nuclear Information System (INIS)

    Wiebe, Leonard I.

    1997-01-01

    Full text. Gene therapy can be used to introduce new genes, or to supplement the function of indigenous genes. At the present time, however, there is non-invasive test to demonstrate efficacy of the gene transfer and expression processes. It has been postulated that scintigraphic imaging can offer unique information on both the site at which the transferred gene is expressed, and the degree of expression, both of which are critical issue for safety and clinical efficacy. Many current studies are based on 'suicide gene therapy' of cancer. Cells modified to express these genes commit metabolic suicide in the presence of an enzyme encoded by the transferred gene and a specifically-convertible pro drug. Pro drug metabolism can lead to selective metabolic trapping, required for scintigraphy. Herpes simplex virus type-1 thymidine kinase (H S V-1 t k + ) has been use for 'suicide' in vivo tumor gene therapy. It has been proposed that radiolabelled nucleosides can be used as radiopharmaceuticals to detect H S V-1 t k + gene expression where the H S V-1 t k + gene serves a reporter or therapeutic function. Animal gene therapy models have been studied using purine-([ 18 F]F H P G; [ 18 F]-A C V), and pyrimidine- ([ 123 / 131 I]I V R F U; [ 124 / 131I ]) antiviral nucleosides. Principles of gene therapy and gene therapy imaging will be reviewed and experimental data for [ 123 / 131I ]I V R F U imaging with the H S V-1 t k + reporter gene will be presented

  4. An enhanced deterministic K-Means clustering algorithm for cancer subtype prediction from gene expression data.

    Science.gov (United States)

    Nidheesh, N; Abdul Nazeer, K A; Ameer, P M

    2017-12-01

    Clustering algorithms with steps involving randomness usually give different results on different executions for the same dataset. This non-deterministic nature of algorithms such as the K-Means clustering algorithm limits their applicability in areas such as cancer subtype prediction using gene expression data. It is hard to sensibly compare the results of such algorithms with those of other algorithms. The non-deterministic nature of K-Means is due to its random selection of data points as initial centroids. We propose an improved, density based version of K-Means, which involves a novel and systematic method for selecting initial centroids. The key idea of the algorithm is to select data points which belong to dense regions and which are adequately separated in feature space as the initial centroids. We compared the proposed algorithm to a set of eleven widely used single clustering algorithms and a prominent ensemble clustering algorithm which is being used for cancer data classification, based on the performances on a set of datasets comprising ten cancer gene expression datasets. The proposed algorithm has shown better overall performance than the others. There is a pressing need in the Biomedical domain for simple, easy-to-use and more accurate Machine Learning tools for cancer subtype prediction. The proposed algorithm is simple, easy-to-use and gives stable results. Moreover, it provides comparatively better predictions of cancer subtypes from gene expression data. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Insulin-Like Growth Factor-1 Inscribes a Gene Expression Profile for Angiogenic Factors and Cancer Progression in Breast Epithelial Cells

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    J.S. Oh

    2002-01-01

    Full Text Available Activation of the insulin-like growth factor-1 receptor (IGF-11R by IGF-1 is associated with the risk and progression of many types of cancer, although despite this it remains unclear how activated IGF-1 R contributes to cancer progression. In this study, gene expression changes elicited by IGF-1 were profiled in breast epithelial cells. We noted that many genes are functionally linked to cancer progression and angiogenesis. To validate some of the changes observed, the RNA and/or protein was confirmed for c-fos, cytochrome P4501Al, cytochrome P450 1131, interleukin-1 beta, fas ligand, vascular endothelial growth factor, and urokinase plasminogen activator. Nuclear proteins were also temporally monitored to address how gene expression changes were regulated. We found that IGF-1 stimulated the nuclear translocation of phosphorylated AKT, hypoxic-inducible factor-1 alpha, and phosphorylated cAMP-responsive element-binding protein, which correlated with temporal changes in gene expression. Next, the promoter regions of IGF-1-regulated genes were searched in silico. The promoters of genes that clustered together had similar regulatory regions. In summary, IGF-1 inscribes a gene expression profile relevant to cancer progression, and this study provides insight into the mechanism(s whereby some of these changes occur.

  6. Lymphangiogenesis in cervical cancer evaluated by expression of the VEGF-C gene in clinical stage IB-IIIB

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    Magdalena Franc

    2015-02-01

    Full Text Available Introduction : The aim of the present study was to evaluate the profile of VEGF-C gene expression in particular stages of cervical cancer (IB-IIIB and to estimate the correlation between VEGF-C mRNA quantity profile and clinical stage. Material and methods : Material for molecular analysis consisted of cervical cancer tissue specimens collected from 38 women (10, 15, 13 cases were classified as IB, IIB and IIIB, respectively. The control group was composed of normal cervical tissues collected from 10 women who underwent hysterectomy for non-oncological reasons. The number of VEGF-C mRNA copies in particular groups was estimated by the reverse transcription quantitative polymerase chain reaction (RT-qPCR method. Results: In the control group the average number of mRNA copies was 134 ± 36 (median: 106, in a group with stage IB it was 16 077 ± 7090 (median: 580, for stage IIB – 35 019 ± 8945 (median: 40 870. The highest number of mRNA VEGF-C copies was derived in a group of patients with cervical cancer of stage IIIB. The average quantity was 56 155 ± 12 470, whereas median 55 981. A statistically significantly higher level of VEGF-C gene expression was disclosed in cervical cancer specimens with stage IIB and IIIB than in the control group. In stage IIIB, the VEGF-C gene expression was significantly higher than in specimens derived from individuals in stage IB. Conclusions : In squamous cell carcinoma of the uterine cervix of stage IB-IIIB genes involved in lymphangio­genesis, especially VEGF-C , are expressed, which expression increases as the clinical stage of cervical cancer is higher.

  7. MO-DE-207B-03: Improved Cancer Classification Using Patient-Specific Biological Pathway Information Via Gene Expression Data

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    Young, M; Craft, D [Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)

    2016-06-15

    Purpose: To develop an efficient, pathway-based classification system using network biology statistics to assist in patient-specific response predictions to radiation and drug therapies across multiple cancer types. Methods: We developed PICS (Pathway Informed Classification System), a novel two-step cancer classification algorithm. In PICS, a matrix m of mRNA expression values for a patient cohort is collapsed into a matrix p of biological pathways. The entries of p, which we term pathway scores, are obtained from either principal component analysis (PCA), normal tissue centroid (NTC), or gene expression deviation (GED). The pathway score matrix is clustered using both k-means and hierarchical clustering, and a clustering is judged by how well it groups patients into distinct survival classes. The most effective pathway scoring/clustering combination, per clustering p-value, thus generates various ‘signatures’ for conventional and functional cancer classification. Results: PICS successfully regularized large dimension gene data, separated normal and cancerous tissues, and clustered a large patient cohort spanning six cancer types. Furthermore, PICS clustered patient cohorts into distinct, statistically-significant survival groups. For a suboptimally-debulked ovarian cancer set, the pathway-classified Kaplan-Meier survival curve (p = .00127) showed significant improvement over that of a prior gene expression-classified study (p = .0179). For a pancreatic cancer set, the pathway-classified Kaplan-Meier survival curve (p = .00141) showed significant improvement over that of a prior gene expression-classified study (p = .04). Pathway-based classification confirmed biomarkers for the pyrimidine, WNT-signaling, glycerophosphoglycerol, beta-alanine, and panthothenic acid pathways for ovarian cancer. Despite its robust nature, PICS requires significantly less run time than current pathway scoring methods. Conclusion: This work validates the PICS method to improve

  8. Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.

    Directory of Open Access Journals (Sweden)

    Melissa Rotunno

    2009-05-01

    Full Text Available Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs tested in candidate genes. We analyzed 25 SNPs (some previously untested in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS. Our findings emphasize the necessity of post

  9. Gene expression patterns in pancreatic tumors, cells and tissues.

    Directory of Open Access Journals (Sweden)

    Anson W Lowe

    2007-03-01

    Full Text Available Cancers of the pancreas originate from both the endocrine and exocrine elements of the organ, and represent a major cause of cancer-related death. This study provides a comprehensive assessment of gene expression for pancreatic tumors, the normal pancreas, and nonneoplastic pancreatic disease.DNA microarrays were used to assess the gene expression for surgically derived pancreatic adenocarcinomas, islet cell tumors, and mesenchymal tumors. The addition of normal pancreata, isolated islets, isolated pancreatic ducts, and pancreatic adenocarcinoma cell lines enhanced subsequent analysis by increasing the diversity in gene expression profiles obtained. Exocrine, endocrine, and mesenchymal tumors displayed unique gene expression profiles. Similarities in gene expression support the pancreatic duct as the origin of adenocarcinomas. In addition, genes highly expressed in other cancers and associated with specific signal transduction pathways were also found in pancreatic tumors.The scope of the present work was enhanced by the inclusion of publicly available datasets that encompass a wide spectrum of human tissues and enabled the identification of candidate genes that may serve diagnostic and therapeutic goals.

  10. Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

    Science.gov (United States)

    Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna

    2011-01-01

    Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute

  11. Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study

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    Skoog Lambert

    2006-06-01

    Full Text Available Abstract Background Postmenopausal hormone-replacement therapy (HRT increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. Methods We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. Results HRT use in patients with estrogen receptor (ER protein positive tumors (n = 72 was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. Conclusion Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.

  12. Enhancer of the rudimentary gene homologue (ERH expression pattern in sporadic human breast cancer and normal breast tissue

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    Knüchel Ruth

    2008-05-01

    Full Text Available Abstract Background The human gene ERH (Enhancer of the Rudimentary gene Homologue has previously been identified by in silico analysis of four million ESTs as a gene differentially expressed in breast cancer. The biological function of ERH protein has not been fully elucidated, however functions in cell cycle progression, pyrimidine metabolism a possible interaction with p21(Cip1/Waf1 via the Ciz1 zinc finger protein have been suggested. The aim of the present study was a systematic characterization of ERH expression in human breast cancer in order to evaluate possible clinical applications of this molecule. Methods The expression pattern of ERH was analyzed using multiple tissue northern blots (MTN on a panel of 16 normal human tissues and two sets of malignant/normal breast and ovarian tissue samples. ERH expression was further analyzed in breast cancer and normal breast tissues and in tumorigenic as well as non-tumorigenic breast cancer cell lines, using quantitative RT-PCR and non-radioisotopic in situ hybridization (ISH. Results Among normal human tissues, ERH expression was most abundant in testis, heart, ovary, prostate, and liver. In the two MTN sets of malignant/normal breast and ovarian tissue,ERH was clearly more abundantly expressed in all tumours than in normal tissue samples. Quantitative RT-PCR analyses showed that ERH expression was significantly more abundant in tumorigenic than in non-tumorigenic breast cancer cell lines (4.5-fold; p = 0.05, two-tailed Mann-Whitney U-test; the same trend was noted in a set of 25 primary invasive breast cancers and 16 normal breast tissue samples (2.5-fold; p = 0.1. These findings were further confirmed by non-radioisotopic ISH in human breast cancer and normal breast tissue. Conclusion ERH expression is clearly up-regulated in malignant as compared with benign breast cells both in primary human breast cancer and in cell models of breast cancer. Since similar results were obtained for ovarian

  13. Radiation Gene-expression Signatures in Primary Breast Cancer Cells.

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    Minafra, Luigi; Bravatà, Valentina; Cammarata, Francesco P; Russo, Giorgio; Gilardi, Maria C; Forte, Giusi I

    2018-05-01

    In breast cancer (BC) care, radiation therapy (RT) is an efficient treatment to control localized tumor. Radiobiological research is needed to understand molecular differences that affect radiosensitivity of different tumor subtypes and the response variability. The aim of this study was to analyze gene expression profiling (GEP) in primary BC cells following irradiation with doses of 9 Gy and 23 Gy delivered by intraoperative electron radiation therapy (IOERT) in order to define gene signatures of response to high doses of ionizing radiation. We performed GEP by cDNA microarrays and evaluated cell survival after IOERT treatment in primary BC cell cultures. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate candidate genes. We showed, for the first time, a 4-gene and a 6-gene signature, as new molecular biomarkers, in two primary BC cell cultures after exposure at 9 Gy and 23 Gy respectively, for which we observed a significantly high survival rate. Gene signatures activated by different doses of ionizing radiation may predict response to RT and contribute to defining a personalized biological-driven treatment plan. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  14. Antimetastatic gene expression profiles mediated by retinoic acid receptor beta 2 in MDA-MB-435 breast cancer cells

    International Nuclear Information System (INIS)

    Wallden, Brett; Emond, Mary; Swift, Mari E; Disis, Mary L; Swisshelm, Karen

    2005-01-01

    The retinoic acid receptor beta 2 (RARβ2) gene modulates proliferation and survival of cultured human breast cancer cells. Previously we showed that ectopic expression of RARβ2 in a mouse xenograft model prevented metastasis, even in the absence of the ligand, all-trans retinoic acid. We investigated both cultured cells and xenograft tumors in order to delineate the gene expression profiles responsible for an antimetastatic phenotype. RNA from MDA-MB-435 human breast cancer cells transduced with RARβ2 or empty retroviral vector (LXSN) was analyzed using Agilent Human 1A Oligo microarrays. The one hundred probes with the greatest differential intensity (p < 0.004, jointly) were determined by selecting the top median log ratios from eight-paired microarrays. Validation of differences in expression was done using Northern blot analysis and quantitative RT-PCR (qRT-PCR). We determined expression of selected genes in xenograft tumors. RARβ2 cells exhibit gene profiles with overrepresentation of genes from Xq28 (p = 2 × 10 -8 ), a cytogenetic region that contains a large portion of the cancer/testis antigen gene family. Other functions or factors impacted by the presence of exogenous RARβ2 include mediators of the immune response and transcriptional regulatory mechanisms. Thirteen of fifteen (87%) of the genes evaluated in xenograft tumors were consistent with differences we found in the cell cultures (p = 0.007). Antimetastatic RARβ2 signalling, direct or indirect, results in an elevation of expression for genes such as tumor-cell antigens (CTAG1 and CTAG2), those involved in innate immune response (e.g., RIG-I/DDX58), and tumor suppressor functions (e.g., TYRP1). Genes whose expression is diminished by RARβ2 signalling include cell adhesion functions (e.g, CD164) nutritional or metabolic processes (e.g., FABP6), and the transcription factor, JUN

  15. Ribavirin restores ESR1 gene expression and tamoxifen sensitivity in ESR1 negative breast cancer cell lines

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    Sappok Anne

    2011-12-01

    Full Text Available Abstract Tumor growth is estrogen independent in approximately one-third of all breast cancers, which makes these patients unresponsive to hormonal treatment. This unresponsiveness to hormonal treatment may be explained through the absence of the estrogen receptor alpha (ESR1. The ESR1 gene re-expression through epigenetic modulators such as DNA methyltransferase inhibitors and/or histone deacetylase inhibitors restores tamoxifen sensitivity in ESR1 negative breast cancer cell lines and opens new treatment horizons in patients who were previously associated with a poor prognosis. In the study presented herein, we tested the ability of ribavirin, which shares some structural similarities with the DNA-methyltransferase inhibitor 5-azacytidine and which is widely known as an anti-viral agent in the treatment of hepatitis C, to restore ESR1 gene re-expression in ESR1 negative breast cancer cell lines. In our study we identified ribavirin to restore ESR1 gene re-expression alone and even more in combination with suberoylanilide hydroxamic acid (SAHA - up to 276 fold induction. Ribavirin and analogs could pave the way to novel translational research projects that aim to restore ESR1 gene re-expression and thus the susceptibility to tamoxifen-based endocrine treatment strategies.

  16. Comparison of lung cancer cell lines representing four histopathological subtypes with gene expression profiling using quantitative real-time PCR

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    Kawaguchi Makoto

    2010-01-01

    Full Text Available Abstract Background Lung cancers are the most common type of human malignancy and are intractable. Lung cancers are generally classified into four histopathological subtypes: adenocarcinoma (AD, squamous cell carcinoma (SQ, large cell carcinoma (LC, and small cell carcinoma (SC. Molecular biological characterization of these subtypes has been performed mainly using DNA microarrays. In this study, we compared the gene expression profiles of these four subtypes using twelve human lung cancer cell lines and the more reliable quantitative real-time PCR (qPCR. Results We selected 100 genes from public DNA microarray data and examined them by DNA microarray analysis in eight test cell lines (A549, ABC-1, EBC-1, LK-2, LU65, LU99, STC 1, RERF-LC-MA and a normal control lung cell line (MRC-9. From this, we extracted 19 candidate genes. We quantified the expression of the 19 genes and a housekeeping gene, GAPDH, with qPCR, using the same eight cell lines plus four additional validation lung cancer cell lines (RERF-LC-MS, LC-1/sq, 86-2, and MS-1-L. Finally, we characterized the four subtypes of lung cancer cell lines using principal component analysis (PCA of gene expression profiling for 12 of the 19 genes (AMY2A, CDH1, FOXG1, IGSF3, ISL1, MALL, PLAU, RAB25, S100P, SLCO4A1, STMN1, and TGM2. The combined PCA and gene pathway analyses suggested that these genes were related to cell adhesion, growth, and invasion. S100P in AD cells and CDH1 in AD and SQ cells were identified as candidate markers of these lung cancer subtypes based on their upregulation and the results of PCA analysis. Immunohistochemistry for S100P and RAB25 was closely correlated to gene expression. Conclusions These results show that the four subtypes, represented by 12 lung cancer cell lines, were well characterized using qPCR and PCA for the 12 genes examined. Certain genes, in particular S100P and CDH1, may be especially important for distinguishing the different subtypes. Our results

  17. Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes

    International Nuclear Information System (INIS)

    Pascal, Laura E; Liu, Alvin Y; Vêncio, Ricardo ZN; Page, Laura S; Liebeskind, Emily S; Shadle, Christina P; Troisch, Pamela; Marzolf, Bruz; True, Lawrence D; Hood, Leroy E

    2009-01-01

    Prostate cancer cells in primary tumors have been typed CD10 - /CD13 - /CD24 hi /CD26 + /CD38 lo /CD44 - /CD104 - . This CD phenotype suggests a lineage relationship between cancer cells and luminal cells. The Gleason grade of tumors is a descriptive of tumor glandular differentiation. Higher Gleason scores are associated with treatment failure. CD26 + cancer cells were isolated from Gleason 3+3 (G3) and Gleason 4+4 (G4) tumors by cell sorting, and their gene expression or transcriptome was determined by Affymetrix DNA array analysis. Dataset analysis was used to determine gene expression similarities and differences between G3 and G4 as well as to prostate cancer cell lines and histologically normal prostate luminal cells. The G3 and G4 transcriptomes were compared to those of prostatic cell types of non-cancer, which included luminal, basal, stromal fibromuscular, and endothelial. A principal components analysis of the various transcriptome datasets indicated a closer relationship between luminal and G3 than luminal and G4. Dataset comparison also showed that the cancer transcriptomes differed substantially from those of prostate cancer cell lines. Genes differentially expressed in cancer are potential biomarkers for cancer detection, and those differentially expressed between G3 and G4 are potential biomarkers for disease stratification given that G4 cancer is associated with poor outcomes. Differentially expressed genes likely contribute to the prostate cancer phenotype and constitute the signatures of these particular cancer cell types

  18. Lung cancer gene expression database analysis incorporating prior knowledge with support vector machine-based classification method

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    Huang Desheng

    2009-07-01

    Full Text Available Abstract Background A reliable and precise classification is essential for successful diagnosis and treatment of cancer. Gene expression microarrays have provided the high-throughput platform to discover genomic biomarkers for cancer diagnosis and prognosis. Rational use of the available bioinformation can not only effectively remove or suppress noise in gene chips, but also avoid one-sided results of separate experiment. However, only some studies have been aware of the importance of prior information in cancer classification. Methods Together with the application of support vector machine as the discriminant approach, we proposed one modified method that incorporated prior knowledge into cancer classification based on gene expression data to improve accuracy. A public well-known dataset, Malignant pleural mesothelioma and lung adenocarcinoma gene expression database, was used in this study. Prior knowledge is viewed here as a means of directing the classifier using known lung adenocarcinoma related genes. The procedures were performed by software R 2.80. Results The modified method performed better after incorporating prior knowledge. Accuracy of the modified method improved from 98.86% to 100% in training set and from 98.51% to 99.06% in test set. The standard deviations of the modified method decreased from 0.26% to 0 in training set and from 3.04% to 2.10% in test set. Conclusion The method that incorporates prior knowledge into discriminant analysis could effectively improve the capacity and reduce the impact of noise. This idea may have good future not only in practice but also in methodology.

  19. Expression of Genes Involved in Cellular Adhesion and Extracellular Matrix Remodeling Correlates with Poor Survival of Patients with Renal Cancer.

    Science.gov (United States)

    Boguslawska, Joanna; Kedzierska, Hanna; Poplawski, Piotr; Rybicka, Beata; Tanski, Zbigniew; Piekielko-Witkowska, Agnieszka

    2016-06-01

    Renal cell carcinoma is the most common highly metastatic kidney malignancy. Adhesion has a crucial role in the metastatic process. TGF (transforming growth factor)-β1 is a pleiotropic cytokine that influences cancerous transformation. We hypothesized that 1) changes in the expression of adhesion related genes may influence survival rate of patients with renal cell carcinoma and 2) TGF-β1 may contribute to changed expression of adhesion related genes. Two-step quantitative real-time polymerase chain reaction arrays were used to analyze the expression of adhesion related genes in 77 tumors and matched pair controls. The prognostic significance of genes was evaluated in TCGA (The Cancer Genome Atlas) data on 468 patients with renal cell carcinoma. Quantitative real-time polymerase chain reaction and Western blot were applied for TGF-β1 analysis. TGF-β1 mediated regulation of gene expression was analyzed by TGF-β1 supplementation of Caki-2 cells and quantitative real-time polymerase chain reaction. The expression of 19 genes related to adhesion and extracellular matrix remodeling was statistically significantly disturbed in renal cell carcinoma compared with controls. The 10-gene expression signature (COL1A1, COL5A1, COL11A1, FN1, ICAM1, ITGAL, ITGAM, ITGB2, THBS2 and TIMP1) correlated with poor survival (HR 2.85, p = 5.7e-10). TGF-β1 expression was 22 times higher in renal cell carcinoma than in controls (p adhesion and extracellular matrix remodeling develops early during renal cell carcinoma carcinogenesis and correlates with poor survival. TGF-β1 contributes to changed expression of extracellular matrix and adhesion related genes. Bioinformatic analysis performed on a broad panel of cancers of nonkidney origin suggests that disturbed expression of genes related to extracellular matrix and adhesion may be a universal feature of cancerous progression. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All

  20. Preliminary screening of the radiosensitivity-associated genes on colorectal cancer

    International Nuclear Information System (INIS)

    Xing Chungen; Yang Xiaodong; Zhou Liying; Wu Yongyou; Jiang Yinfen; Dai Hong; Lv Xiaodong; Gong Wei

    2007-01-01

    The screening of radiosensitive genes of human colorectal cancer was made by gene chip. Two human colorectal cancer cell lines LOVO and SW480 were cultivated and the total RNA was extracted from at least lxl0 7 cells. Then the gene expression profiling was performed by HG-U133 Plus 2.0 Array and the difference of gene expression has been analyzed. The results shows that there are 16882 genes expressed in LOVO cell and 17114 genes expressed in SW480 cell through gene expression profiling. It has been found that the genes with 2-fold expressed differentially include 908 genes up-regulated and 1312 genes down-regulated. The same genes, such as Fas and NFkB which is up-regulated, Caspas6, and RAD21 which is down-regulated, have been proved to be related to radiosensitivity. The genes with high expression level including CEACAM5, THBS1, SERPINE2, ARL7, HPGD in LOVO cell may also be related to the radiosensitivity. And the genes with high expression level including SCD, NQ01, LYZ, KRT20, ATP1B1 in SW480 cell may be related to the radioresistance of human colorectal cancer. It could be concluded that the radiosensitivity of colorectal cancer can be reflected from gene and protein expression level. And gene expression profiling is a fast and sensitive tool to predict the radiosensitivity and screen radiosensitive genes of colorectal cancer. (authors)

  1. Imaging gene expression in gene therapy

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    Wiebe, Leonard I. [Alberta Univ., Edmonton (Canada). Noujaim Institute for Pharmaceutical Oncology Research

    1997-12-31

    Full text. Gene therapy can be used to introduce new genes, or to supplement the function of indigenous genes. At the present time, however, there is non-invasive test to demonstrate efficacy of the gene transfer and expression processes. It has been postulated that scintigraphic imaging can offer unique information on both the site at which the transferred gene is expressed, and the degree of expression, both of which are critical issue for safety and clinical efficacy. Many current studies are based on `suicide gene therapy` of cancer. Cells modified to express these genes commit metabolic suicide in the presence of an enzyme encoded by the transferred gene and a specifically-convertible pro drug. Pro drug metabolism can lead to selective metabolic trapping, required for scintigraphy. Herpes simplex virus type-1 thymidine kinase (H S V-1 t k{sup +}) has been use for `suicide` in vivo tumor gene therapy. It has been proposed that radiolabelled nucleosides can be used as radiopharmaceuticals to detect H S V-1 t k{sup +} gene expression where the H S V-1 t k{sup +} gene serves a reporter or therapeutic function. Animal gene therapy models have been studied using purine-([{sup 18} F]F H P G; [{sup 18} F]-A C V), and pyrimidine- ([{sup 123}/{sup 131} I]I V R F U; [{sup 124}/{sup 131I}]) antiviral nucleosides. Principles of gene therapy and gene therapy imaging will be reviewed and experimental data for [{sup 123}/{sup 131I}]I V R F U imaging with the H S V-1 t k{sup +} reporter gene will be presented

  2. Statistical Considerations for Immunohistochemistry Panel Development after Gene Expression Profiling of Human Cancers

    Science.gov (United States)

    Betensky, Rebecca A.; Nutt, Catherine L.; Batchelor, Tracy T.; Louis, David N.

    2005-01-01

    In recent years there have been a number of microarray expression studies in which different types of tumors were classified by identifying a panel of differentially expressed genes. Immunohistochemistry is a practical and robust method for extending gene expression data to common pathological specimens with the advantage of being applicable to paraffin-embedded tissues. However, the number of assays required for successful immunohistochemical classification remains unclear. We propose a simulation-based method for assessing sample size for an immunohistochemistry investigation after a promising gene expression study of human tumors. The goals of such an immunohistochemistry study would be to develop and validate a marker panel that yields improved prognostic classification of cancer patients. We demonstrate how the preliminary gene expression data, coupled with certain realistic assumptions, can be used to estimate the number of immunohistochemical assays required for development. These assumptions are more tenable than alternative assumptions that would be required for crude analytic sample size calculations and that may yield underpowered and inefficient studies. We applied our methods to the design of an immunohistochemistry study for glioma classification and estimated the number of assays required to ensure satisfactory technical and prognostic validation. Simulation approaches for computing power and sample size that are based on existing gene expression data provide a powerful tool for efficient design of follow-up genomic studies. PMID:15858152

  3. Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection

    International Nuclear Information System (INIS)

    Gregg, Jennifer L; Brown, Kathleen E; Mintz, Eric M; Piontkivska, Helen; Fraizer, Gail C

    2010-01-01

    The prostate gland represents a multifaceted system in which prostate epithelia and stroma have distinct physiological roles. To understand the interaction between stroma and glandular epithelia, it is essential to delineate the gene expression profiles of these two tissue types in prostate cancer. Most studies have compared tumor and normal samples by performing global expression analysis using a mixture of cell populations. This report presents the first study of prostate tumor tissue that examines patterns of differential expression between specific cell types using laser capture microdissection (LCM). LCM was used to isolate distinct cell-type populations and identify their gene expression differences using oligonucleotide microarrays. Ten differentially expressed genes were then analyzed in paired tumor and non-neoplastic prostate tissues by quantitative real-time PCR. Expression patterns of the transcription factors, WT1 and EGR1, were further compared in established prostate cell lines. WT1 protein expression was also examined in prostate tissue microarrays using immunohistochemistry. The two-step method of laser capture and microarray analysis identified nearly 500 genes whose expression levels were significantly different in prostate epithelial versus stromal tissues. Several genes expressed in epithelial cells (WT1, GATA2, and FGFR-3) were more highly expressed in neoplastic than in non-neoplastic tissues; conversely several genes expressed in stromal cells (CCL5, CXCL13, IGF-1, FGF-2, and IGFBP3) were more highly expressed in non-neoplastic than in neoplastic tissues. Notably, EGR1 was also differentially expressed between epithelial and stromal tissues. Expression of WT1 and EGR1 in cell lines was consistent with these patterns of differential expression. Importantly, WT1 protein expression was demonstrated in tumor tissues and was absent in normal and benign tissues. The prostate represents a complex mix of cell types and there is a need to analyze

  4. EXSPRESSION OF MDR-GENES AND MONORESISTANCE GENES IN NON-SMALL-CELL LUNG CANCER

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    E. L. Yumov

    2014-01-01

    Full Text Available We studied the expression of multidrug resistance genes (MDR and monoresistance genes in normal bronchial tissue and tumor tissue of the non-small cell lung cancer (NSCLC after neoadjuvant chemotherapy (NACT (vinorelbine-carboplatine. The study included 30 patients with NSCLC (Т2–4N0–3M0. Normal bronchial tissue, normal lung tissue and tumor tissue collected during surgery following neoadjuvant chemotherapy (NACT served as a material of the study. The expression levels of MDR genes (ABCB1, ABCB2, ABCC1, ABCC2, ABCС5, ABCG1, ABCG2, GSTP and MVP, and monoresistance genes (BRCA1, ERCC1, RRM1, TOP1, TOP2A, TUBB3 and TYMS were estimated by quantitative reverse transcriptase PCR (RT-qPCR. The expression levels of some MDR genes and monoresistance genes (АВСВ1, АВСВ2, ABCG1, ERCC1, GSTP1 and MVP were significantly higher in the bronchi than in tumor tissue. The expression of ABCG1, ABCG2 and ERCC1 genes was higher in patients with T1-2 cancer than in patients with T3-4 cancer. Patients with adenocarcinoma had higher expression of BRCA1, MVP and ABCB1 genes than patients with squamous cell lung cancer. A tendency towards reduction in the expression level of MDR-genes and monoresistance genes was observed in patients with partial tumor regression compared to that observed in patients with stable disease. These findings were consistent with the previous data on reduction in the MDR-gene expression after chemotherapy with a good response in breast cancer patients.

  5. Gene Expression Programs in Response to Hypoxia: Cell Type Specificity and Prognostic Significance in Human Cancers.

    Directory of Open Access Journals (Sweden)

    2006-01-01

    Full Text Available BACKGROUND: Inadequate oxygen (hypoxia triggers a multifaceted cellular response that has important roles in normal physiology and in many human diseases. A transcription factor, hypoxia-inducible factor (HIF, plays a central role in the hypoxia response; its activity is regulated by the oxygen-dependent degradation of the HIF-1alpha protein. Despite the ubiquity and importance of hypoxia responses, little is known about the variation in the global transcriptional response to hypoxia among different cell types or how this variation might relate to tissue- and cell-specific diseases. METHODS AND FINDINGS: We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1alpha RNA in renal cells, and it could be diminished by reducing HIF-1alpha expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use. CONCLUSIONS: The transcriptional response to hypoxia varies among human cells. Some of this variation is traceable to variation in expression of the HIF1A gene. A gene-expression signature of the cellular response to hypoxia is associated with a significantly poorer prognosis

  6. Homeopathic medicines do not alter growth and gene expression in prostate and breast cancer cells in vitro.

    Science.gov (United States)

    Thangapazham, Rajesh L; Gaddipati, Jaya P; Rajeshkumar, N V; Sharma, Anuj; Singh, Anoop K; Ives, John A; Maheshwari, Radha K; Jonas, Wayne B

    2006-12-01

    Homeopathy is an alternative medical system practiced in all parts of the world. Although several theories are proposed to explain the mechanisms of action, none are scientifically verified. In this study, the authors investigate the effect of selected homeopathic remedies often used to treat prostate and breast cancer. The authors investigated the effect of the homeopathic medicines Conium maculatum, Sabal serrulata, Thuja occidentalis, Asterias, Phytolacca, and Carcinosin on prostate and breast cancer cell (DU-145, LNCaP, MAT-LyLu, MDA-MB-231) growth and on gene expression that regulates apoptosis, using MTT and multiprobe ribonuclease protection assay. None of the homeopathic remedies tested in different potencies produced significant inhibitory or growth-promoting activity in either prostate or breast cancer cells. Also, gene expression studies by ribonuclease protection assay produced no significant changes in mRNA levels of bax, bcl-2, bcl-x, caspase-1, caspase-2, caspase-3, Fas, or FasL after treatment with homeopathic medicines. The results demonstrate that the highly diluted homeopathic remedies used by homeopathic practitioners for cancer show no measurable effects on cell growth or gene expression in vitro using currently available methodologies.

  7. Differential expression of the klf6 tumor suppressor gene upon cell damaging treatments in cancer cells

    International Nuclear Information System (INIS)

    Gehrau, Ricardo C.; D'Astolfo, Diego S.; Andreoli, Veronica; Bocco, Jose L.; Koritschoner, Nicolas P.

    2011-01-01

    The mammalian Krueppel-like factor 6 (KLF6) is involved in critical roles such as growth-related signal transduction, cell proliferation and differentiation, development, apoptosis and angiogenesis. Also, KLF6 appears to be an emerging key factor during cancer development and progression. Its expression is thoroughly regulated by several cell-damaging stimuli. DNA damaging agents at lethal concentrations induce a p53-independent down-regulation of the klf6 gene. To investigate the impact of external stimuli on human klf6 gene expression, its mRNA level was analyzed using a cancer cell line profiling array system, consisting in an assortment of immobilized cDNAs from multiple cell lines treated with several cell-damaging agents at growth inhibitory concentrations (IC 50 ). Cell-damaging agents affected the klf6 expression in 62% of the cDNA samples, though the expression pattern was not dependent on the cell origin type. Interestingly, significant differences (p 50 concentrations of physical and chemical stimuli in a p53-dependent manner. Most of these agents are frequently used in cancer therapy. Induction of klf6 expression in the absence of functional p53 directly correlates with cell death triggered by these compounds, whereas it is down-regulated in p53+/+ cells. Hence, klf6 expression level could represent a valuable marker for the efficiency of cell death upon cancer treatment.

  8. Oral cancer cells with different potential of lymphatic metastasis displayed distinct biologic behaviors and gene expression profiles.

    Science.gov (United States)

    Zhuang, Zhang; Jian, Pan; Longjiang, Li; Bo, Han; Wenlin, Xiao

    2010-02-01

    Oral squamous cell carcinoma (OSCC) often spreads from the primary tumor to regional lymph nodes in the early stage. Better understanding of the biology of lymphatic spread of oral cancer cells is important for improving the survival rate of cancer patients. We established the cell line LNMTca8113 by repeated injections in foot pads of nude mice, which had a much higher lymphatic metastasis rate than its parental cell line Tca8113. Then, we compared the biologic behaviors of cancer cells between them. Moreover, microarray-based expression profiles between them were also compared, and a panel of differential genes was validated using real-time-PCR. In contrast to Tca8113 cells, LNMTca8113 cells were more proliferative and resistant to apoptosis in the absence of serum, and had enhanced ability of inducing capillary-like structures. Moreover, microarray-based expression profiles between them identified 1341 genes involved in cell cycle, cell adhesion, lymphangiogenesis, regulation of apoptosis, and so on. Some genes dedicating to the metastatic potential, including JAM2, TNC, CTSC, LAMB1, VEGFC, HAPLN1, ACPP, GDF9 and FGF11, were upregulated in LNMTca8113 cells. These results suggested that LNMTca8113 and Tca8113 cells were proper models for lymphatic metastasis study because there were differences in biologic behaviors and metastasis-related genes between them. Additionally, the differentially expressed gene profiles in cancer progression may be helpful in exploring therapeutic targets and provide the foundation for further functional validation of these specific candidate genes for OSCC.

  9. Expression profiles of variation integration genes in bladder urothelial carcinoma.

    Science.gov (United States)

    Wang, J M; Wang, Y Q; Gao, Z L; Wu, J T; Shi, B K; Yu, C C

    2014-04-30

    Bladder cancer is a common cancer worldwide and its incidence continues to increase. There are approximately 261,000 cases of bladder cancer resulting in 115,000 deaths annually. This study aimed to integrate bladder cancer genome copy number variation information and bladder cancer gene transcription level expression data to construct a causal-target module network of the range of bladder cancer-related genomes. Here, we explored the control mechanism underlying bladder cancer phenotype expression regulation by the major bladder cancer genes. We selected 22 modules as the initial module network to expand the search to screen more networks. After bootstrapping 100 times, we obtained 16 key regulators. These 16 key candidate regulatory genes were further expanded to identify the expression changes of 11,676 genes in 275 modules, which may all have the same regulation. In conclusion, a series of modules associated with the terms 'cancer' or 'bladder' were considered to constitute a potential network.

  10. Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations.

    Science.gov (United States)

    Ganzinelli, M; Mariani, P; Cattaneo, D; Fossati, R; Fruscio, R; Corso, S; Ricci, F; Broggini, M; Damia, G

    2011-05-01

    The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established. Copyright © 2010 Elsevier Ltd. All rights reserved.

  11. [Analysis of tissue-specific differentially methylated genes with differential gene expression in non-small cell lung cancer].

    Science.gov (United States)

    Yin, L G; Zou, Z Q; Zhao, H Y; Zhang, C L; Shen, J G; Qi, L; Qi, M; Xue, Z Q

    2014-01-01

    Adenocarcinoma (ADC) and squamous cell carcinomas (SCC) are two subtypes of non-small cell lung carcinomas which are regarded as the leading cause of cancer-related malignancy worldwide. The aim of this study is to detect the differentially methylated loci (DMLs) and differentially methylated genes (DMGs) of these two tumor sets, and then to illustrate the different expression level of specific methylated genes. Using TCGA database and Illumina HumanMethylation 27 arrays, we first screened the DMGs and DMLs in tumor samples. Then, we explored the BiologicalProcess terms of hypermethylated and hypomethylated genes using Functional Gene Ontology (GO) catalogues. Hypermethylation intensively occurred in CpG-island, whereas hypomethylation was located in non-CpG-island. Most SCC and ADC hypermethylated genes involved GO function of DNA dependenit regulation of transcription, and hypomethylated genes mainly 'enriched in the term of immune responses. Additionally, the expression level of specific differentially methylated genesis distinctbetween ADC and SCC. It is concluded that ADC and SCC have different methylated status that might play an important role in carcinogenesis.

  12. THE EXPRESSION AND CLINICAL VALUE OF APOPTOSIS CONTROL GENE Bcl-2 AND Bax IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    ZHENG Jun; YAO Zhen-xiang; ZHANG Jing

    1999-01-01

    Objective: To study the expression and clinical value of apoptosis control gene bcl-2 and bax in breast cancer.Methods: Protein bax and bcl-2 in 41 breast cancers obtained from operations in our hospital in 1996 were detected using ABC immunohistochemical stain assay and compared with 10 cases with normal breast tissues.Results: The positive rate of bax in normal breast tissue was 90% and in breast cancer was 59%, with a significant statistical difference between them (P<0.05), but there was no statistical difference in bcl-2 protein expression. Among the 41 breast cancer, the group with lymph node metastasis (21 cases) had obviously low bax expression (43%) and high bcl-2 expression (76%), showing significant difference to the group without lymph node metastasis (P<0.05).Conclusion: The antiapoptosis function of bcl-2 was stronger than bax in breast cancer. Protein bax and bcl-2 assay may be useful in understanding the biological behaviors of breast cancer.

  13. The prognostic value of temporal in vitro and in vivo derived hypoxia gene-expression signatures in breast cancer

    International Nuclear Information System (INIS)

    Starmans, Maud H.W.; Chu, Kenneth C.; Haider, Syed; Nguyen, Francis; Seigneuric, Renaud; Magagnin, Michael G.; Koritzinsky, Marianne; Kasprzyk, Arek; Boutros, Paul C.; Wouters, Bradly G.

    2012-01-01

    Background and purpose: Recent data suggest that in vitro and in vivo derived hypoxia gene-expression signatures have prognostic power in breast and possibly other cancers. However, both tumour hypoxia and the biological adaptation to this stress are highly dynamic. Assessment of time-dependent gene-expression changes in response to hypoxia may thus provide additional biological insights and assist in predicting the impact of hypoxia on patient prognosis. Materials and methods: Transcriptome profiling was performed for three cell lines derived from diverse tumour-types after hypoxic exposure at eight time-points, which include a normoxic time-point. Time-dependent sets of co-regulated genes were identified from these data. Subsequently, gene ontology (GO) and pathway analyses were performed. The prognostic power of these novel signatures was assessed in parallel with previous in vitro and in vivo derived hypoxia signatures in a large breast cancer microarray meta-dataset (n = 2312). Results: We identified seven recurrent temporal and two general hypoxia signatures. GO and pathway analyses revealed regulation of both common and unique underlying biological processes within these signatures. None of the new or previously published in vitro signatures consisting of hypoxia-induced genes were prognostic in the large breast cancer dataset. In contrast, signatures of repressed genes, as well as the in vivo derived signatures of hypoxia-induced genes showed clear prognostic power. Conclusions: Only a subset of hypoxia-induced genes in vitro demonstrates prognostic value when evaluated in a large clinical dataset. Despite clear evidence of temporal patterns of gene-expression in vitro, the subset of prognostic hypoxia regulated genes cannot be identified based on temporal pattern alone. In vivo derived signatures appear to identify the prognostic hypoxia induced genes. The prognostic value of hypoxia-repressed genes is likely a surrogate for the known importance of

  14. [Study of testicular cancer gene expression in samples of oral leukoplakia and squamous cell carcinoma of the mouth].

    Science.gov (United States)

    Skorodumova, L O; Muraev, A A; Zakharova, E S; Shepelev, M V; Korobko, I V; Zaderenko, I A; Ivanov, S Iu; Gnuchev, N V; Georgiev, G P; Larin, S S

    2012-01-01

    Cancer-testis (CT) antigens are normally expressed mostly in human germ cells, there is also an aberrant expression in some tumor cells. This expression profile makes them potential tumor growth biomarkers and a promising target for tumor immunotherapy. Specificity of CT genes expression in oral malignant and potentially malignant diseases, e.g. oral leukoplakia, is not yet studied. Data on CT genes expression profile in leukoplakia would allow developing new diagnostic methods with potential value for immunotherapy and prophylaxis of leukoplakia malignization. In our study we compared CT genes expression in normal oral mucosa, oral leukoplakia and oral squamous cell carcinoma. We are the first to describe CT genes expression in oral leukoplakia without dysplasia. This findings make impossible differential diagnosis of oral leukoplakia and squamous cell carcinoma on the basis of CT genes expression. The prognostic value of CT genes expression is still unclear, therefore the longitudinal studies are necessary.

  15. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    International Nuclear Information System (INIS)

    Asting, Annika Gustafsson; Carén, Helena; Andersson, Marianne; Lönnroth, Christina; Lagerstedt, Kristina; Lundholm, Kent

    2011-01-01

    Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue

  16. COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status

    Directory of Open Access Journals (Sweden)

    Lagerstedt Kristina

    2011-06-01

    Full Text Available Abstract Background Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. Method Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX-2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. Results Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX-2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1β, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-κB, TCF4 showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3 were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. Conclusions Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue.

  17. Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines

    LENUS (Irish Health Repository)

    O’Neill, Fiona

    2012-06-18

    AbstractBackgroundLapatinib, a tyrosine kinase inhibitor of HER2 and EGFR and is approved, in combination with capecitabine, for the treatment of trastuzumab-refractory metastatic breast cancer. In order to establish a possible gene expression response to lapatinib, a panel of breast cancer cell lines with varying sensitivity to lapatinib were analysed using a combination of microarray and qPCR profiling.MethodsCo-inertia analysis (CIA), a data integration technique, was used to identify transcription factors associated with the lapatinib response on a previously published dataset of 96 microarrays. RNA was extracted from BT474, SKBR3, EFM192A, HCC1954, MDAMB453 and MDAMB231 breast cancer cell lines displaying a range of lapatinib sensitivities and HER2 expression treated with 1 μM of lapatinib for 12 hours and quantified using Taqman RT-PCR. A fold change ≥ ± 2 was considered significant.ResultsA list of 421 differentially-expressed genes and 8 transcription factors (TFs) whose potential regulatory impact was inferred in silico, were identified as associated with lapatinib response. From this group, a panel of 27 genes (including the 8 TFs) were selected for qPCR validation. 5 genes were determined to be significantly differentially expressed following the 12 hr treatment of 1 μM lapatinib across all six cell lines. Furthermore, the expression of 4 of these genes (RB1CC1, FOXO3A, NR3C1 and ERBB3) was directly correlated with the degree of sensitivity of the cell line to lapatinib and their expression was observed to “switch” from up-regulated to down-regulated when the cell lines were arranged in a lapatinib-sensitive to insensitive order. These included the novel lapatinib response-associated genes RB1CC1 and NR3C1. Additionally, Cyclin D1 (CCND1), a common regulator of the other four proteins, was also demonstrated to observe a proportional response to lapatinib exposure.ConclusionsA panel of 5 genes were determined to be differentially

  18. Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression.

    Directory of Open Access Journals (Sweden)

    Christian J Gröger

    Full Text Available The epithelial to mesenchymal transition (EMT represents a crucial event during cancer progression and dissemination. EMT is the conversion of carcinoma cells from an epithelial to a mesenchymal phenotype that associates with a higher cell motility as well as enhanced chemoresistance and cancer stemness. Notably, EMT has been increasingly recognized as an early event of metastasis. Numerous gene expression studies (GES have been conducted to obtain transcriptome signatures and marker genes to understand the regulatory mechanisms underlying EMT. Yet, no meta-analysis considering the multitude of GES of EMT has been performed to comprehensively elaborate the core genes in this process. Here we report the meta-analysis of 18 independent and published GES of EMT which focused on different cell types and treatment modalities. Computational analysis revealed clustering of GES according to the type of treatment rather than to cell type. GES of EMT induced via transforming growth factor-β and tumor necrosis factor-α treatment yielded uniformly defined clusters while GES of models with alternative EMT induction clustered in a more complex fashion. In addition, we identified those up- and downregulated genes which were shared between the multitude of GES. This core gene list includes well known EMT markers as well as novel genes so far not described in this process. Furthermore, several genes of the EMT-core gene list significantly correlated with impaired pathological complete response in breast cancer patients. In conclusion, this meta-analysis provides a comprehensive survey of available EMT expression signatures and shows fundamental insights into the mechanisms that are governing carcinoma progression.

  19. Integrative analysis of miRNA and gene expression reveals regulatory networks in tamoxifen-resistant breast cancer

    DEFF Research Database (Denmark)

    Joshi, Tejal; Elias, Daniel; Stenvang, Jan

    2016-01-01

    and 14-3-3 family genes. Integrating the inferred miRNA-target relationships, we investigated the functional importance of 2 central genes, SNAI2 and FYN, which showed increased expression in TamR cells, while their corresponding regulatory miRNA were downregulated. Using specific chemical inhibitors......Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer, however, tamoxifen resistance is frequently observed. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA......-mediated gene regulation in three clinically-relevant tamoxifen-resistant breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all Tam...

  20. 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.

  1. Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells

    Directory of Open Access Journals (Sweden)

    Mitrugno Valentina

    2010-11-01

    Full Text Available Abstract Background Basal-like carcinoma are aggressive breast cancers that frequently carry p53 inactivating mutations, lack estrogen receptor-α (ERα and express the cancer stem cell markers CD133 and CD44. These tumors also over-express Interleukin 6 (IL-6, a pro-inflammatory cytokine that stimulates the growth of breast cancer stem/progenitor cells. Results Here we show that p53 deficiency in breast cancer cells induces a loss of methylation at IL-6 proximal promoter region, which is maintained by an IL-6 autocrine loop. IL-6 also elicits the loss of methylation at the CD133 promoter region 1 and of CD44 proximal promoter, enhancing CD133 and CD44 gene transcription. In parallel, IL-6 induces the methylation of estrogen receptor (ERα promoter and the loss of ERα mRNA expression. Finally, IL-6 induces the methylation of IL-6 distal promoter and of CD133 promoter region 2, which harbour putative repressor regions. Conclusion We conclude that IL-6, whose methylation-dependent autocrine loop is triggered by the inactivation of p53, induces an epigenetic reprogramming that drives breast carcinoma cells towards a basal-like/stem cell-like gene expression profile.

  2. Deregulation of an imprinted gene network in prostate cancer.

    Science.gov (United States)

    Ribarska, Teodora; Goering, Wolfgang; Droop, Johanna; Bastian, Klaus-Marius; Ingenwerth, Marc; Schulz, Wolfgang A

    2014-05-01

    Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes.

  3. Triple negative breast cancers have a reduced expression of DNA repair genes.

    Directory of Open Access Journals (Sweden)

    Enilze Ribeiro

    Full Text Available DNA repair is a key determinant in the cellular response to therapy and tumor repair status could play an important role in tailoring patient therapy. Our goal was to evaluate the mRNA of 13 genes involved in different DNA repair pathways (base excision, nucleotide excision, homologous recombination, and Fanconi anemia in paraffin embedded samples of triple negative breast cancer (TNBC compared to luminal A breast cancer (LABC. Most of the genes involved in nucleotide excision repair and Fanconi Anemia pathways, and CHK1 gene were significantly less expressed in TNBC than in LABC. PARP1 levels were higher in TNBC than in LABC. In univariate analysis high level of FANCA correlated with an increased overall survival and event free survival in TNBC; however multivariate analyses using Cox regression did not confirm FANCA as independent prognostic factor. These data support the evidence that TNBCs compared to LABCs harbour DNA repair defects.

  4. Gene expression profiles help identify the Tissue of Origin for metastatic brain cancers

    Directory of Open Access Journals (Sweden)

    VandenBerg Scott R

    2010-04-01

    Full Text Available Abstract Background Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork® Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. Methods Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. Results Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3% cases. Discussion This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers.

  5. Theranostic Imaging of Cancer Gene Therapy.

    Science.gov (United States)

    Sekar, Thillai V; Paulmurugan, Ramasamy

    2016-01-01

    Gene-directed enzyme prodrug therapy (GDEPT) is a promising therapeutic approach for treating cancers of various phenotypes. This strategy is independent of various other chemotherapeutic drugs used for treating cancers where the drugs are mainly designed to target endogenous cellular mechanisms, which are different in various cancer subtypes. In GDEPT an external enzyme, which is different from the cellular proteins, is expressed to convert the injected prodrug in to a toxic metabolite, that normally kill cancer cells express this protein. Theranostic imaging is an approach used to directly monitor the expression of these gene therapy enzymes while evaluating therapeutic effect. We recently developed a dual-GDEPT system where we combined mutant human herpes simplex thymidine kinase (HSV1sr39TK) and E. coli nitroreductase (NTR) enzyme, to improve therapeutic efficiency of cancer gene therapy by simultaneously injecting two prodrugs at a lower dose. In this approach we use two different prodrugs such as ganciclovir (GCV) and CB1954 to target two different cellular mechanisms to kill cancer cells. The developed dual GDEPT system was highly efficacious than that of either of the system used independently. In this chapter, we describe the complete protocol involved for in vitro and in vivo imaging of therapeutic cancer gene therapy evaluation.

  6. Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.

    Directory of Open Access Journals (Sweden)

    Varun V Prabhu

    Full Text Available Cancer stem cells (CSCs correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1 known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3 significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.

  7. Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC201 in solid tumors.

    Science.gov (United States)

    Prabhu, Varun V; Lulla, Amriti R; Madhukar, Neel S; Ralff, Marie D; Zhao, Dan; Kline, Christina Leah B; Van den Heuvel, A Pieter J; Lev, Avital; Garnett, Mathew J; McDermott, Ultan; Benes, Cyril H; Batchelor, Tracy T; Chi, Andrew S; Elemento, Olivier; Allen, Joshua E; El-Deiry, Wafik S

    2017-01-01

    Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.

  8. Id-1 gene and gene products as therapeutic targets for treatment of breast cancer and other types of carcinoma

    Science.gov (United States)

    Desprez, Pierre-Yves; Campisi, Judith

    2014-08-19

    A method for treatment of breast cancer and other types of cancer. The method comprises targeting and modulating Id-1 gene expression, if any, for the Id-1 gene, or gene products in breast or other epithelial cancers in a patient by delivering products that modulate Id-1 gene expression. When expressed, Id-1 gene is a prognostic indicator that cancer cells are invasive and metastatic.

  9. Reduced RAR-β gene expression in Benzo(a)Pyrene induced lung cancer mice is upregulated by DOTAP lipo-ATRA treatment.

    Science.gov (United States)

    Viswanathan, S; Berlin Grace, V M

    2018-05-16

    Molecular targeted therapy for specific genes is an emerging research. Retinoic Acid Receptor (RAR-β) is a key tumor suppressor which is found to be lost drastically during much cancer progression. We hence, analyzed the expression level of RAR-β gene during B(a)P induced lung cancer development in mice and studied the lung cancer targeted action of All Trans Retinoic Acid (ATRA) in DOTAP liposomal formulation. The effect of its treatment on lung cancer was determined by histopathological analysis. RAR-β gene expression was assessed by RT-PCR and qPCR. A distinct band for RAR-β gene (density - 0.5123 for lung and 0.5160 for liver) was observed in normal mice, whereas no visible band was observed in cancer induced group, indicating loss of RAR-β gene expression. Both ATRA and lipo-ATRA treated groups showed detectable RAR-β expression with relatively lesser density than the normal group. The expression was more intense in lipo-ATRA treatment (density-0.2973) compared with free ATRA treatment (density-0.1549) in lung tissues. The qPCR results also have highlighted a highly significant (p ≤ 0.01) variation RQ values between lipo-ATRA group (15.46 ± 1.54) and free ATRA group (7.58 ± 1.30) in lung tissue sample on 30th day. The mean RQ value for normal lung on 30th day was 20.86 ± 2.58 against the cancer control. The 120th day mice also showed the similar RAR-β expression pattern with further declined expression levels as there was no treatment given after 30 days. Interestingly, the lipo-ATRA treatment could show a highly significant (p ≤ 0.001) expression (12.00 ± 2.31) when compared with free ATRA treatment (3.31 ± 0.58) which implies that the lipo-ATRA formulation could result in sustained delivery of ATRA in target site. Histopathology of lung and liver on 120th day also revealed an effective therapeutic indication in lipo-ATRA treatment compared to free ATRA treatment due to lipo-ATRA's stealth property and it

  10. Altered expression of hypoxia-inducible factor-1α (HIF-1α and its regulatory genes in gastric cancer tissues.

    Directory of Open Access Journals (Sweden)

    Jihan Wang

    Full Text Available Tissue hypoxia induces reprogramming of cell metabolism and may result in normal cell transformation and cancer progression. Hypoxia-inducible factor 1-alpha (HIF-1α, the key transcription factor, plays an important role in gastric cancer development and progression. This study aimed to investigate the underlying regulatory signaling pathway in gastric cancer using gastric cancer tissue specimens. The integration of gene expression profile and transcriptional regulatory element database (TRED was pursued to identify HIF-1α ↔ NFκB1 → BRCA1 → STAT3 ← STAT1 gene pathways and their regulated genes. The data showed that there were 82 differentially expressed genes that could be regulated by these five transcription factors in gastric cancer tissues and these genes formed 95 regulation modes, among which seven genes (MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS, and TFF3 were hub molecules that are regulated at least by two of these five transcription factors simultaneously and were associated with hypoxia, inflammation, and immune disorder. Real-Time PCR and western blot showed increasing of HIF-1α in mRNA and protein levels as well as TIMP1, TFF3 in mRNA levels in gastric cancer tissues. The data are the first study to demonstrate HIF-1α-regulated transcription factors and their corresponding network genes in gastric cancer. Further study with a larger sample size and more functional experiments is needed to confirm these data and then translate into clinical biomarker discovery and treatment strategy for gastric cancer.

  11. 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

    -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. RESULTS: 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...... 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...

  12. Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes.

    Science.gov (United States)

    Cobleigh, Melody A; Tabesh, Bita; Bitterman, Pincas; Baker, Joffre; Cronin, Maureen; Liu, Mei-Lan; Borchik, Russell; Mosquera, Juan-Miguel; Walker, Michael G; Shak, Steven

    2005-12-15

    This study, along with two others, was done to develop the 21-gene Recurrence Score assay (Oncotype DX) that was validated in a subsequent independent study and is used to aid decision making about chemotherapy in estrogen receptor (ER)-positive, node-negative breast cancer patients. Patients with >or=10 nodes diagnosed from 1979 to 1999 were identified. RNA was extracted from paraffin blocks, and expression of 203 candidate genes was quantified using reverse transcription-PCR (RT-PCR). Seventy-eight patients were studied. As of August 2002, 77% of patients had distant recurrence or breast cancer death. Univariate Cox analysis of clinical and immunohistochemistry variables indicated that HER2/immunohistochemistry, number of involved nodes, progesterone receptor (PR)/immunohistochemistry (% cells), and ER/immunohistochemistry (% cells) were significantly associated with distant recurrence-free survival (DRFS). Univariate Cox analysis identified 22 genes associated with DRFS. Higher expression correlated with shorter DRFS for the HER2 adaptor GRB7 and the macrophage marker CD68. Higher expression correlated with longer DRFS for tumor protein p53-binding protein 2 (TP53BP2) and the ER axis genes PR and Bcl2. Multivariate methods, including stepwise variable selection and bootstrap resampling of the Cox proportional hazards regression model, identified several genes, including TP53BP2 and Bcl2, as significant predictors of DRFS. Tumor gene expression profiles of archival tissues, some more than 20 years old, provide significant information about risk of distant recurrence even among patients with 10 or more nodes.

  13. The claudin gene family: expression in normal and neoplastic tissues

    International Nuclear Information System (INIS)

    Hewitt, Kyle J; Agarwal, Rachana; Morin, Patrice J

    2006-01-01

    The claudin (CLDN) genes encode a family of proteins important in tight junction formation and function. Recently, it has become apparent that CLDN gene expression is frequently altered in several human cancers. However, the exact patterns of CLDN expression in various cancers is unknown, as only a limited number of CLDN genes have been investigated in a few tumors. We identified all the human CLDN genes from Genbank and we used the large public SAGE database to ascertain the gene expression of all 21 CLDN in 266 normal and neoplastic tissues. Using real-time RT-PCR, we also surveyed a subset of 13 CLDN genes in 24 normal and 24 neoplastic tissues. We show that claudins represent a family of highly related proteins, with claudin-16, and -23 being the most different from the others. From in silico analysis and RT-PCR data, we find that most claudin genes appear decreased in cancer, while CLDN3, CLDN4, and CLDN7 are elevated in several malignancies such as those originating from the pancreas, bladder, thyroid, fallopian tubes, ovary, stomach, colon, breast, uterus, and the prostate. Interestingly, CLDN5 is highly expressed in vascular endothelial cells, providing a possible target for antiangiogenic therapy. CLDN18 might represent a biomarker for gastric cancer. Our study confirms previously known CLDN gene expression patterns and identifies new ones, which may have applications in the detection, prognosis and therapy of several human cancers. In particular we identify several malignancies that express CLDN3 and CLDN4. These cancers may represent ideal candidates for a novel therapy being developed based on CPE, a toxin that specifically binds claudin-3 and claudin-4

  14. Intrafocal heterogeneity of ERG protein expression and gene fusion pattern in prostate cancer.

    Science.gov (United States)

    Suh, Ja Hee; Park, Jeong Hwan; Lee, Cheol; Moon, Kyung Chul

    2017-10-01

    Prostate cancer is considered to be highly heterogeneous, with various morphologic features and biologic behaviors. The TMPRSS2-ERG gene fusion is the most frequently observed genetic aberration in prostate cancer. The aim of this study was to elucidate the intrafocal heterogeneity of ERG gene fusion status. ERG immunohistochemistry (IHC) was performed in samples from 168 prostate cancer patients who had undergone radical prostatectomy, and 40 cases showing ERG-positive IHC staining were selected for tissue microarray (TMA) construction. Two to six representative cores were selected from each tumor focus. In the cases with heterogeneous ERG IHC staining intensity, the areas showing different intensities were separately selected. Using the TMA blocks, IHC and fluorescence in situ hybridization (FISH) were conducted to evaluate the heterogeneity of ERG protein expression and ERG fusion gene patterns, respectively, in a single tumor focus. Heterogeneity of ERG IHC staining was defined as the simultaneous presence of negative and positive cores in the same tumor focus. Heterogeneity of ERG FISH was defined by the presence of cores with positive and negative FISH signals or cores with break-apart and interstitial deletion FISH signals in the same tumor focus. A total of 202 TMA cores were isolated from 40 ERG-positive cases. Of the 202 total cores, 19 were negative for ERG IHC staining, and 46 showed 1+, 52 showed 2+, and 85 showed 3+ ERG staining intensity. Eleven cores were negative for ERG FISH signal, 119 cores showed ERG break-apart FISH signals, and the remaining 72 cores revealed interstitial deletion. Intrafocal heterogeneity of ERG IHC staining was found in 20% (8/40) of cases, and intrafocal heterogeneity of ERG gene fusion pattern was found in 32.5% (13/40) of cases. In summary, this study showed significantly frequent intrafocal heterogeneity of ERG protein expression, gene fusion status and fusion pattern. This heterogeneity can be caused by the development

  15. bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses.

    Science.gov (United States)

    Jézéquel, Pascal; Frénel, Jean-Sébastien; Campion, Loïc; Guérin-Charbonnel, Catherine; Gouraud, Wilfried; Ricolleau, Gabriel; Campone, Mario

    2013-01-01

    We recently developed a user-friendly web-based application called bc-GenExMiner (http://bcgenex.centregauducheau.fr), which offered the possibility to evaluate prognostic informativity of genes in breast cancer by means of a 'prognostic module'. In this study, we develop a new module called 'correlation module', which includes three kinds of gene expression correlation analyses. The first one computes correlation coefficient between 2 or more (up to 10) chosen genes. The second one produces two lists of genes that are most correlated (positively and negatively) to a 'tested' gene. A gene ontology (GO) mining function is also proposed to explore GO 'biological process', 'molecular function' and 'cellular component' terms enrichment for the output lists of most correlated genes. The third one explores gene expression correlation between the 15 telomeric and 15 centromeric genes surrounding a 'tested' gene. These correlation analyses can be performed in different groups of patients: all patients (without any subtyping), in molecular subtypes (basal-like, HER2+, luminal A and luminal B) and according to oestrogen receptor status. Validation tests based on published data showed that these automatized analyses lead to results consistent with studies' conclusions. In brief, this new module has been developed to help basic researchers explore molecular mechanisms of breast cancer. DATABASE URL: http://bcgenex.centregauducheau.fr

  16. Hypoxia-inducible bidirectional shRNA expression vector delivery using PEI/chitosan-TBA copolymers for colorectal Cancer gene therapy.

    Science.gov (United States)

    Javan, Bita; Atyabi, Fatemeh; Shahbazi, Majid

    2018-04-12

    This investigation was conducted to construct a hypoxia/colorectal dual-specific bidirectional short hairpin RNA (shRNA) expression vector and to transfect it into the colon cancer cell line HT-29 with PEI/chitosan-TBA nanoparticles for the simultaneous knock down of β-catenin and Bcl-2 under hypoxia. To construct a pRNA-bipHRE-CEA vector, the carcinoma embryonic antigen (CEA) promoter designed in two directions and the vascular endothelial growth factor (VEGF) enhancer were inserted between two promoters for hypoxic cancer specific gene expression. To confirm the therapeutic effect of the dual-specific vector, β-catenin and Bcl-2 shRNAs were inserted downstream of each promoter. The physicochemical properties, the cytotoxicity, and the transfection efficiency of these PEI/chitosan-TBA nanoparticles were investigated. In addition, the antitumor effects of the designed vector on the expression of β-catenin and Bcl-2, cell cycle distribution, and apoptosis were investigated in vitro. The silencing effect of the hypoxia-response shRNA expression vector was relatively low (18%-25%) under normoxia, whereas it was significantly increased to approximately 50%-60% in the HT-29 cell line. Moreover, the cancer cells showed significant G0/G1 arrest and increased apoptosis due to gene silencing under hypoxia. Furthermore, MTS assay, fluorescence microscopy images, and flow cytometry analyses confirmed that the PEI/chitosan-TBA blend system provided effective transfection with low cytotoxicity. This novel hypoxia-responsive shRNA expression vector may be useful for RNA interference (RNAi)-based cancer gene therapy in hypoxic colorectal tumors. Moreover, the PEI/chitosan-TBA copolymer might be a promising gene carrier for use in gene transfer in vivo. Copyright © 2017. Published by Elsevier Inc.

  17. Gene expression markers in circulating tumor cells may predict bone metastasis and response to hormonal treatment in breast cancer.

    Science.gov (United States)

    Wang, Haiying; Molina, Julian; Jiang, John; Ferber, Matthew; Pruthi, Sandhya; Jatkoe, Timothy; Derecho, Carlo; Rajpurohit, Yashoda; Zheng, Jian; Wang, Yixin

    2013-11-01

    Circulating tumor cells (CTCs) have recently attracted attention due to their potential as prognostic and predictive markers for the clinical management of metastatic breast cancer patients. The isolation of CTCs from patients may enable the molecular characterization of these cells, which may help establish a minimally invasive assay for the prediction of metastasis and further optimization of treatment. Molecular markers of proven clinical value may therefore be useful in predicting disease aggressiveness and response to treatment. In our earlier study, we identified a gene signature in breast cancer that appears to be significantly associated with bone metastasis. Among the genes that constitute this signature, trefoil factor 1 (TFF1) was identified as the most differentially expressed gene associated with bone metastasis. In this study, we investigated 25 candidate gene markers in the CTCs of metastatic breast cancer patients with different metastatic sites. The panel of the 25 markers was investigated in 80 baseline samples (first blood draw of CTCs) and 30 follow-up samples. In addition, 40 healthy blood donors (HBDs) were analyzed as controls. The assay was performed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with RNA extracted from CTCs captured by the CellSearch system. Our study indicated that 12 of the genes were uniquely expressed in CTCs and 10 were highly expressed in the CTCs obtained from patients compared to those obtained from HBDs. Among these genes, the expression of keratin 19 was highly correlated with the CTC count. The TFF1 expression in CTCs was a strong predictor of bone metastasis and the patients with a high expression of estrogen receptor β in CTCs exhibited a better response to hormonal treatment. Molecular characterization of these genes in CTCs may provide a better understanding of the mechanism underlying tumor metastasis and identify gene markers in CTCs for predicting disease progression and

  18. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer.

    Science.gov (United States)

    Sparano, Joseph A; Gray, Robert J; Makower, Della F; Pritchard, Kathleen I; Albain, Kathy S; Hayes, Daniel F; Geyer, Charles E; Dees, Elizabeth C; Perez, Edith A; Olson, John A; Zujewski, JoAnne; Lively, Tracy; Badve, Sunil S; Saphner, Thomas J; Wagner, Lynne I; Whelan, Timothy J; Ellis, Matthew J; Paik, Soonmyung; Wood, William C; Ravdin, Peter; Keane, Maccon M; Gomez Moreno, Henry L; Reddy, Pavan S; Goggins, Timothy F; Mayer, Ingrid A; Brufsky, Adam M; Toppmeyer, Deborah L; Kaklamani, Virginia G; Atkins, James N; Berenberg, Jeffrey L; Sledge, George W

    2015-11-19

    Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence). Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6). Among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for

  19. Gene expression analysis in human breast cancer associated blood vessels.

    Directory of Open Access Journals (Sweden)

    Dylan T Jones

    Full Text Available Angiogenesis is essential for solid tumour growth, whilst the molecular profiles of tumour blood vessels have been reported to be different between cancer types. Although presently available anti-angiogenic strategies are providing some promise for the treatment of some cancers it is perhaps not surprisingly that, none of the anti-angiogenic agents available work on all tumours. Thus, the discovery of novel anti-angiogenic targets, relevant to individual cancer types, is required. Using Affymetrix microarray analysis of laser-captured, CD31-positive blood vessels we have identified 63 genes that are upregulated significantly (5-72 fold in angiogenic blood vessels associated with human invasive ductal carcinoma (IDC of the breast as compared with blood vessels in normal human breast. We tested the angiogenic capacity of a subset of these genes. Genes were selected based on either their known cellular functions, their enriched expression in endothelial cells and/or their sensitivity to anti-VEGF treatment; all features implicating their involvement in angiogenesis. For example, RRM2, a ribonucleotide reductase involved in DNA synthesis, was upregulated 32-fold in IDC-associated blood vessels; ATF1, a nuclear activating transcription factor involved in cellular growth and survival was upregulated 23-fold in IDC-associated blood vessels and HEX-B, a hexosaminidase involved in the breakdown of GM2 gangliosides, was upregulated 8-fold in IDC-associated blood vessels. Furthermore, in silico analysis confirmed that AFT1 and HEX-B also were enriched in endothelial cells when compared with non-endothelial cells. None of these genes have been reported previously to be involved in neovascularisation. However, our data establish that siRNA depletion of Rrm2, Atf1 or Hex-B had significant anti-angiogenic effects in VEGF-stimulated ex vivo mouse aortic ring assays. Overall, our results provide proof-of-principle that our approach can identify a cohort of

  20. Aspirin Has Antitumor Effects via Expression of Calpain Gene in Cervical Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sang Koo Lee

    2008-01-01

    Full Text Available Aspirin and other nonsteroidal anti-inflammatory drugs show efficacy in the prevention of cancers. It is known that they can inhibit cyclooxygenases, and some studies have shown that they can induce apoptosis. Our objective in this study was to investigate the mechanism by which aspirin exerts its apoptosis effects in human cervical cancer HeLa cells. The effect of aspirin on the gene expression was studied by differential mRNA display RT-PCR. Among the isolated genes, mu-type calpain gene was upregulated by aspirin treatment. To examine whether calpain mediates the antitumor effects, HeLa cells were stably transfected with the mammalian expression vector pCR3.1 containing mu-type calpain cDNA (pCRCAL/HeLa, and tumor formations were measured in nude mice. When tumor burden was measured by day 49, HeLa cells and pCR/HeLa cells (vector control produced tumors of 2126 mm3 and 1638 mm3, respectively, while pCRCAL/HeLa cells produced markedly smaller tumor of 434 mm3 in volume. The caspase-3 activity was markedly elevated in pCRCAL/HeLa cells. The increased activity levels of caspase-3 in pCRCAL/HeLa cells, in parallel with the decreased tumor formation, suggest a correlation between caspase-3 activity and calpain protein. Therefore, we conclude that aspirin-induced calpain mediates an antitumor effect via caspase-3 in cervical cancer cells.

  1. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

    Science.gov (United States)

    Weijenberg, Matty P; Lüchtenborg, Margreet; de Goeij, Anton F P M; Brink, Mirian; van Muijen, Goos N P; de Bruïne, Adriaan P; Goldbohm, R Alexandra; van den Brandt, Piet A

    2007-10-01

    To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) oncogene. After 7.3 years of follow-up of the Netherlands Cohort Study (n = 120,852), adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed, based on 401 colon and 130 rectal cancer patients. Total, saturated and monounsaturated fat were not associated with the risk of colon or rectal cancer, or different molecular subgroups. There was also no association between polyunsaturated fat and the risk of overall or subgroups of rectal cancer. Linoleic acid, the most abundant polyunsaturated fatty acid in the diet, was associated with increased risk of colon tumors with only a KRAS mutation and no additional truncating APC mutation or lack of MLH1 expression (RR = 1.41, 95% CI 1.18-1.69 for one standard deviation (i.e., 7.5 g/day) increase in intake, p-trend over the quartiles of intake colon tumors without any of the gene defects, or with tumors harboring aberrations in either MLH1 or APC. Linoleic acid intake is associated with colon tumors with an aberrant KRAS gene, but an intact APC gene and MLH1 expression, suggesting a unique etiology of tumors with specific genetic aberrations.

  2. Stress associated gene expression in blood cells is related to outcome in radiotherapy treated head and neck cancer patients

    International Nuclear Information System (INIS)

    Bøhn, Siv K; Blomhoff, Rune; Russnes, Kjell M; Sakhi, Amrit K; Thoresen, Magne; Holden, Marit; Moskaug, JanØ; Myhrstad, Mari C; Olstad, Ole K; Smeland, Sigbjørn

    2012-01-01

    We previously observed that a radiotherapy-induced biochemical response in plasma was associated with favourable outcome in head and neck squamous carcinoma cancer (HNSCC) patients. The aim of the present study was to compare stress associated blood cell gene expression between two sub-groups of HNSCC patients with different biochemical responses to radiotherapy. Out of 87 patients (histologically verified), 10 biochemical ‘responders’ having a high relative increase in plasma oxidative damage and a concomitant decrease in plasma antioxidants during radiotherapy and 10 ‘poor-responders’ were selected for gene-expression analysis and compared using gene set enrichment analysis. There was a significant induction of stress-relevant gene-sets in the responders following radiotherapy compared to the poor-responders. The relevance of the involvement of similar stress associated gene expression for HNSCC cancer and radioresistance was verified using two publicly available data sets of 42 HNSCC cases and 14 controls (GEO GSE6791), and radiation resistant and radiation sensitive HNSCC xenografts (E-GEOD-9716). Radiotherapy induces a systemic stress response, as revealed by induction of stress relevant gene expression in blood cells, which is associated to favourable outcome in a cohort of 87 HNSCC patients. Whether these changes in gene expression reflects a systemic effect or are biomarkers of the tumour micro-environmental status needs further study. Raw data are available at ArrayExpress under accession number E-MEXP-2460

  3. Regularization strategies for hyperplane classifiers: application to cancer classification with gene expression data.

    Science.gov (United States)

    Andries, Erik; Hagstrom, Thomas; Atlas, Susan R; Willman, Cheryl

    2007-02-01

    Linear discrimination, from the point of view of numerical linear algebra, can be treated as solving an ill-posed system of linear equations. In order to generate a solution that is robust in the presence of noise, these problems require regularization. Here, we examine the ill-posedness involved in the linear discrimination of cancer gene expression data with respect to outcome and tumor subclasses. We show that a filter factor representation, based upon Singular Value Decomposition, yields insight into the numerical ill-posedness of the hyperplane-based separation when applied to gene expression data. We also show that this representation yields useful diagnostic tools for guiding the selection of classifier parameters, thus leading to improved performance.

  4. Gene expression profiling: cell cycle deregulation and aneuploidy do not cause breast cancer formation in WAP-SVT/t transgenic animals.

    Science.gov (United States)

    Klein, Andreas; Guhl, Eva; Zollinger, Raphael; Tzeng, Yin-Jeh; Wessel, Ralf; Hummel, Michael; Graessmann, Monika; Graessmann, Adolf

    2005-05-01

    Microarray studies revealed that as a first hit the SV40 T/t antigen causes deregulation of 462 genes in mammary gland cells (ME cells) of WAP-SVT/t transgenic animals. The majority of deregulated genes are cell proliferation specific and Rb-E2F dependent, causing ME cell proliferation and gland hyperplasia but not breast cancer formation. In the breast tumor cells a further 207 genes are differentially expressed, most of them belonging to the cell communication category. In tissue culture breast tumor cells frequently switch off WAP-SVT/t transgene expression and regain the morphology and growth characteristics of normal ME cells, although the tumor-revertant cells are aneuploid and only 114 genes regain the expression level of normal ME cells. The profile of retransformants shows that only 38 deregulated genes are tumor-specific, and that none of them is considered to be a typical breast cancer gene.

  5. Preparation of oligonucleotide microarray for radiation-associated gene expression detection and its application in lung cancer cell lines

    International Nuclear Information System (INIS)

    Guo Wanfeng; Lin Ruxian; Huang Jian; Guo Guozhen; Wang Shengqi

    2005-01-01

    Objective: The response of tumor cell to radiation is accompanied by complex change in patterns of gene expression. It is highly probable that a better understanding of molecular and genetic changes can help to sensitize the radioresistant tumor cells. Methods: Oligonucleotide microarray provides a powerful tool for high-throughput identifying a wider range of genes involved in the radioresistance. Therefore, the authors designed one oligonucleotide microarray according to the biological effect of IR. By using different radiosensitive lung cancer cell lines, the authors identified genes showing altered expression in lung cancer cell lines. To provide independent confirmation of microarray data, semi-quantitative RT-PCR was performed on a selection of genes. Results: In radioresistant A549 cell lines, a total of 18 genes were selected as having significant fold-changes compared to NCI-H446, 8 genes were up-regulated and 10 genes were down-regulated. Subsequently, A549 and NCI-H446 cells were delivered by ionizing radiation. In A549 cell line, we found 22 (19 up-regulated and 3 down-regulated) and 26 (8 up-regulated and 18 down-regulated) differentially expressed genes at 6h and 24h after ionizing radiation. In NCI-H446 cell line, we identified 17 (9 up-regulated and 8 down-regulated) and 18 (6 up-regulated and 12 down-regulated) differentially expressed genes at 6 h and 24 h after ionizing radiation. The authors tested seven genes (MDM2, p53, XRCC5, Bcl-2, PIM2, NFKBIA and Cyclin B1) for RT-PCR, and found that the results were in good agreement with those from the microarray data except for NFKBIA gene, even though the value for each mRNA level might be different between the two measurements. In present study, the authors identified some genes with cell proliferation and anti-apoptosis, such as MdM2, BCL-2, PKCz and PIM2 expression levels increased in A549 cells and decreased in NCI-H446 cells after radiation, and other genes with DNA repair, such as XRCC5, ERCC5

  6. Prediction of Metastasis and Recurrence in Colorectal Cancer Based on Gene Expression Analysis: Ready for the Clinic?

    Energy Technology Data Exchange (ETDEWEB)

    Shibayama, Masaki [Sysmex Corporation, Central Research Laboratories, Kobe 651-2271 (Japan); Maak, Matthias; Nitsche, Ulrich [Chirurgische Klinik, Klinikum Rechts der Isar der TUM, München 81657 (Germany); Gotoh, Kengo [Sysmex Corporation, Central Research Laboratories, Kobe 651-2271 (Japan); Rosenberg, Robert; Janssen, Klaus-Peter, E-mail: klaus-peter.janssen@lrz.tum.de [Chirurgische Klinik, Klinikum Rechts der Isar der TUM, München 81657 (Germany)

    2011-07-07

    Cancers of the colon and rectum, which rank among the most frequent human tumors, are currently treated by surgical resection in locally restricted tumor stages. However, disease recurrence and formation of local and distant metastasis frequently occur even in cases with successful curative resection of the primary tumor (R0). Recent technological advances in molecular diagnostic analysis have led to a wealth of knowledge about the changes in gene transcription in all stages of colorectal tumors. Differential gene expression, or transcriptome analysis, has been proposed by many groups to predict disease recurrence, clinical outcome, and also response to therapy, in addition to the well-established clinico-pathological factors. However, the clinical usability of gene expression profiling as a reliable and robust prognostic tool that allows evidence-based clinical decisions is currently under debate. In this review, we will discuss the most recent data on the prognostic significance and potential clinical application of genome wide expression analysis in colorectal cancer.

  7. Prediction of Metastasis and Recurrence in Colorectal Cancer Based on Gene Expression Analysis: Ready for the Clinic?

    International Nuclear Information System (INIS)

    Shibayama, Masaki; Maak, Matthias; Nitsche, Ulrich; Gotoh, Kengo; Rosenberg, Robert; Janssen, Klaus-Peter

    2011-01-01

    Cancers of the colon and rectum, which rank among the most frequent human tumors, are currently treated by surgical resection in locally restricted tumor stages. However, disease recurrence and formation of local and distant metastasis frequently occur even in cases with successful curative resection of the primary tumor (R0). Recent technological advances in molecular diagnostic analysis have led to a wealth of knowledge about the changes in gene transcription in all stages of colorectal tumors. Differential gene expression, or transcriptome analysis, has been proposed by many groups to predict disease recurrence, clinical outcome, and also response to therapy, in addition to the well-established clinico-pathological factors. However, the clinical usability of gene expression profiling as a reliable and robust prognostic tool that allows evidence-based clinical decisions is currently under debate. In this review, we will discuss the most recent data on the prognostic significance and potential clinical application of genome wide expression analysis in colorectal cancer

  8. Detection of EBV Infection and Gene Expression in Oral Cancer from Patients in Taiwan by Microarray Analysis

    Directory of Open Access Journals (Sweden)

    Ching-Yu Yen

    2009-01-01

    Full Text Available Epstein-Barr virus is known to cause nasopharyngeal carcinoma. Although oral cavity is located close to the nasal pharynx, the pathogenetic role of Epstein-Barr virus (EBV in oral cancers is unclear. This molecular epidemiology study uses EBV genomic microarray (EBV-chip to simultaneously detect the prevalent rate and viral gene expression patterns in 57 oral squamous cell carcinoma biopsies (OSCC collected from patients in Taiwan. The majority of the specimens (82.5% were EBV-positive that probably expressed coincidently the genes for EBNAs, LMP2A and 2B, and certain structural proteins. Importantly, the genes fabricated at the spots 61 (BBRF1, BBRF2, and BBRF3 and 68 (BDLF4 and BDRF1 on EBV-chip were actively expressed in a significantly greater number of OSCC exhibiting exophytic morphology or ulceration than those tissues with deep invasive lesions (P=.0265 and .0141, resp.. The results may thus provide the lead information for understanding the role of EBV in oral cancer pathogenesis.

  9. G-protein inwardly rectifying potassium channel 1 (GIRK 1) gene expression correlates with tumor progression in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Takanami, Iwao; Inoue, Yoshimasa; Gika, Masatoshi

    2004-01-01

    G-protein inwardly rectifying potassium channel 1 (GIRK1) is thought to play a role in cell proliferation in cancer, and GIRK1 gene expression level may define a more aggressive phenotype. We detected GIRK1 expression in tissue specimens from patients with non-small cell lung cancers (NSCLCs) and assessed their clinical characteristics. Using reverse transcription-polymerase chain reaction (RT-PCR) analyses, we quantified the expression of GIRK1 in 72 patients with NSCLCs to investigate the relationship between GIRK1 expression and clinicopathologic factors and prognosis. In 72 NSCLC patients, 50 (69%) samples were evaluated as having high GIRK1 gene expression, and 22 (31%) were evaluated as having low GIRK1 gene expression. GIRK1 gene expression was significantly associated with lymph node metastasis, stage (p = 0.0194 for lymph node metastasis; p = 0.0207 for stage). The overall and stage I survival rates for patients with high GIRK1 gene expressed tumors was significantly worse than for those individuals whose tumors had low GIRK1 expression (p = 0.0004 for the overall group; p = 0.0376 for stage I). These data indicate that GIRK1 may contribute to tumor progression and GIRK1 gene expression can serve as a useful prognostic marker in the overall and stage I NSCLCs

  10. Determination of Six Transmembrane Protein of Prostate 2 Gene Expression and Intracellular Localization in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Bora İrer

    2017-12-01

    Full Text Available Objective: In this study, we aimed to determine the relationship between the RNA and protein expression profile of six transmembrane protein of prostate 2 (STAMP2 gene and androgen and the intracellular localization of STAMP2. Materials and Methods: RNA and protein were obtained from androgen treated lymph node carcinoma of the prostate (LNCaP cells, untreated LNCaP cells, DU145 cells with no androgen receptor, and STAMP2 transfected COS-7 cells. The expression profile of STAMP2 gene and the effect of androgenes on the expression was shown in RNA and protein levels by using Northern and Western blotting methods. In addition, intracellular localization of the naturally synthesized STAMP2 protein and the transfected STAMP2 protein in COS-7 cells after androgen administration in both LNCaP cells was determined by immunofluorescence microscopy. Results: We found that the RNA and protein expression of STAMP2 gene in LNCaP cells are regulated by androgenes, the power of expression is increased with the duration of androgen treatment and there is no STAMP2 expression in DU145 cells which has no androgen receptor. As a result of the immunofluorescence microscopy study we observed that STAMP2 protein was localized at golgi complex and cell membrane. Conclusion: In conclusion, we have demonstrated that STAMP2 may play an important role in the pathogenesis of the prostate cancer and in the androgen-dependent androgen-independent staging of prostate cancer. In addition, STAMP2 protein, which is localized in the intracellular golgi complex and cell membrane, may be a new target molecule for prostate cancer diagnosis and treatment.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation

    International Nuclear Information System (INIS)

    Schulz, Wolfgang A; Ingenwerth, Marc; Djuidje, Carolle E; Hader, Christiane; Rahnenführer, Jörg; Engers, Rainer

    2010-01-01

    The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network. Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as „cortical cytoskeleton' genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry. EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively. Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with

  13. Prognostic Gene Expression Profiles in Breast Cancer

    DEFF Research Database (Denmark)

    Sørensen, Kristina Pilekær

    Each year approximately 4,800 Danish women are diagnosed with breast cancer. Several clinical and pathological factors are used as prognostic and predictive markers to categorize the patients into groups of high or low risk. Around 90% of all patients are allocated to the high risk group...... clinical courses, and they may be useful as novel prognostic biomarkers in breast cancer. The aim of the present project was to predict the development of metastasis in lymph node negative breast cancer patients by RNA profiling. We collected and analyzed 82 primary breast tumors from patients who...... and the time of event. Previous findings have shown that high expression of the lncRNA HOTAIR is correlated with poor survival in breast cancer. We validated this finding by demonstrating that high HOTAIR expression in our primary tumors was significantly associated with worse prognosis independent...

  14. Prediction of the prognosis of breast cancer in routine histologic specimens using a simplified, low-cost gene expression signature

    DEFF Research Database (Denmark)

    Marcell, S.A.; Balazs, A.; Emese, A.

    2013-01-01

    Prediction of the prognosis of breast cancer in routine histologic specimens using a simplified, low-cost gene expression signature Background: Grade 2 breast carcinomas do not form a uniform prognostic group. Aim: To extend the number of patients and the investigated genes of a previously...... grade 2 breast carcinomas into prognostic groups. Gene expression was investigated by polymerase chain reaction in 249 formalin-fixed, paraffin-embedded breast tumors. The results were correlated with relapse-free survival. Results: Histologically grade 2 carcinomas were split into good and a poor...... identified prognostic signature described by the authors that reflect chromosomal instability in order to refine characterization of grade 2 breast cancers and identify driver genes. Methods: Using publicly available databases, the authors selected 9 target and 3 housekeeping genes that are capable to divide...

  15. Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome.

    Science.gov (United States)

    Light, Kathleen C; Agarwal, Neeraj; Iacob, Eli; White, Andrea T; Kinney, Anita Y; VanHaitsma, Timothy A; Aizad, Hannah; Hughen, Ronald W; Bateman, Lucinda; Light, Alan R

    2013-12-01

    Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions. Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors. PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, pfatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001). PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Correlation of plasma nitrite/nitrate levels and inducible nitric oxide gene expression among women with cervical abnormalities and cancer.

    Science.gov (United States)

    Sowjanya, A Pavani; Rao, Meera; Vedantham, Haripriya; Kalpana, Basany; Poli, Usha Rani; Marks, Morgan A; Sujatha, M

    2016-01-30

    Cervical cancer is caused by infection with high risk human papillomavirus (HR-HPV). Inducible nitric oxide synthase (iNOS), a soluble factor involved in chronic inflammation, may modulate cervical cancer risk among HPV infected women. The aim of the study was to measure and correlate plasma nitrite/nitrate levels with tissue specific expression of iNOS mRNA among women with different grades of cervical lesions and cervical cancer. Tissue biopsy and plasma specimens were collected from 120 women with cervical neoplasia or cancer (ASCUS, LSIL, HSIL and invasive cancer) and 35 women without cervical abnormalities. Inducible nitric oxide synthase (iNOS) mRNA from biopsy and plasma nitrite/nitrate levels of the same study subjects were measured. Single nucleotide polymorphism (SNP) analysis was performed on the promoter region and Ser608Leu (rs2297518) in exon 16 of the iNOS gene. Differences in iNOS gene expression and plasma nitrite/nitrate levels were compared across disease stage using linear and logistic regression analysis. Compared to normal controls, women diagnosed with HSIL or invasive cancer had a significantly higher concentration of plasma nitrite/nitrate and a higher median fold-change in iNOS mRNA gene expression. Genotyping of the promoter region showed three different variations: A pentanucleotide repeat (CCTTT) n, -1026T > G (rs2779249) and a novel variant -1153T > A. These variants were associated with increased levels of plasma nitrite/nitrate across all disease stages. The higher expression of iNOS mRNA and plasma nitrite/nitrate among women with pre-cancerous lesions suggests a role for nitric oxide in the natural history of cervical cancer. Copyright © 2015. Published by Elsevier Inc.

  17. Cisplatin induces expression of drug resistance-related genes through c-jun N-terminal kinase pathway in human lung cancer cells.

    Science.gov (United States)

    Xu, Li; Fu, Yingya; Li, Youlun; Han, Xiaoli

    2017-08-01

    Change of multidrug resistance-related genes (e.g., lung resistance protein, LRP) and overexpression of anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are responsible for cisplatin resistance. In our study, we investigated the mechanism by which cisplatin induces LRP, Bcl-2, Bcl-xL, XIAP, and Survivin expression in human lung adenocarcinoma A549 cells and human H446 small cell lung cancer cells at mRNA and protein levels. In our study, cell proliferation was assessed with CCK-8 assays, and cell apoptosis was assessed with flow cytometric analysis and Annexin-V/PI staining. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting. Cisplatin increased Bcl-2, LRP, and Survivin expression, but decreased Bcl-xL and XIAP expression in a dose-dependent manner. Preincubation with JNK-specific inhibitor, SP600125, significantly inhibited these genes' expression at mRNA and protein levels, enhanced chemosensitivity of lung cancer cells to cisplatin, and promoted cisplatin-induced apoptosis. Our data suggest that the JNK signaling pathway plays an important role in cisplatin resistance. Lung resistance protein (LRP) and anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are involved in the process. The results reminded us of a novel therapy target for lung cancer treatment.

  18. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.

    Science.gov (United States)

    Gianni, Luca; Zambetti, Milvia; Clark, Kim; Baker, Joffre; Cronin, Maureen; Wu, Jenny; Mariani, Gabriella; Rodriguez, Jaime; Carcangiu, Marialuisa; Watson, Drew; Valagussa, Pinuccia; Rouzier, Roman; Symmans, W Fraser; Ross, Jeffrey S; Hortobagyi, Gabriel N; Pusztai, Lajos; Shak, Steven

    2005-10-10

    We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk. Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays. Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) -related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit. Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.

  19. mRMR-ABC: A Hybrid Gene Selection Algorithm for Cancer Classification Using Microarray Gene Expression Profiling

    Directory of Open Access Journals (Sweden)

    Hala Alshamlan

    2015-01-01

    Full Text Available An artificial bee colony (ABC is a relatively recent swarm intelligence optimization approach. In this paper, we propose the first attempt at applying ABC algorithm in analyzing a microarray gene expression profile. In addition, we propose an innovative feature selection algorithm, minimum redundancy maximum relevance (mRMR, and combine it with an ABC algorithm, mRMR-ABC, to select informative genes from microarray profile. The new approach is based on a support vector machine (SVM algorithm to measure the classification accuracy for selected genes. We evaluate the performance of the proposed mRMR-ABC algorithm by conducting extensive experiments on six binary and multiclass gene expression microarray datasets. Furthermore, we compare our proposed mRMR-ABC algorithm with previously known techniques. We reimplemented two of these techniques for the sake of a fair comparison using the same parameters. These two techniques are mRMR when combined with a genetic algorithm (mRMR-GA and mRMR when combined with a particle swarm optimization algorithm (mRMR-PSO. The experimental results prove that the proposed mRMR-ABC algorithm achieves accurate classification performance using small number of predictive genes when tested using both datasets and compared to previously suggested methods. This shows that mRMR-ABC is a promising approach for solving gene selection and cancer classification problems.

  20. mRMR-ABC: A Hybrid Gene Selection Algorithm for Cancer Classification Using Microarray Gene Expression Profiling.

    Science.gov (United States)

    Alshamlan, Hala; Badr, Ghada; Alohali, Yousef

    2015-01-01

    An artificial bee colony (ABC) is a relatively recent swarm intelligence optimization approach. In this paper, we propose the first attempt at applying ABC algorithm in analyzing a microarray gene expression profile. In addition, we propose an innovative feature selection algorithm, minimum redundancy maximum relevance (mRMR), and combine it with an ABC algorithm, mRMR-ABC, to select informative genes from microarray profile. The new approach is based on a support vector machine (SVM) algorithm to measure the classification accuracy for selected genes. We evaluate the performance of the proposed mRMR-ABC algorithm by conducting extensive experiments on six binary and multiclass gene expression microarray datasets. Furthermore, we compare our proposed mRMR-ABC algorithm with previously known techniques. We reimplemented two of these techniques for the sake of a fair comparison using the same parameters. These two techniques are mRMR when combined with a genetic algorithm (mRMR-GA) and mRMR when combined with a particle swarm optimization algorithm (mRMR-PSO). The experimental results prove that the proposed mRMR-ABC algorithm achieves accurate classification performance using small number of predictive genes when tested using both datasets and compared to previously suggested methods. This shows that mRMR-ABC is a promising approach for solving gene selection and cancer classification problems.

  1. The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data.

    Science.gov (United States)

    Bozovic-Spasojevic, Ivana; Zardavas, Dimitrios; Brohée, Sylvain; Ameye, Lieveke; Fumagalli, Debora; Ades, Felipe; de Azambuja, Evandro; Bareche, Yacine; Piccart, Martine; Paesmans, Marianne; Sotiriou, Christos

    2017-06-01

    Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain. Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a meta-analysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data. Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37-0.58, P expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72-0.92; P = 0.0007) and OS (HR 0.84; 95% CI, 0.75-0.94; P = 0.02) only in univariate analysis. Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702-12. ©2016 AACR . ©2016 American Association for Cancer Research.

  2. Clinical value of prognosis gene expression signatures in colorectal cancer: a systematic review.

    Directory of Open Access Journals (Sweden)

    Rebeca Sanz-Pamplona

    Full Text Available INTRODUCTION: The traditional staging system is inadequate to identify those patients with stage II colorectal cancer (CRC at high risk of recurrence or with stage III CRC at low risk. A number of gene expression signatures to predict CRC prognosis have been proposed, but none is routinely used in the clinic. The aim of this work was to assess the prediction ability and potential clinical usefulness of these signatures in a series of independent datasets. METHODS: A literature review identified 31 gene expression signatures that used gene expression data to predict prognosis in CRC tissue. The search was based on the PubMed database and was restricted to papers published from January 2004 to December 2011. Eleven CRC gene expression datasets with outcome information were identified and downloaded from public repositories. Random Forest classifier was used to build predictors from the gene lists. Matthews correlation coefficient was chosen as a measure of classification accuracy and its associated p-value was used to assess association with prognosis. For clinical usefulness evaluation, positive and negative post-tests probabilities were computed in stage II and III samples. RESULTS: Five gene signatures showed significant association with prognosis and provided reasonable prediction accuracy in their own training datasets. Nevertheless, all signatures showed low reproducibility in independent data. Stratified analyses by stage or microsatellite instability status showed significant association but limited discrimination ability, especially in stage II tumors. From a clinical perspective, the most predictive signatures showed a minor but significant improvement over the classical staging system. CONCLUSIONS: The published signatures show low prediction accuracy but moderate clinical usefulness. Although gene expression data may inform prognosis, better strategies for signature validation are needed to encourage their widespread use in the clinic.

  3. Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 2

    OpenAIRE

    Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van, Klaske

    2013-01-01

    Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still ab...

  4. Hypothalamic gene expression of appetite regulators in a cancer-cachectic mouse model [Dataset 1

    OpenAIRE

    Dwarkasing, Jvalini; Dijk, Francina J.; Boekschoten, Mark; Faber, Joyce; Argilès, Josep M.; Lavianio, Alessandro; Muller, Michael; Witkamp, Renger; Norren, van, Klaske

    2013-01-01

    Appetite is frequently affected in cancer patients, leading to anorexia and consequently insufficient food intake. In this study, we report on hypothalamic gene expression profile of a cancer cachectic mouse model with increased food intake. In this model, mice bearing C26 colon adenocarcinoma have an increased food intake subsequently to the loss of body weight. We hypothesize that in this model, appetite regulating systems in the hypothalamus, which apparently fail in anorexia, are still ab...

  5. c-Myc activates BRCA1 gene expression through distal promoter elements in breast cancer cells

    International Nuclear Information System (INIS)

    Chen, Yinghua; Xu, Jinhua; Borowicz, Stanley; Collins, Cindy; Huo, Dezheng; Olopade, Olufunmilayo I

    2011-01-01

    The BRCA1 gene plays an important role in the maintenance of genomic stability. BRCA1 inactivation contributes to breast cancer tumorigenesis. An increasing number of transcription factors have been shown to regulate BRCA1 expression. c-Myc can act as a transcriptional activator, regulating up to 15% of all genes in the human genome and results from a high throughput screen suggest that BRCA1 is one of its targets. In this report, we used cultured breast cancer cells to examine the mechanisms of transcriptional activation of BRCA1 by c-Myc. c-Myc was depleted using c-Myc-specific siRNAs in cultured breast cancer cells. BRCA1 mRNA expression and BRCA1 protein expression were determined by quantitative RT-PCR and western blot, respectively and BRCA1 promoter activities were examined under these conditions. DNA sequence analysis was conducted to search for high similarity to E boxes in the BRCA1 promoter region. The association of c-Myc with the BRCA1 promoter in vivo was tested by a chromatin immunoprecipitation assay. We investigated the function of the c-Myc binding site in the BRCA1 promoter region by a promoter assay with nucleotide substitutions in the putative E boxes. BRCA1-dependent DNA repair activities were measured by a GFP-reporter assay. Depletion of c-Myc was found to be correlated with reduced expression levels of BRCA1 mRNA and BRCA1 protein. Depletion of c-Myc decreased BRCA1 promoter activity, while ectopically expressed c-Myc increased BRCA1 promoter activity. In the distal BRCA1 promoter, DNA sequence analysis revealed two tandem clusters with high similarity, and each cluster contained a possible c-Myc binding site. c-Myc bound to these regions in vivo. Nucleotide substitutions in the c-Myc binding sites in these regions abrogated c-Myc-dependent promoter activation. Furthermore, breast cancer cells with reduced BRCA1 expression due to depletion of c-Myc exhibited impaired DNA repair activity. The distal BRCA1 promoter region is associated with c

  6. Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: Role of transcription factors

    International Nuclear Information System (INIS)

    Chandrasekharan, Sabarinath; Kandasamy, Krishna Kumar; Dayalan, Pavithra; Ramamurthy, Viraragavan

    2013-01-01

    Highlights: •Estradiol (E2) at low dose induced cell proliferation in breast cancer cells. •E2 at high concentration induced cell stress in breast cancer cells. •Estrogen receptor physically interacts only with a few transcription factors. •Differential expression of genes with Oct-1 binding sites increased under stress. •Transcription factor binding sites showed distinct spatial distribution on genes. -- Abstract: Background: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet. Methodology: Meta-analysis of the expression data of MCF7 cells treated with low (1 nM) or high (100 nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25 kb upstream and downstream from the transcription start site (TSS) of these genes. Results: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes. Discussion: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress–rescue responses were induced

  7. Estrogen induced concentration dependent differential gene expression in human breast cancer (MCF7) cells: Role of transcription factors

    Energy Technology Data Exchange (ETDEWEB)

    Chandrasekharan, Sabarinath, E-mail: csab@bio.psgtech.ac.in [Department of Biotechnology, PSG College of Technology, Coimbatore 641004 (India); Kandasamy, Krishna Kumar [Max Planck Institute for Biology of Ageing, Cologne (Germany); Dayalan, Pavithra; Ramamurthy, Viraragavan [Department of Biotechnology, PSG College of Technology, Coimbatore 641004 (India)

    2013-08-02

    Highlights: •Estradiol (E2) at low dose induced cell proliferation in breast cancer cells. •E2 at high concentration induced cell stress in breast cancer cells. •Estrogen receptor physically interacts only with a few transcription factors. •Differential expression of genes with Oct-1 binding sites increased under stress. •Transcription factor binding sites showed distinct spatial distribution on genes. -- Abstract: Background: Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet. Methodology: Meta-analysis of the expression data of MCF7 cells treated with low (1 nM) or high (100 nM) dose of estradiol (E2) was performed. We identified genes differentially expressed at the low or the high dose, and examined the nature of regulatory elements in the vicinity of these genes. Specifically, we looked for the difference in the presence, abundance and spatial distribution of binding sites for estrogen receptor (ER) and selected transcription factors (TFs) in the genomic region up to 25 kb upstream and downstream from the transcription start site (TSS) of these genes. Results: It was observed that at high dose E2 induced the expression of stress responsive genes, while at low dose, genes involved in cell cycle were induced. We found that the occurrence of transcription factor binding regions (TFBRs) for certain factors such as Sp1 and SREBP1 were higher on regulatory regions of genes expressed at low dose. At high concentration of E2, genes with a higher frequency of Oct-1 binding regions were predominantly involved. In addition, there were differences in the spatial distribution pattern of the TFBRs in the genomic regions among the two sets of genes. Discussion: E2 induced predominantly proliferative/metabolic response at low concentrations; but at high concentration, stress–rescue responses were induced

  8. Classification between normal and tumor tissues based on the pair-wise gene expression ratio

    International Nuclear Information System (INIS)

    Yap, YeeLeng; Zhang, XueWu; Ling, MT; Wang, XiangHong; Wong, YC; Danchin, Antoine

    2004-01-01

    Precise classification of cancer types is critically important for early cancer diagnosis and treatment. Numerous efforts have been made to use gene expression profiles to improve precision of tumor classification. However, reliable cancer-related signals are generally lacking. Using recent datasets on colon and prostate cancer, a data transformation procedure from single gene expression to pair-wise gene expression ratio is proposed. Making use of the internal consistency of each expression profiling dataset this transformation improves the signal to noise ratio of the dataset and uncovers new relevant cancer-related signals (features). The efficiency in using the transformed dataset to perform normal/tumor classification was investigated using feature partitioning with informative features (gene annotation) as discriminating axes (single gene expression or pair-wise gene expression ratio). Classification results were compared to the original datasets for up to 10-feature model classifiers. 82 and 262 genes that have high correlation to tissue phenotype were selected from the colon and prostate datasets respectively. Remarkably, data transformation of the highly noisy expression data successfully led to lower the coefficient of variation (CV) for the within-class samples as well as improved the correlation with tissue phenotypes. The transformed dataset exhibited lower CV when compared to that of single gene expression. In the colon cancer set, the minimum CV decreased from 45.3% to 16.5%. In prostate cancer, comparable CV was achieved with and without transformation. This improvement in CV, coupled with the improved correlation between the pair-wise gene expression ratio and tissue phenotypes, yielded higher classification efficiency, especially with the colon dataset – from 87.1% to 93.5%. Over 90% of the top ten discriminating axes in both datasets showed significant improvement after data transformation. The high classification efficiency achieved suggested

  9. An enhanced topologically significant directed random walk in cancer classification using gene expression datasets

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    Choon Sen Seah

    2017-12-01

    Full Text Available Microarray technology has become one of the elementary tools for researchers to study the genome of organisms. As the complexity and heterogeneity of cancer is being increasingly appreciated through genomic analysis, cancerous classification is an emerging important trend. Significant directed random walk is proposed as one of the cancerous classification approach which have higher sensitivity of risk gene prediction and higher accuracy of cancer classification. In this paper, the methodology and material used for the experiment are presented. Tuning parameter selection method and weight as parameter are applied in proposed approach. Gene expression dataset is used as the input datasets while pathway dataset is used to build a directed graph, as reference datasets, to complete the bias process in random walk approach. In addition, we demonstrate that our approach can improve sensitive predictions with higher accuracy and biological meaningful classification result. Comparison result takes place between significant directed random walk and directed random walk to show the improvement in term of sensitivity of prediction and accuracy of cancer classification.

  10. [Expression and significance of CK7 and CK19 in colon cancer].

    Science.gov (United States)

    Zhang, Xin; Zheng, Peng-sheng

    2010-02-01

    To detect the cytokeratin (CK) genes expression in the colon cancer, and investigate the expression variability in different pathological types and clinical stages. The CK gene expression pattern in normal colon, colon cancer tissues and colon cancer cell lines were analyzed by using Immunohistochemical, Immunocytochemical and Western blot ways. CK7 and CK19 didn't express in normal colon tissues. CK7 was low or not expressed in the colon cancer, and CK19 was highly expressed in the colon cancer. There were significant deviation (Pcolon cancer, and CK7-)/CK19+ may be one of the expression characteristics in colon cancer.

  11. Reduced expression of N-Myc downstream-regulated gene 2 in human thyroid cancer

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    Ma Jianjun

    2008-10-01

    Full Text Available Abstract Background NDRG2 (N-Myc downstream-regulated gene 2 was initially cloned in our laboratory. Previous results have shown that NDRG2 expressed differentially in normal and cancer tissues. Specifically, NDRG2 mRNA was down-regulated or undetectable in several human cancers, and over-expression of NDRG2 inhibited the proliferation of cancer cells. NDRG2 also exerts important functions in cell differentiation and tumor suppression. However, it remains unclear whether NDRG2 participates in carcinogenesis of the thyroid. Methods In this study, we investigated the expression profile of human NDRG2 in thyroid adenomas and carcinomas, by examining tissues from individuals with thyroid adenomas (n = 40 and carcinomas (n = 35, along with corresponding normal tissues. Immunohistochemistry, quantitative RT-PCR and western blot methods were utilized to determine both the protein and mRNA expression status of Ndrg2 and c-Myc. Results The immunostaining analysis revealed a decrease of Ndrg2 expression in thyroid carcinomas. When comparing adenomas or carcinomas with adjacent normal tissue from the same individual, the mRNA expression level of NDRG2 was significantly decreased in thyroid carcinoma tissues, while there was little difference in adenoma tissues. This differential expression was confirmed at the protein level by western blotting. However, there were no significant correlations of NDRG2 expression with gender, age, different histotypes of thyroid cancers or distant metastases. Conclusion Our data indicates that NDRG2 may participate in thyroid carcinogenesis. This finding provides novel insight into the important role of NDRG2 in the development of thyroid carcinomas. Future studies are needed to address whether the down-regulation of NDRG2 is a cause or a consequence of the progression from a normal thyroid to a carcinoma.

  12. Reduced expression of N-Myc downstream-regulated gene 2 in human thyroid cancer

    International Nuclear Information System (INIS)

    Zhao, Huadong; Chen, Suning; Lin, Wei; Shi, Hai; Ma, Jianjun; Liu, Xinping; Ma, Qingjiu; Yao, Libo; Zhang, Jian; Lu, Jianguo; He, Xianli; Chen, Changsheng; Li, Xiaojun; Gong, Li; Bao, Guoqiang; Fu, Qiang

    2008-01-01

    NDRG2 (N-Myc downstream-regulated gene 2) was initially cloned in our laboratory. Previous results have shown that NDRG2 expressed differentially in normal and cancer tissues. Specifically, NDRG2 mRNA was down-regulated or undetectable in several human cancers, and over-expression of NDRG2 inhibited the proliferation of cancer cells. NDRG2 also exerts important functions in cell differentiation and tumor suppression. However, it remains unclear whether NDRG2 participates in carcinogenesis of the thyroid. In this study, we investigated the expression profile of human NDRG2 in thyroid adenomas and carcinomas, by examining tissues from individuals with thyroid adenomas (n = 40) and carcinomas (n = 35), along with corresponding normal tissues. Immunohistochemistry, quantitative RT-PCR and western blot methods were utilized to determine both the protein and mRNA expression status of Ndrg2 and c-Myc. The immunostaining analysis revealed a decrease of Ndrg2 expression in thyroid carcinomas. When comparing adenomas or carcinomas with adjacent normal tissue from the same individual, the mRNA expression level of NDRG2 was significantly decreased in thyroid carcinoma tissues, while there was little difference in adenoma tissues. This differential expression was confirmed at the protein level by western blotting. However, there were no significant correlations of NDRG2 expression with gender, age, different histotypes of thyroid cancers or distant metastases. Our data indicates that NDRG2 may participate in thyroid carcinogenesis. This finding provides novel insight into the important role of NDRG2 in the development of thyroid carcinomas. Future studies are needed to address whether the down-regulation of NDRG2 is a cause or a consequence of the progression from a normal thyroid to a carcinoma

  13. Gene set-based module discovery in the breast cancer transcriptome

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    Zhang Michael Q

    2009-02-01

    Full Text Available Abstract Background Although microarray-based studies have revealed global view of gene expression in cancer cells, we still have little knowledge about regulatory mechanisms underlying the transcriptome. Several computational methods applied to yeast data have recently succeeded in identifying expression modules, which is defined as co-expressed gene sets under common regulatory mechanisms. However, such module discovery methods are not applied cancer transcriptome data. Results In order to decode oncogenic regulatory programs in cancer cells, we developed a novel module discovery method termed EEM by extending a previously reported module discovery method, and applied it to breast cancer expression data. Starting from seed gene sets prepared based on cis-regulatory elements, ChIP-chip data, and gene locus information, EEM identified 10 principal expression modules in breast cancer based on their expression coherence. Moreover, EEM depicted their activity profiles, which predict regulatory programs in each subtypes of breast tumors. For example, our analysis revealed that the expression module regulated by the Polycomb repressive complex 2 (PRC2 is downregulated in triple negative breast cancers, suggesting similarity of transcriptional programs between stem cells and aggressive breast cancer cells. We also found that the activity of the PRC2 expression module is negatively correlated to the expression of EZH2, a component of PRC2 which belongs to the E2F expression module. E2F-driven EZH2 overexpression may be responsible for the repression of the PRC2 expression modules in triple negative tumors. Furthermore, our network analysis predicts regulatory circuits in breast cancer cells. Conclusion These results demonstrate that the gene set-based module discovery approach is a powerful tool to decode regulatory programs in cancer cells.

  14. Identification of valid reference genes for the normalization of RT-qPCR expression studies in human breast cancer cell lines treated with and without transient transfection.

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    Lin-Lin Liu

    Full Text Available Reverse transcription-quantitative polymerase chain reaction (RT-qPCR is a powerful technique for examining gene expression changes during tumorigenesis. Target gene expression is generally normalized by a stably expressed endogenous reference gene; however, reference gene expression may differ among tissues under various circumstances. Because no valid reference genes have been documented for human breast cancer cell lines containing different cancer subtypes treated with transient transfection, we identified appropriate and reliable reference genes from thirteen candidates in a panel of 10 normal and cancerous human breast cell lines under experimental conditions with/without transfection treatments with two transfection reagents. Reference gene expression stability was calculated using four algorithms (geNorm, NormFinder, BestKeeper and comparative delta Ct, and the recommended comprehensive ranking was provided using geometric means of the ranking values using the RefFinder tool. GeNorm analysis revealed that two reference genes should be sufficient for all cases in this study. A stability analysis suggests that 18S rRNA-ACTB is the best reference gene combination across all cell lines; ACTB-GAPDH is best for basal breast cancer cell lines; and HSPCB-ACTB is best for ER+ breast cancer cells. After transfection, the stability ranking of the reference gene fluctuated, especially with Lipofectamine 2000 transfection reagent in two subtypes of basal and ER+ breast cell lines. Comparisons of relative target gene (HER2 expression revealed different expressional patterns depending on the reference genes used for normalization. We suggest that identifying the most stable and suitable reference genes is critical for studying specific cell lines under certain circumstances.

  15. Nonviral Delivery Systems For Cancer Gene Therapy: Strategies And Challenges.

    Science.gov (United States)

    Shim, Gayong; Kim, Dongyoon; Le, Quoc-Viet; Park, Gyu Thae; Kwon, Taekhyun; Oh, Yu-Kyoung

    2018-01-19

    Gene therapy has been receiving widespread attention due to its unique advantage in regulating the expression of specific target genes. In the field of cancer gene therapy, modulation of gene expression has been shown to decrease oncogenic factors in cancer cells or increase immune responses against cancer. Due to the macromolecular size and highly negative physicochemical features of plasmid DNA, efficient delivery systems are an essential ingredient for successful gene therapy. To date, a variety of nanostructures and materials have been studied as nonviral gene delivery systems. In this review, we will cover nonviral delivery strategies for cancer gene therapy, with a focus on target cancer genes and delivery materials. Moreover, we will address current challenges and perspectives for nonviral delivery-based cancer gene therapeutics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Casticin induced apoptotic cell death and altered associated gene expression in human colon cancer colo 205 cells.

    Science.gov (United States)

    Shang, Hung-Sheng; Liu, Jia-You; Lu, Hsu-Feng; Chiang, Han-Sun; Lin, Chia-Hain; Chen, Ann; Lin, Yuh-Feng; Chung, Jing-Gung

    2017-08-01

    Casticin, a polymethoxyflavone, derived from natural plant Fructus Viticis exhibits biological activities including anti-cancer characteristics. The anti-cancer and alter gene expression of casticin on human colon cancer cells and the underlying mechanisms were investigated. Flow cytometric assay was used to measure viable cell, cell cycle and sub-G1 phase, reactive oxygen species (ROS) and Ca 2+ productions, level of mitochondria membrane potential (ΔΨ m ) and caspase activity. Western blotting assay was used to detect expression of protein level associated with cell death. Casticin induced cell morphological changes, decreased cell viability and induced G2/M phase arrest in colo 205 cells. Casticin increased ROS production but decreased the levels of ΔΨ m , and Ca 2+ , increased caspase-3, -8, and -9 activities. The cDNA microarray indicated that some of the cell cycle associated genes were down-regulated such as cyclin-dependent kinase inhibitor 1A (CDKN1A) (p21, Cip1) and p21 protein (Cdc42/Rac)-activated kinase 3 (PAK3). TNF receptor-associated protein 1 (TRAP1), CREB1 (cAMP responsive element binding protein 1) and cyclin-dependent kinase inhibitor 1B (CDKN1B) (p27, Kip1) genes were increased but matrix metallopeptidase 2 (MMP-2), toll-like receptor 4 (TLR4), PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, bet), and CaMK4 (calcium/calmodulin-dependent protein kinase IV) genes were inhibited. Results suggest that casticin induced cell apoptosis via the activation of the caspase- and/or mitochondria-dependent signaling cascade, the accumulation of ROS and altered associated gene expressions in colo 205 human colon cancer cells. © 2016 Wiley Periodicals, Inc.

  17. The ordering of expression among a few genes can provide simple cancer biomarkers and signal BRCA1 mutations

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    Parmigiani Giovanni

    2009-08-01

    Full Text Available Abstract Background A major challenge in computational biology is to extract knowledge about the genetic nature of disease from high-throughput data. However, an important obstacle to both biological understanding and clinical applications is the "black box" nature of the decision rules provided by most machine learning approaches, which usually involve many genes combined in a highly complex fashion. Achieving biologically relevant results argues for a different strategy. A promising alternative is to base prediction entirely upon the relative expression ordering of a small number of genes. Results We present a three-gene version of "relative expression analysis" (RXA, a rigorous and systematic comparison with earlier approaches in a variety of cancer studies, a clinically relevant application to predicting germline BRCA1 mutations in breast cancer and a cross-study validation for predicting ER status. In the BRCA1 study, RXA yields high accuracy with a simple decision rule: in tumors carrying mutations, the expression of a "reference gene" falls between the expression of two differentially expressed genes, PPP1CB and RNF14. An analysis of the protein-protein interactions among the triplet of genes and BRCA1 suggests that the classifier has a biological foundation. Conclusion RXA has the potential to identify genomic "marker interactions" with plausible biological interpretation and direct clinical applicability. It provides a general framework for understanding the roles of the genes involved in decision rules, as illustrated for the difficult and clinically relevant problem of identifying BRCA1 mutation carriers.

  18. Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer

    International Nuclear Information System (INIS)

    Harries, Lorna W; Perry, John RB; McCullagh, Paul; Crundwell, Malcolm

    2010-01-01

    Genome wide association studies (GWAS) have identified several genetic variants that are associated with prostate cancer. Most of these variants, like other GWAS association signals, are located in non-coding regions of potential candidate genes, and thus could act at the level of the mRNA transcript. We measured the expression and isoform usage of seven prostate cancer candidate genes in benign and malignant prostate by real-time PCR, and correlated these factors with cancer status and genotype at the GWAS risk variants. We determined that levels of LMTK2 transcripts in prostate adenocarcinomas were only 32% of those in benign tissues (p = 3.2 × 10 -7 ), and that an independent effect of genotype at variant rs6465657 on LMTK2 expression in benign (n = 39) and malignant tissues (n = 21) was also evident (P = 0.002). We also identified that whilst HNF1B(C) and MSMB2 comprised the predominant isoforms in benign tissues (90% and 98% of total HNF1B or MSMB expression), HNF1B(B) and MSMB1 were predominant in malignant tissue (95% and 96% of total HNF1B or MSMB expression; P = 1.7 × 10 -7 and 4 × 10 -4 respectively), indicating major shifts in isoform usage. Our results indicate that the amount or nature of mRNA transcripts expressed from the LMTK2, HNF1B and MSMB candidate genes is altered in prostate cancer, and provides further evidence for a role for these genes in this disorder. The alterations in isoform usage we detect highlights the potential importance of alternative mRNA processing and moderation of mRNA stability as potentially important disease mechanisms

  19. Early diffusion of gene expression profiling in breast cancer patients associated with areas of high income inequality.

    Science.gov (United States)

    Ponce, Ninez A; Ko, Michelle; Liang, Su-Ying; Armstrong, Joanne; Toscano, Michele; Chanfreau-Coffinier, Catherine; Haas, Jennifer S

    2015-04-01

    With the Affordable Care Act reducing coverage disparities, social factors could prominently determine where and for whom innovations first diffuse in health care markets. Gene expression profiling is a potentially cost-effective innovation that guides chemotherapy decisions in early-stage breast cancer, but adoption has been uneven across the United States. Using a sample of commercially insured women, we evaluated whether income inequality in metropolitan areas was associated with receipt of gene expression profiling during its initial diffusion in 2006-07. In areas with high income inequality, gene expression profiling receipt was higher than elsewhere, but it was associated with a 10.6-percentage-point gap between high- and low-income women. In areas with low rates of income inequality, gene expression profiling receipt was lower, with no significant differences by income. Even among insured women, income inequality may indirectly shape diffusion of gene expression profiling, with benefits accruing to the highest-income patients in the most unequal places. Policies reducing gene expression profiling disparities should address low-inequality areas and, in unequal places, practice settings serving low-income patients. Project HOPE—The People-to-People Health Foundation, Inc.

  20. Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

    International Nuclear Information System (INIS)

    Glaysher, Sharon; Modi, Paul; Rahamim, Joe; Smith, Mark E; Amer, Khalid; Addis, Bruce; Poole, Matthew; Narayanan, Ajit; Gulliford, Tim J; Andreotti, Peter E; Cree, Ian A; Yiannakis, Dennis; Gabriel, Francis G; Johnson, Penny; Polak, Marta E; Knight, Louise A; Goldthorpe, Zoe; Peregrin, Katharine; Gyi, Mya

    2009-01-01

    NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer

  1. Gene expression of the mismatch repair gene MSH2 in primary colorectal cancer

    DEFF Research Database (Denmark)

    Jensen, Lars Henrik; Kuramochi, Hidekazu; Crüger, Dorthe Gylling

    2011-01-01

    promoter was only detected in 14 samples and only at a low level with no correlation to gene expression. MSH2 gene expression was not a prognostic factor for overall survival in univariate or multivariate analysis. The gene expression of MSH2 is a potential quantitative marker ready for further clinical...

  2. Different Effects of BORIS/CTCFL on Stemness Gene Expression, Sphere Formation and Cell Survival in Epithelial Cancer Stem Cells.

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    Loredana Alberti

    Full Text Available Cancer stem cells are cancer cells characterized by stem cell properties and represent a small population of tumor cells that drives tumor development, progression, metastasis and drug resistance. To date, the molecular mechanisms that generate and regulate cancer stem cells are not well defined. BORIS (Brother of Regulator of Imprinted Sites or CTCFL (CTCF-like is a DNA-binding protein that is expressed in normal tissues only in germ cells and is re-activated in tumors. Recent evidences have highlighted the correlation of BORIS/CTCFL expression with poor overall survival of different cancer patients. We have previously shown an association of BORIS-expressing cells with stemness gene expression in embryonic cancer cells. Here, we studied the role of BORIS in epithelial tumor cells. Using BORIS-molecular beacon that was already validated, we were able to show the presence of BORIS mRNA in cancer stem cell-enriched populations (side population and spheres of cervical, colon and breast tumor cells. BORIS silencing studies showed a decrease of sphere formation capacity in breast and colon tumor cells. Importantly, BORIS-silencing led to down-regulation of hTERT, stem cell (NANOG, OCT4, SOX2 and BMI1 and cancer stem cell markers (ABCG2, CD44 and ALDH1 genes. Conversely, BORIS-induction led to up-regulation of the same genes. These phenotypes were observed in cervical, colon and invasive breast tumor cells. However, a completely different behavior was observed in the non-invasive breast tumor cells (MCF7. Indeed, these cells acquired an epithelial mesenchymal transition phenotype after BORIS silencing. Our results demonstrate that BORIS is associated with cancer stem cell-enriched populations of several epithelial tumor cells and the different phenotypes depend on the origin of tumor cells.

  3. Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data [version 2; referees: 2 approved

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    Linh Nguyen

    2017-03-01

    Full Text Available Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets, such as those by Genomics of Drug Sensitivity in Cancer (GDSC consortium, were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than standard k-fold cross-validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug. Regarding overall classification performance, about two thirds of the drugs are better predicted by the multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: Thanks to this unbiased validation, we now know that this type of models can predict in vitro tumour response to some of these

  4. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma

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    Lu Lizhi

    2006-12-01

    Full Text Available Abstract Background Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown. Results In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol and etoposide (VP16 compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors. Conclusion Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in

  5. Gene expression profiling of histologically normal breast tissue in females with human epidermal growth factor receptor 2‑positive breast cancer.

    Science.gov (United States)

    Zubor, Pavol; Hatok, Jozef; Moricova, Petra; Kapustova, Ivana; Kajo, Karol; Mendelova, Andrea; Sivonova, Monika Kmetova; Danko, Jan

    2015-02-01

    Gene expression profile‑based taxonomy of breast cancer (BC) has been described as a significant breakthrough in comprehending the differences in the origin and behavior of cancer to allow individually tailored therapeutic approaches. In line with this, we hypothesized that the gene expression profile of histologically normal epithelium (HNEpi) could harbor certain genetic abnormalities predisposing breast tissue cells to develop human epidermal growth factor receptor 2 (HER2)‑positive BC. Thus, the aim of the present study was to assess gene expression in normal and BC tissue (BCTis) from patients with BC in order to establish its value as a potential diagnostic marker for cancer development. An array study evaluating a panel of 84 pathway‑ and disease‑specific genes in HER2‑positive BC and tumor‑adjacent HNEpi was performed using quantitative polymerase chain reaction in 12 patients using microdissected samples from frozen tissue. Common prognostic and predictive parameters of BC were assessed by immunohistochemistry and in situ hybridization. In the BCTis and HNEpi samples of 12 HER2‑positive subjects with BC, the expression of 2,016 genes was assessed. A total of 39.3% of genes were deregulated at a minimal two‑fold deregulation rate and 10.7% at a five‑fold deregulation rate in samples of HNEpi or BCTis. Significant differences in gene expression between BCTis and HNEpi samples were revealed for BCL2L2, CD44, CTSD, EGFR, ERBB2, ITGA6, NGFB, RPL27, SCBG2A1 and SCGB1D2 genes (Pbreast tissue revealed gene expression abnormalities that may represent potential markers of increased risk for HER2‑positive malignant transformation of breast tissue, and may be able to be employed as predictors of prognosis.

  6. Gene expression study and pathway analysis of histological subtypes of intestinal metaplasia that progress to gastric cancer.

    Directory of Open Access Journals (Sweden)

    Osmel Companioni

    Full Text Available Intestinal metaplasia (IM is a precursor lesion that precedes gastric cancer (GC. There are two IM histological subtypes, complete (CIM and incomplete (IIM, the latter having higher progression rates to GC. This study was aimed at analysing gene expression and molecular processes involved in the progression from normal mucosa to IM, and also from IM subtypes to GC.We used expression data to compare the transcriptome of healthy gastric mucosa to that of IM not progressing to GC, and the transcriptome of IM subtypes that had progressed to GC to those that did not progress. Some deregulated genes were validated and pathway analyses were performed.Comparison of IM subtypes that had progressed to GC with those that did not progress showed smaller differences in the expression profiles than the comparison of IM that did not progress with healthy mucosa. New transcripts identified in IM not progressing to GC included TRIM, TMEM, homeobox and transporter genes and SNORD116. Comparison to normal mucosa identified non tumoral Warburg effect and melatonin degradation as previously unreported processes involved in IM. Overexpressed antigen processing is common to both IM-subtypes progressing to GC, but IIM showed more over-expressed oncogenic genes and molecular processes than CIM.There are greater differences in gene expression and molecular processes involved in the progression from normal healthy mucosa to IM than from IM to gastric cancer. While antigen processing is common in both IM-subtypes progressing to GC, more oncogenic processes are observed in the progression of IIM.

  7. Effect of cyclophilin A on gene expression in human pancreatic cancer cells.

    Science.gov (United States)

    Li, Min; Wang, Hao; Li, Fei; Fisher, William E; Chen, Changyi; Yao, Qizhi

    2005-11-01

    We previously found that cyclophilin A (CypA) is overexpressed in human pancreatic cancer cells and stimulates cell proliferation through CD147. In this study, we further investigated the effect of CypA on gene expression of several key molecules that are involved in pancreatic cancer cell proliferation. Human pancreatic cancer cell lines (Panc-1, MIA PaCa-2, and BxPC-3) and human pancreatic ductal epithelial (HPDE) cells were used. The messenger RNA (mRNA) levels of CypA, CypB, CD147, neuropilins (NRPs), vascular endothelial growth factor (VEGF), and VEGF receptors upon the treatment of exogenous recombinant human CypA were determined by real-time reverse-transcription polymerase chain reaction. Exogenous human recombinant CypA reduced the mRNA levels of NRP-1 and VEGF, but not endogenous CypA, CypB, and CD147, in Panc-1, MIA PaCa-2, and BxPC-3 cells. In contrast, HPDE cells showed a decrease of endogenous CypA and CD147 mRNA, but not detectable changes of CypB, NRPs, and VEGF mRNA levels upon exogenous CypA treatment. These data show that exogenous CypA downregulates NRP-1 and VEGF expression in pancreatic cancer cells. This effect is different in normal HPDE cells. Thus, soluble CypA may affect cell growth of pancreatic cancer.

  8. Gene expression profiling of circulating tumor cells and peripheral blood mononuclear cells from breast cancer patients

    Czech Academy of Sciences Publication Activity Database

    Hensler, M.; Vancurova, I.; Becht, E.; Palata, O.; Strnad, P.; Tesarova, P.; Cabinakova, M.; Švec, David; Kubista, Mikael; Bartunkova, J.; Spisek, R.; Sojka, L.

    2016-01-01

    Roč. 5, č. 4 (2016), e1102827 ISSN 2162-402X Institutional support: RVO:86652036 Keywords : Breast cancer * gene expression profiling * circulating tumor cells Subject RIV: FD - Oncology ; Hematology Impact factor: 7.719, year: 2016

  9. 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.

  10. Association between expression of random gene sets and survival is evident in multiple cancer types and may be explained by sub-classification

    Science.gov (United States)

    2018-01-01

    One of the goals of cancer research is to identify a set of genes that cause or control disease progression. However, although multiple such gene sets were published, these are usually in very poor agreement with each other, and very few of the genes proved to be functional therapeutic targets. Furthermore, recent findings from a breast cancer gene-expression cohort showed that sets of genes selected randomly can be used to predict survival with a much higher probability than expected. These results imply that many of the genes identified in breast cancer gene expression analysis may not be causal of cancer progression, even though they can still be highly predictive of prognosis. We performed a similar analysis on all the cancer types available in the cancer genome atlas (TCGA), namely, estimating the predictive power of random gene sets for survival. Our work shows that most cancer types exhibit the property that random selections of genes are more predictive of survival than expected. In contrast to previous work, this property is not removed by using a proliferation signature, which implies that proliferation may not always be the confounder that drives this property. We suggest one possible solution in the form of data-driven sub-classification to reduce this property significantly. Our results suggest that the predictive power of random gene sets may be used to identify the existence of sub-classes in the data, and thus may allow better understanding of patient stratification. Furthermore, by reducing the observed bias this may allow more direct identification of biologically relevant, and potentially causal, genes. PMID:29470520

  11. Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome

    Directory of Open Access Journals (Sweden)

    Jill M. Siegfried

    2015-11-01

    Full Text Available Non–small cell lung cancers (NSCLCs frequently express estrogen receptor (ER β, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50 breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERβ and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERβ and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERβ-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERβ-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERβ-positive cases and squamous cell carcinoma.

  12. Gene expression and adaptive noncoding changes during human evolution.

    Science.gov (United States)

    Babbitt, Courtney C; Haygood, Ralph; Nielsen, William J; Wray, Gregory A

    2017-06-05

    Despite evidence for adaptive changes in both gene expression and non-protein-coding, putatively regulatory regions of the genome during human evolution, the relationship between gene expression and adaptive changes in cis-regulatory regions remains unclear. Here we present new measurements of gene expression in five tissues of humans and chimpanzees, and use them to assess this relationship. We then compare our results with previous studies of adaptive noncoding changes, analyzing correlations at the level of gene ontology groups, in order to gain statistical power to detect correlations. Consistent with previous studies, we find little correlation between gene expression and adaptive noncoding changes at the level of individual genes; however, we do find significant correlations at the level of biological function ontology groups. The types of function include processes regulated by specific transcription factors, responses to genetic or chemical perturbations, and differentiation of cell types within the immune system. Among functional categories co-enriched with both differential expression and noncoding adaptation, prominent themes include cancer, particularly epithelial cancers, and neural development and function.

  13. Clinicopathologic and gene expression parameters predict liver cancer prognosis

    International Nuclear Information System (INIS)

    Hao, Ke; Zhong, Hua; Greenawalt, Danielle; Ferguson, Mark D; Ng, Irene O; Sham, Pak C; Poon, Ronnie T; Molony, Cliona; Schadt, Eric E; Dai, Hongyue; Luk, John M; Lamb, John; Zhang, Chunsheng; Xie, Tao; Wang, Kai; Zhang, Bin; Chudin, Eugene; Lee, Nikki P; Mao, Mao

    2011-01-01

    The prognosis of hepatocellular carcinoma (HCC) varies following surgical resection and the large variation remains largely unexplained. Studies have revealed the ability of clinicopathologic parameters and gene expression to predict HCC prognosis. However, there has been little systematic effort to compare the performance of these two types of predictors or combine them in a comprehensive model. Tumor and adjacent non-tumor liver tissues were collected from 272 ethnic Chinese HCC patients who received curative surgery. We combined clinicopathologic parameters and gene expression data (from both tissue types) in predicting HCC prognosis. Cross-validation and independent studies were employed to assess prediction. HCC prognosis was significantly associated with six clinicopathologic parameters, which can partition the patients into good- and poor-prognosis groups. Within each group, gene expression data further divide patients into distinct prognostic subgroups. Our predictive genes significantly overlap with previously published gene sets predictive of prognosis. Moreover, the predictive genes were enriched for genes that underwent normal-to-tumor gene network transformation. Previously documented liver eSNPs underlying the HCC predictive gene signatures were enriched for SNPs that associated with HCC prognosis, providing support that these genes are involved in key processes of tumorigenesis. When applied individually, clinicopathologic parameters and gene expression offered similar predictive power for HCC prognosis. In contrast, a combination of the two types of data dramatically improved the power to predict HCC prognosis. Our results also provided a framework for understanding the impact of gene expression on the processes of tumorigenesis and clinical outcome

  14. Chemokine CXCL3 mediates prostate cancer cells proliferation, migration and gene expression changes in an autocrine/paracrine fashion.

    Science.gov (United States)

    Xin, Hua; Cao, Yu; Shao, Ming-Liang; Zhang, Wei; Zhang, Chun-Bin; Wang, Jing-Tao; Liang, Li-Chun; Shao, Wen-Wu; Qi, Ya-Ling; Li, Yue; Zhang, Ze-Yu; Yang, Zhe; Sun, Yu-Hong; Zhang, Peng-Xia; Jia, Lin-Lin; Wang, Wei-Qun

    2018-05-01

    We have previously indicated that CXCL3 was upregulated in the tissues of prostate cancer, and exogenous administration of CXCL3 played a predominant role in the tumorigenicity of prostate cancer cells. In the present study, we further explored the role and the underlying mechanism of CXCL3 overexpression in the oncogenic potential of prostate cancer in an autocrine/paracrine fashion. CXCL3-overexpressing prostate cancer cell line PC-3 and immortalized prostate stromal cell line WPMY-1 were established by gene transfection. CCK-8, transwell assays and growth of tumor xenografts were conducted to characterize the effects of CXCL3 on PC-3 cells' proliferation and migration. Western blotting was conducted to test whether CXCL3 could affect the expression of tumorigenesis-associated genes. The results showed that CXCL3 overexpression in PC-3 cells and the PC-3 cells treated with the supernatants of CXCL3-transfected WPMY-1 cells stimulated the proliferation and migration of PC-3 cells in vitro and in a nude mouse xenograft model. Western blotting revealed higher levels of p-ERK, Akt and Bcl-2 and lower levels of Bax in the tumor xenografts transplanted with CXCL3-transfected PC-3 cells. Moreover, the tumor xenografts derived from the PC-3 cells treated with supernatants of CXCL3-transfected WPMY-1 cells showed higher expression of ERK, Akt and Bcl-2 and lower expression of Bax. These findings suggest that CXCL3 autocrine/paracrine pathways are involved in the development of prostate cancer by regulating the expression of the target genes that are related to the progression of malignancies.

  15. Cis-regulatory somatic mutations and gene-expression alteration in B-cell lymphomas.

    Science.gov (United States)

    Mathelier, Anthony; Lefebvre, Calvin; Zhang, Allen W; Arenillas, David J; Ding, Jiarui; Wasserman, Wyeth W; Shah, Sohrab P

    2015-04-23

    With the rapid increase of whole-genome sequencing of human cancers, an important opportunity to analyze and characterize somatic mutations lying within cis-regulatory regions has emerged. A focus on protein-coding regions to identify nonsense or missense mutations disruptive to protein structure and/or function has led to important insights; however, the impact on gene expression of mutations lying within cis-regulatory regions remains under-explored. We analyzed somatic mutations from 84 matched tumor-normal whole genomes from B-cell lymphomas with accompanying gene expression measurements to elucidate the extent to which these cancers are disrupted by cis-regulatory mutations. We characterize mutations overlapping a high quality set of well-annotated transcription factor binding sites (TFBSs), covering a similar portion of the genome as protein-coding exons. Our results indicate that cis-regulatory mutations overlapping predicted TFBSs are enriched in promoter regions of genes involved in apoptosis or growth/proliferation. By integrating gene expression data with mutation data, our computational approach culminates with identification of cis-regulatory mutations most likely to participate in dysregulation of the gene expression program. The impact can be measured along with protein-coding mutations to highlight key mutations disrupting gene expression and pathways in cancer. Our study yields specific genes with disrupted expression triggered by genomic mutations in either the coding or the regulatory space. It implies that mutated regulatory components of the genome contribute substantially to cancer pathways. Our analyses demonstrate that identifying genomically altered cis-regulatory elements coupled with analysis of gene expression data will augment biological interpretation of mutational landscapes of cancers.

  16. Qualitative and quantitative expression status of the human chromosome 20 genes in cancer tissues and the representative cell lines.

    Science.gov (United States)

    Wang, Quanhui; Wen, Bo; Yan, Guangrong; Wei, Junying; Xie, Liqi; Xu, Shaohang; Jiang, Dahai; Wang, Tingyou; Lin, Liang; Zi, Jin; Zhang, Ju; Zhou, Ruo; Zhao, Haiyi; Ren, Zhe; Qu, Nengrong; Lou, Xiaomin; Sun, Haidan; Du, Chaoqin; Chen, Chuangbin; Zhang, Shenyan; Tan, Fengji; Xian, Youqi; Gao, Zhibo; He, Minghui; Chen, Longyun; Zhao, Xiaohang; Xu, Ping; Zhu, Yunping; Yin, Xingfeng; Shen, Huali; Zhang, Yang; Jiang, Jing; Zhang, Chengpu; Li, Liwei; Chang, Cheng; Ma, Jie; Yan, Guoquan; Yao, Jun; Lu, Haojie; Ying, Wantao; Zhong, Fan; He, Qing-Yu; Liu, Siqi

    2013-01-04

    Under the guidance of the Chromosome-centric Human Proteome Project (C-HPP), (1, 2) we conducted a systematic survey of the expression status of genes located at human chromosome 20 (Chr.20) in three cancer tissues, gastric, colon, and liver carcinoma, and their representative cell lines. We have globally profiled proteomes in these samples with combined technology of LC-MS/MS and acquired the corresponding mRNA information upon RNA-seq and RNAchip. In total, 323 unique proteins were identified, covering 60% of the coding genes (323/547) in Chr.20. With regards to qualitative information of proteomics, we overall evaluated the correlation of the identified Chr.20 proteins with target genes of transcription factors or of microRNA, conserved genes and cancer-related genes. As for quantitative information, the expression abundances of Chr.20 genes were found to be almost consistent in both tissues and cell lines of mRNA in all individual chromosome regions, whereas those of Chr.20 proteins in cells are different from tissues, especially in the region of 20q13.33. Furthermore, the abundances of Chr.20 proteins were hierarchically evaluated according to tissue- or cancer-related distribution. The analysis revealed several cancer-related proteins in Chr.20 are tissue- or cell-type dependent. With integration of all the acquired data, for the first time we established a solid database of the Chr.20 proteome.

  17. Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data

    OpenAIRE

    REN, ZHONGLU; WANG, WENHUI; LI, JINMING

    2015-01-01

    Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristi...

  18. The gene regulatory network for breast cancer: Integrated regulatory landscape of cancer hallmarks

    Directory of Open Access Journals (Sweden)

    Frank eEmmert-Streib

    2014-02-01

    Full Text Available In this study, we infer the breast cancer gene regulatory network from gene expression data. This network is obtained from the application of the BC3Net inference algorithm to a large-scale gene expression data set consisting of $351$ patient samples. In order to elucidate the functional relevance of the inferred network, we are performing a Gene Ontology (GO analysis for its structural components. Our analysis reveals that most significant GO-terms we find for the breast cancer network represent functional modules of biological processes that are described by known cancer hallmarks, including translation, immune response, cell cycle, organelle fission, mitosis, cell adhesion, RNA processing, RNA splicing and response to wounding. Furthermore, by using a curated list of census cancer genes, we find an enrichment in these functional modules. Finally, we study cooperative effects of chromosomes based on information of interacting genes in the beast cancer network. We find that chromosome $21$ is most coactive with other chromosomes. To our knowledge this is the first study investigating the genome-scale breast cancer network.

  19. EXPRESSION OF SURVIVIN AND E-CADHERIN IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    TIAN Xiao-feng; LIU Ji-hong; WANG Li-fen; FENG XIAO-Mei; YAO Ji-hong

    2005-01-01

    Objective: Survivin is a member of the inhibitor of apoptosis (IAP) family, and is involved in the regulation of cell division. E-cadherin functionally belongs to transmembrane glycoproteins family, it is responsible for intercellular junction mechanism that is crucial for the mutual association of vertebrate cells. These genes are thought to be associated with cancer aggression. This study was to investigate the relationship between surviving gene, E-cadherin expression and invasion clinicopathological features of breast cancer. Methods: The expression of surviving gene and E-cadherin were detected by SP immunohistochemical technique in tissues of 66 breast cancer, 20 breast fibroadenoma and 20 adjacent breast tissue. Results: The positive rate of surviving gene expression in breast cancer was 42.2%, significantly higher (P=0.025) than those in breast fibroadenoma (35.0%), and adjacent breast tissue (10.0%). The positive rate of E-cadherin in the groups of adjacent breast tissue, breast fibroadenoma and breast cancer were 100%, 100% and 42.4%, there was significant difference between the group of benign and malignant tumor (P=0.005). The positive rate of surviving in breast cancer with local lymph node metastasis was significant higher than that in breast cancer without lymph node metastasis (P=0.01), and E-cadherin in breast cancer with local lymph node metastasis was significant lower than that without lymph node metastasis (P=o.o1). There was no significant difference among the groups of pathological types and TNM stages in the expression of surviving (P=0.966 & P=0.856), but there was significant difference in the expression of E-cadherin among these groups (P=0.01 & P=0.023). Conclusion: The loss or decrease of E-cadherin expression may promote the exfoliation of cancerous cells from original tissues, and surviving gene may promote the viability of the exfoliated cancer cells and the formation of new metastasis focus. These 2 factors cooperate with each other

  20. Systematic assessment of multi-gene predictors of pan-cancer cell line sensitivity to drugs exploiting gene expression data [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Linh Nguyen

    2016-12-01

    Full Text Available Background: Selected gene mutations are routinely used to guide the selection of cancer drugs for a given patient tumour. Large pharmacogenomic data sets were introduced to discover more of these single-gene markers of drug sensitivity. Very recently, machine learning regression has been used to investigate how well cancer cell line sensitivity to drugs is predicted depending on the type of molecular profile. The latter has revealed that gene expression data is the most predictive profile in the pan-cancer setting. However, no study to date has exploited GDSC data to systematically compare the performance of machine learning models based on multi-gene expression data against that of widely-used single-gene markers based on genomics data. Methods: Here we present this systematic comparison using Random Forest (RF classifiers exploiting the expression levels of 13,321 genes and an average of 501 tested cell lines per drug. To account for time-dependent batch effects in IC50 measurements, we employ independent test sets generated with more recent GDSC data than that used to train the predictors and show that this is a more realistic validation than K-fold cross-validation. Results and Discussion: Across 127 GDSC drugs, our results show that the single-gene markers unveiled by the MANOVA analysis tend to achieve higher precision than these RF-based multi-gene models, at the cost of generally having a poor recall (i.e. correctly detecting only a small part of the cell lines sensitive to the drug. Regarding overall classification performance, about two thirds of the drugs are better predicted by multi-gene RF classifiers. Among the drugs with the most predictive of these models, we found pyrimethamine, sunitinib and 17-AAG. Conclusions: We now know that this type of models can predict in vitro tumour response to these drugs. These models can thus be further investigated on in vivo tumour models.

  1. [Effect of sodium phenylbutyrate on the apoptosis of human tongue squamous cancer cell line and expression of p21 and survivin genes].

    Science.gov (United States)

    Chen, Wei-qiang; Feng, Feng-lan; Gu, Hong-biao; Pan, De-shun

    2010-07-01

    To examine the effects of sodium phenylbutyrate on the apoptosis of human tongue squamous cancer cell line and expression of p21 and survivin genes. The inhibition effects of sodium phenylbutyrate on Tca8113 and human tongue squamous cell carcinoma (TCSSA) cell lines were detected by methyl thiazoly terazolium (MTT) and the apoptosis of the cancer cells after being induced by sodium phenylbutyrate examined by flow cytometry (FCM). The expression of p21 and survivin genes were observed with Western blotting and RT-PCR. Compared with control group, the level of p21 mRNA and protein of Tca8113 cellline increased to 0.09 ± 0.08 and increased 0.72 ± 0.10, that of TCSSA cellline increased 1.34 ± 0.12 and 1.56 ± 0.09 (P Sodium phenylbutyrate inhibited the cell proliferation, promoted cell apoptosis and arrested the cells in G₁/G₀ phase. The amount of p21 mRNA and protein were increased, and the expression of survivin gene was decreased. Sodium phenylbutyrate exhibited remarkable inhibitory effects on human tongue squamous cancer cell proliferation and induced cancer cell apoptosis. The mechanism may be due to up-regulation of p21 gene and down-regulation of survivin gene. The mRNA level of p21 gene and survivin gene showed a strong correlation.

  2. In silico analysis of stomach lineage specific gene set expression pattern in gastric cancer.

    Science.gov (United States)

    Pandi, Narayanan Sathiya; Suganya, Sivagurunathan; Rajendran, Suriliyandi

    2013-10-04

    Stomach lineage specific gene products act as a protective barrier in the normal stomach and their expression maintains the normal physiological processes, cellular integrity and morphology of the gastric wall. However, the regulation of stomach lineage specific genes in gastric cancer (GC) is far less clear. In the present study, we sought to investigate the role and regulation of stomach lineage specific gene set (SLSGS) in GC. SLSGS was identified by comparing the mRNA expression profiles of normal stomach tissue with other organ tissue. The obtained SLSGS was found to be under expressed in gastric tumors. Functional annotation analysis revealed that the SLSGS was enriched for digestive function and gastric epithelial maintenance. Employing a single sample prediction method across GC mRNA expression profiles identified the under expression of SLSGS in proliferative type and invasive type gastric tumors compared to the metabolic type gastric tumors. Integrative pathway activation prediction analysis revealed a close association between estrogen-α signaling and SLSGS expression pattern in GC. Elevated expression of SLSGS in GC is associated with an overall increase in the survival of GC patients. In conclusion, our results highlight that estrogen mediated regulation of SLSGS in gastric tumor is a molecular predictor of metabolic type GC and prognostic factor in GC. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo.

    Science.gov (United States)

    Hirashima, Kyotaro; Seimiya, Hiroyuki

    2015-02-27

    Telomere erosion causes cell mortality, suggesting that longer telomeres enable more cell divisions. In telomerase-positive human cancer cells, however, telomeres are often kept shorter than those of surrounding normal tissues. Recently, we showed that cancer cell telomere elongation represses innate immune genes and promotes their differentiation in vivo. This implies that short telomeres contribute to cancer malignancy, but it is unclear how such genetic repression is caused by elongated telomeres. Here, we report that telomeric repeat-containing RNA (TERRA) induces a genome-wide alteration of gene expression in telomere-elongated cancer cells. Using three different cell lines, we found that telomere elongation up-regulates TERRA signal and down-regulates innate immune genes such as STAT1, ISG15 and OAS3 in vivo. Ectopic TERRA oligonucleotides repressed these genes even in cells with short telomeres under three-dimensional culture conditions. This appeared to occur from the action of G-quadruplexes (G4) in TERRA, because control oligonucleotides had no effect and a nontelomeric G4-forming oligonucleotide phenocopied the TERRA oligonucleotide. Telomere elongation and G4-forming oligonucleotides showed similar gene expression signatures. Most of the commonly suppressed genes were involved in the innate immune system and were up-regulated in various cancers. We propose that TERRA G4 counteracts cancer malignancy by suppressing innate immune genes. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. Analysis of gene expression of myo1c and inpp5k genes involved in endometrial adenocarcinoma

    International Nuclear Information System (INIS)

    Koul, A.M.; Nadeem, A.; Baryalai, P.

    2012-01-01

    Abstract: Inpp5k gene encodes a protein which plays a very vital role in a number of metabolic pathways. It is very significant in the glucose metabolism where it regulates the signalling of the insulin pathway. But the full molecular details of the pathways regulated by Inpp5k encoded protein are not known. It is speculated that Inpp5k gene expression is altered in case of endometrial adenocarcinoma. Myolc gene encodes for a protein called Myosin-lc which acts an actin-based molecular motor in the cells. II has been studied that this gene down-regulates during endometrial adenocarcinoma and colorectal cancers. In this study the expression analysis of these two was carried out using multiplex PCR. An endogenous control was used for this PCR. ACTS gene served as the endogenous control because of it being a house keeping gene. It thus shows a universal expression in all cells. Thus in this study the gene expression of Inpp5k and Myulc genes was comparatively analysed with ACTS gene. The results that came out of this study showed an over-expression of Inpp5k gene and down-regulation of myolc gene with respect to ACTS gene in cancer cell lines as was indicated by the previous studies with these genes. Expression of both genes i.e. Inpp5k and Myolc was statistically compared between normal and cancerous cell lines and was found statistically significant at a value of P< O.O I in most of the cases. (author)

  5. Alterations in LMTK2, MSMB and HNF1B gene expression are associated with the development of prostate cancer

    Directory of Open Access Journals (Sweden)

    McCullagh Paul

    2010-06-01

    Full Text Available Abstract Background Genome wide association studies (GWAS have identified several genetic variants that are associated with prostate cancer. Most of these variants, like other GWAS association signals, are located in non-coding regions of potential candidate genes, and thus could act at the level of the mRNA transcript. Methods We measured the expression and isoform usage of seven prostate cancer candidate genes in benign and malignant prostate by real-time PCR, and correlated these factors with cancer status and genotype at the GWAS risk variants. Results We determined that levels of LMTK2 transcripts in prostate adenocarcinomas were only 32% of those in benign tissues (p = 3.2 × 10-7, and that an independent effect of genotype at variant rs6465657 on LMTK2 expression in benign (n = 39 and malignant tissues (n = 21 was also evident (P = 0.002. We also identified that whilst HNF1B(C and MSMB2 comprised the predominant isoforms in benign tissues (90% and 98% of total HNF1B or MSMB expression, HNF1B(B and MSMB1 were predominant in malignant tissue (95% and 96% of total HNF1B or MSMB expression; P = 1.7 × 10-7 and 4 × 10-4 respectively, indicating major shifts in isoform usage. Conclusions Our results indicate that the amount or nature of mRNA transcripts expressed from the LMTK2, HNF1B and MSMB candidate genes is altered in prostate cancer, and provides further evidence for a role for these genes in this disorder. The alterations in isoform usage we detect highlights the potential importance of alternative mRNA processing and moderation of mRNA stability as potentially important disease mechanisms.

  6. Elevated expression of prostate cancer-associated genes is linked to down-regulation of microRNAs

    International Nuclear Information System (INIS)

    Erdmann, Kati; Kaulke, Knut; Thomae, Cathleen; Huebner, Doreen; Sergon, Mildred; Froehner, Michael; Wirth, Manfred P; Fuessel, Susanne

    2014-01-01

    Recent evidence suggests that the prostate cancer (PCa)-specific up-regulation of certain genes such as AMACR, EZH2, PSGR, PSMA and TRPM8 could be associated with an aberrant expression of non-coding microRNAs (miRNA). In silico analyses were used to search for miRNAs being putative regulators of PCa-associated genes. The expression of nine selected miRNAs (hsa-miR-101, -138, -186, -224, -26a, -26b, -374a, -410, -660) as well as of the aforementioned PCa-associated genes was analyzed by quantitative PCR using 50 malignant (Tu) and matched non-malignant (Tf) tissue samples from prostatectomy specimens as well as 30 samples from patients with benign prostatic hyperplasia (BPH). Then, correlations between paired miRNA and target gene expression levels were analyzed. Furthermore, the effect of exogenously administered miR-26a on selected target genes was determined by quantitative PCR and Western Blot in various PCa cell lines. A luciferase reporter assay was used for target validation. The expression of all selected miRNAs was decreased in PCa tissue samples compared to either control group (Tu vs Tf: -1.35 to -5.61-fold; Tu vs BPH: -1.17 to -5.49-fold). The down-regulation of most miRNAs inversely correlated with an up-regulation of their putative target genes with Spearman correlation coefficients ranging from -0.107 to -0.551. MiR-186 showed a significantly diminished expression in patients with non-organ confined PCa and initial metastases. Furthermore, over-expression of miR-26a reduced the mRNA and protein expression of its potential target gene AMACR in vitro. Using the luciferase reporter assay AMACR was validated as new target for miR-26a. The findings of this study indicate that the expression of specific miRNAs is decreased in PCa and inversely correlates with the up-regulation of their putative target genes. Consequently, miRNAs could contribute to oncogenesis and progression of PCa via an altered miRNA-target gene-interaction

  7. Expression of the Long Intergenic Non-Protein Coding RNA 665 (LINC00665) Gene and the Cell Cycle in Hepatocellular Carcinoma Using The Cancer Genome Atlas, the Gene Expression Omnibus, and Quantitative Real-Time Polymerase Chain Reaction.

    Science.gov (United States)

    Wen, Dong-Yue; Lin, Peng; Pang, Yu-Yan; Chen, Gang; He, Yun; Dang, Yi-Wu; Yang, Hong

    2018-05-05

    BACKGROUND Long non-coding RNAs (lncRNAs) have a role in physiological and pathological processes, including cancer. The aim of this study was to investigate the expression of the long intergenic non-protein coding RNA 665 (LINC00665) gene and the cell cycle in hepatocellular carcinoma (HCC) using database analysis including The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and quantitative real-time polymerase chain reaction (qPCR). MATERIAL AND METHODS Expression levels of LINC00665 were compared between human tissue samples of HCC and adjacent normal liver, clinicopathological correlations were made using TCGA and the GEO, and qPCR was performed to validate the findings. Other public databases were searched for other genes associated with LINC00665 expression, including The Atlas of Noncoding RNAs in Cancer (TANRIC), the Multi Experiment Matrix (MEM), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) networks. RESULTS Overexpression of LINC00665 in patients with HCC was significantly associated with gender, tumor grade, stage, and tumor cell type. Overexpression of LINC00665 in patients with HCC was significantly associated with overall survival (OS) (HR=1.47795%; CI: 1.046-2.086). Bioinformatics analysis identified 469 related genes and further analysis supported a hypothesis that LINC00665 regulates pathways in the cell cycle to facilitate the development and progression of HCC through ten identified core genes: CDK1, BUB1B, BUB1, PLK1, CCNB2, CCNB1, CDC20, ESPL1, MAD2L1, and CCNA2. CONCLUSIONS Overexpression of the lncRNA, LINC00665 may be involved in the regulation of cell cycle pathways in HCC through ten identified hub genes.

  8. Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC

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    Amer Khalid

    2009-08-01

    Full Text Available Abstract Background NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE tissue. Results There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

  9. Endocrine aspects of cancer gene therapy.

    Science.gov (United States)

    Barzon, Luisa; Boscaro, Marco; Palù, Giorgio

    2004-02-01

    The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene targeting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, including the possibility to exploit hormone and hormone receptor functions for regulating therapeutic gene expression, the use of endocrine-specific genes as new therapeutic tools, the effects of viral vector delivery and transgene expression on the endocrine system, and the endocrine response to viral vector delivery. Present ethical concerns of gene therapy and the risk of germ cell transduction are also discussed, along with potential lines of innovation to improve cell and gene targeting.

  10. Replication error deficient and proficient colorectal cancer gene expression differences caused by 3'UTR polyT sequence deletions

    DEFF Research Database (Denmark)

    Wilding, Jennifer L; McGowan, Simon; Liu, Ying

    2010-01-01

    , and have distinct pathologies. Regulatory sequences controlling all aspects of mRNA processing, especially including message stability, are found in the 3'UTR sequence of most genes. The relevant sequences are typically A/U-rich elements or U repeats. Microarray analysis of 14 RER+ (deficient) and 16 RER......- (proficient) colorectal cancer cell lines confirms a striking difference in expression profiles. Analysis of the incidence of mononucleotide repeat sequences in the 3'UTRs, 5'UTRs, and coding sequences of those genes most differentially expressed in RER+ versus RER- cell lines has shown that much...... of this differential expression can be explained by the occurrence of a massive enrichment of genes with 3'UTR T repeats longer than 11 base pairs in the most differentially expressed genes. This enrichment was confirmed by analysis of two published consensus sets of RER differentially expressed probesets for a large...

  11. Expression analysis of miRNA and target mRNAs in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng, X.R. [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Lu, P. [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Mei, J.Z.; Liu, G.J. [Medical Oncology Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Fan, Q.X. [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China)

    2014-08-01

    We aimed to investigate miRNAs and related mRNAs through a network-based approach in order to learn the crucial role that they play in the biological processes of esophageal cancer. Esophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC)-related miRNA and gene expression data were downloaded from the Gene Expression Omnibus database, and differentially expressed miRNAs and genes were selected. Target genes of differentially expressed miRNAs were predicted and their regulatory networks were constructed. Differentially expressed miRNA analysis selected four miRNAs associated with EAC and ESCC, among which hsa-miR-21 and hsa-miR-202 were shared by both diseases. hsa-miR-202 was reported for the first time to be associated with esophageal cancer in the present study. Differentially expressed miRNA target genes were mainly involved in cancer-related and signal-transduction pathways. Functional categories of these target genes were related to transcriptional regulation. The results may indicate potential target miRNAs and genes for future investigations of esophageal cancer.

  12. Comparison of Inhibitory Effect of Curcumin Nanoparticles and Free Curcumin in Human Telomerase Reverse Transcriptase Gene Expression in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Nosratollah Zarghami

    2013-02-01

    Full Text Available Purpose: Telomerase is expressed in most cancers, including breast cancer. Curcumin, a polyphenolic compound that obtained from the herb of Curcuma longa, has many anticancer effects. But, its effect is low due to poor water solubility. In order to improve its solubility and drug delivery, we have utilized a β-cyclodextrin-curcumin inclusion complex. Methods: To evaluate cytotoxic effects of cyclodextrin-curcumin and free curcumin, MTT assay was done. Cells were treated with equal concentration of cyclodextrin-curcumin and free curcumin. Telomerase gene expression level in two groups was compared by Real-time PCR. Results: MTT assay demonstrated that β-cyclodextrin-curcumin enhanced curcumin delivery in T47D breast cancer cells. The level of telomerase gene expression in cells treated with cyclodextrin-curcumin was lower than that of cells treated with free curcumin (P=0.001. Conclusion: Results are suggesting that cyclodextrin-curcumin complex can be more effective than free curcumin in inhibition of telomerase expression.

  13. Intracellular delivery of potential therapeutic genes: prospects in cancer gene therapy.

    Science.gov (United States)

    Bakhtiar, Athirah; Sayyad, Mustak; Rosli, Rozita; Maruyama, Atsushi; Chowdhury, Ezharul H

    2014-01-01

    Conventional therapies for malignant cancer such as chemotherapy and radiotherapy are associated with poor survival rates owing to the development of cellular resistance to cancer drugs and the lack of targetability, resulting in unwanted adverse effects on healthy cells and necessitating the lowering of therapeutic dose with consequential lower efficacy of the treatment. Gene therapy employing different types of viral and non-viral carriers to transport gene(s) of interest and facilitating production of the desirable therapeutic protein(s) has tremendous prospects in cancer treatments due to the high-level of specificity in therapeutic action of the expressed protein(s) with diminished off-target effects, although cancer cell-specific delivery of transgene(s) still poses some challenges to be addressed. Depending on the potential therapeutic target genes, cancer gene therapy could be categorized into tumor suppressor gene replacement therapy, immune gene therapy and enzyme- or prodrug-based therapy. This review would shed light on the current progress of delivery of potentially therapeutic genes into various cancer cells in vitro and animal models utilizing a variety of viral and non-viral vectors.

  14. cis sequence effects on gene expression

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    Jacobs Kevin

    2007-08-01

    Full Text Available Abstract Background Sequence and transcriptional variability within and between individuals are typically studied independently. The joint analysis of sequence and gene expression variation (genetical genomics provides insight into the role of linked sequence variation in the regulation of gene expression. We investigated the role of sequence variation in cis on gene expression (cis sequence effects in a group of genes commonly studied in cancer research in lymphoblastoid cell lines. We estimated the proportion of genes exhibiting cis sequence effects and the proportion of gene expression variation explained by cis sequence effects using three different analytical approaches, and compared our results to the literature. Results We generated gene expression profiling data at N = 697 candidate genes from N = 30 lymphoblastoid cell lines for this study and used available candidate gene resequencing data at N = 552 candidate genes to identify N = 30 candidate genes with sufficient variance in both datasets for the investigation of cis sequence effects. We used two additive models and the haplotype phylogeny scanning approach of Templeton (Tree Scanning to evaluate association between individual SNPs, all SNPs at a gene, and diplotypes, with log-transformed gene expression. SNPs and diplotypes at eight candidate genes exhibited statistically significant (p cis sequence effects in our study, respectively. Conclusion Based on analysis of our results and the extant literature, one in four genes exhibits significant cis sequence effects, and for these genes, about 30% of gene expression variation is accounted for by cis sequence variation. Despite diverse experimental approaches, the presence or absence of significant cis sequence effects is largely supported by previously published studies.

  15. Differential gene expression before and after ionizing radiation of subcutaneous fibroblasts identifies breast cancer patients resistant to radiation-induced fibrosis

    DEFF Research Database (Denmark)

    Alsner, Jan; Rødningen, Olaug K.; Overgaard, Jens

    2007-01-01

    BACKGROUND AND PURPOSE: Differentially gene expression between patients with either very low or very high risk of radiation-induced fibrosis (RIF) in patient-derived fibroblasts after irradiation has previously been reported. In the present study, we are investigating the robustness of radiation...... and changes in radiation-induced gene expression in fibroblasts. MATERIAL AND METHODS: Gene expression was analysed by quantitative real-time PCR before and after a fractionated scheme with 3x3.5Gy/3 days in fibroblasts derived from 26 patients with breast cancer treated with post-mastectomy radiotherapy....... RESULTS: Robust radiation-induced changes in gene expression were observed, with differential gene expression between low and high risk patients being most pronounced for the fold induction level ('after' value divided by 'before' value for each patient). When including patients with intermediate risk...

  16. Fatigue and gene expression in human leukocytes: Increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue

    Science.gov (United States)

    Bower, Julienne E.; Ganz, Patricia A.; Irwin, Michael R.; Arevalo, Jesusa M.G.; Cole, Steve W.

    2013-01-01

    Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n = 11) and non-fatigued controls (n = 10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p < .05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. PMID:20854893

  17. Alterations in Bronchial Airway miRNA Expression for Lung Cancer Detection.

    Science.gov (United States)

    Pavel, Ana B; Campbell, Joshua D; Liu, Gang; Elashoff, David; Dubinett, Steven; Smith, Kate; Whitney, Duncan; Lenburg, Marc E; Spira, Avrum

    2017-11-01

    We have previously shown that gene expression alterations in normal-appearing bronchial epithelial cells can serve as a lung cancer detection biomarker in smokers. Given that miRNAs regulate airway gene expression responses to smoking, we evaluated whether miRNA expression is also altered in the bronchial epithelium of smokers with lung cancer. Using epithelial brushings from the mainstem bronchus of patients undergoing bronchoscopy for suspected lung cancer (as part of the AEGIS-1/2 clinical trials), we profiled miRNA expression via small-RNA sequencing from 347 current and former smokers for which gene expression data were also available. Patients were followed for one year postbronchoscopy until a final diagnosis of lung cancer ( n = 194) or benign disease ( n = 153) was made. Following removal of 6 low-quality samples, we used 138 patients (AEGIS-1) as a discovery set to identify four miRNAs (miR-146a-5p, miR-324-5p, miR-223-3p, and miR-223-5p) that were downregulated in the bronchial airway of lung cancer patients (ANOVA P cancer patients (GSEA FDR lung cancer significantly improves its performance (AUC) in the 203 samples (AEGIS-1/2) serving an independent test set (DeLong P lung cancer, and that they may regulate cancer-associated gene expression differences. Cancer Prev Res; 10(11); 651-9. ©2017 AACR . ©2017 American Association for Cancer Research.

  18. Short rare hTERT-VNTR2-2nd alleles are associated with prostate cancer susceptibility and influence gene expression

    International Nuclear Information System (INIS)

    Yoon, Se-Lyun; Cheon, Sang-Hyeon; Leem, Sun-Hee; Jung, Se-Il; Do, Eun-Ju; Lee, Se-Ra; Lee, Sang-Yeop; Chu, In-Sun; Kim, Wun-Jae; Jung, Jaeil; Kim, Choung Soo

    2010-01-01

    The hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2 nd . We investigated how allelic variation in hTERT-VNTR2-2 nd may affect susceptibility to prostate cancer. A case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines. Three new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2 nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines. This is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2 nd locus may function as a modifier of prostate cancer risk by affecting gene expression

  19. Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer.

    Science.gov (United States)

    Baker, J B; Dutta, D; Watson, D; Maddala, T; Munneke, B M; Shak, S; Rowinsky, E K; Xu, L-A; Harbison, C T; Clark, E A; Mauro, D J; Khambata-Ford, S

    2011-02-01

    Although it is accepted that metastatic colorectal cancers (mCRCs) that carry activating mutations in KRAS are unresponsive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, a significant fraction of KRAS wild-type (wt) mCRCs are also unresponsive to anti-EGFR therapy. Genes encoding EGFR ligands amphiregulin (AREG) and epiregulin (EREG) are promising gene expression-based markers but have not been incorporated into a test to dichotomise KRAS wt mCRC patients with respect to sensitivity to anti-EGFR treatment. We used RT-PCR to test 110 candidate gene expression markers in primary tumours from 144 KRAS wt mCRC patients who received monotherapy with the anti-EGFR antibody cetuximab. Results were correlated with multiple clinical endpoints: disease control, objective response, and progression-free survival (PFS). Expression of many of the tested candidate genes, including EREG and AREG, strongly associate with all clinical endpoints. Using multivariate analysis with two-layer five-fold cross-validation, we constructed a four-gene predictive classifier. Strikingly, patients below the classifier cutpoint had PFS and disease control rates similar to those of patients with KRAS mutant mCRC. Gene expression appears to identify KRAS wt mCRC patients who receive little benefit from cetuximab. It will be important to test this model in an independent validation study.

  20. Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

    International Nuclear Information System (INIS)

    Thomassen, Mads; Tan, Qihua; Kruse, Torben A

    2008-01-01

    Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. We have analyzed 8 publicly available gene expression data sets. A global approach, 'gene set enrichment analysis' as well as an approach focusing on a subset of significantly differently regulated genes, GenMAPP, has been applied to rank pathway gene sets according to differential regulation in metastasizing tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. The major findings are up-regulation of cell cycle pathways and a metabolic shift towards glucose metabolism reflected in several pathways in metastasizing tumors. Growth factor pathways seem to play dual roles; EGF and PDGF pathways are decreased, while VEGF and sex-hormone pathways are increased in tumors that metastasize. Furthermore, migration, proteasome, immune system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. By pathway meta-analysis many biological mechanisms beyond major characteristics such as proliferation are identified. Transcription factor analysis identifies a number of key factors that support central pathways. Several previously proposed treatment targets are identified and several new pathways that may

  1. Iodine-131 dose dependent gene expression in thyroid cancers and corresponding normal tissues following the Chernobyl accident.

    Directory of Open Access Journals (Sweden)

    Michael Abend

    Full Text Available The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131 doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T and normal (N tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N on 64 whole genome microarrays (Agilent, 4×44 K. Associations of differential gene expression (log(2(T/N with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N. The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493 were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis.

  2. Molecular Biology In Young Women With Breast Cancer: From Tumor Gene Expression To DNA Mutations.

    Science.gov (United States)

    Gómez-Flores-Ramos, Liliana; Castro-Sánchez, Andrea; Peña-Curiel, Omar; Mohar-Betancourt, Alejandro

    2017-01-01

    Young women with breast cancer (YWBC) represent roughly 15% of breast cancer (BC) cases in Latin America and other developing regions. Breast tumors occurring at an early age are more aggressive and have an overall worse prognosis compared to breast tumors in postmenopausal women. The expression of relevant proliferation biomarkers such as endocrine receptors and human epidermal growth factor receptor 2 appears to be unique in YWBC. Moreover, histopathological, molecular, genetic, and genomic studies have shown that YWBC exhibit a higher frequency of aggressive subtypes, differential tumor gene expression, increased genetic susceptibility, and specific genomic signatures, compared to older women with BC. This article reviews the current knowledge on tumor biology and genomic signatures in YWBC.

  3. Modulation of RIZ gene expression is associated to estradiol control of MCF-7 breast cancer cell proliferation

    International Nuclear Information System (INIS)

    Gazzerro, Patrizia; Abbondanza, Ciro; D'Arcangelo, Andrea; Rossi, Mariangela; Medici, Nicola; Moncharmont, Bruno; Puca, Giovanni Alfredo

    2006-01-01

    The retinoblastoma protein-interacting zinc-finger (RIZ) gene, a member of the nuclear protein methyltransferase superfamily, is characterized by the presence of the N-terminal PR domain. The RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the PR (PRDI-BF1 and RIZ homologous) domain, RIZ2 lacks it. RIZ gene expression is altered in a variety of human cancers and RIZ1 is now considered to be a candidate tumor suppressor. Estradiol treatment of MCF-7 cells produced a selective decrease of RIZ1 transcript and an increase of total RIZ mRNA. Experiments of chromatin immunoprecipitation indicated that RIZ2 protein expression was controlled by estrogen receptor and RIZ1 had a direct repressor function on c-myc gene expression. To investigate the role of RIZ gene products as regulators of the proliferation/differentiation transition, we analyzed the effects of forced suppression of RIZ1 induced in MCF-7 cells by siRNA of the PR domain-containing form. Silencing of RIZ1 expression stimulated cell proliferation, similar to the effect of estradiol on these cells, associated with a transient increase of c-myc expression

  4. Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes.

    NARCIS (Netherlands)

    Weijenberg, M.P.; Luchtenborg, M.; Goeij, A.F. de; Brink, M.; Muijen, G.N.P. van; Bruine, A.P. de; Goldbohm, R.A.; Brandt, P.A. van den

    2007-01-01

    OBJECTIVE: To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat

  5. Selenium is critical for cancer-signaling gene expression but not cell proliferation in human colon Caco-2 cells.

    Science.gov (United States)

    Zeng, Huawei; Botnen, James H

    2007-01-01

    Selenium (Se) is a potential anticarcinogenic nutrient, and the essential role of Se in cell growth is well recognized but certain cancer cells appear to have acquired a survival advantage under conditions of Se-deficiency. To understand the molecular basis of Se-anticancer effects at nutritional doses (nmol/L) for cultured cells, we generated Se-deficient colon Caco-2 cells by gradually reducing serum in media because serum contains a trace amount of Se. The glutathione peroxidase (GPx) activity of Se-deficient Caco-2 cells was 10.8 mU/mg protein compared to 133.6 approximately 146.3 mU/mg protein in Caco-2 cells supplemented with 500 nmol/L selenite, SeMSC or SeMet (three tested Se-chemical forms) after 7-d culture in serum free media. Interestingly, there were no detectable differences in cell growth, cell cycle progression between Se-deficient cells and cells supplemented with 500 nmol/L Se. To examine differential cancer signaling-gene expression between Se-deficient and Se-supplemented cells, we employed a cancer signal pathway-specific array assay coupled with the real time PCR analysis. Our data demonstrate that although Caco-2 cells are resistant to Se deprivation, Se may exert its anticancer property through increasing the expression of humoral defense gene (A2M) and tumor suppressor-related genes (IGFBP3, HHIP) while decreasing pro-inflammatory gene (CXC L9, HSPB2) expression.

  6. Expression of core clock genes in colorectal tumour cells compared with normal mucosa

    DEFF Research Database (Denmark)

    Fonnes, S; Donatsky, A M; Gögenur, I

    2015-01-01

    AIM: Experimental studies have shown that some circadian core clock genes may act as tumour suppressors and have an important role in the response to oncological treatment. This study investigated the evidence regarding modified expression of core clock genes in colorectal cancer and its...... expression of colorectal cancer cells compared with healthy mucosa cells from specimens analysed by real-time or quantitative real-time polymer chain reaction. The expression of the core clock genes Period, Cryptochrome, Bmal1 and Clock in colorectal tumours were compared with healthy mucosa and correlated...... with clinicopathological features and survival. RESULTS: Seventy-four articles were identified and 11 studies were included. Overall, gene expression of Period was significantly decreased in colorectal cancer cells compared with healthy mucosa cells. This tendency was also seen in the gene expression of Clock. Other core...

  7. Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling.

    Directory of Open Access Journals (Sweden)

    Stéphanie Cornen

    Full Text Available Breast cancers (BCs of the luminal B subtype are estrogen receptor-positive (ER+, highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs, DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15 and UTRN (6q24, were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.

  8. The development of genes associated with radiosensitivity of cervical cancer

    International Nuclear Information System (INIS)

    Li Hongyan; Chen Zhihua; He Guifang

    2007-01-01

    It has a good application prospect to predict effects of radiotherapy by examining radiosensitivity of patients with cervical cancers before their radiotherapy. Prediction of tumor cell radiosensitivity according to their level of gene expression and gene therapy to reverse radio-resistance prior to radiation on cervical cancers are heated researches on tumor therapy. The expression of some proliferation-related genes, apoptosis-related genes and hypoxia-related genes can inerease the radiosensitivity of cervical cancer. Microarray technology may have more direct applications to the study of biological pathway contributing to radiation resistance and may lead to development of alternative treatment modalities. (authors)

  9. A mammalianized synthetic nitroreductase gene for high-level expression

    International Nuclear Information System (INIS)

    Grohmann, Maik; Paulmann, Nils; Fleischhauer, Sebastian; Vowinckel, Jakob; Priller, Josef; Walther, Diego J

    2009-01-01

    The nitroreductase/5-(azaridin-1-yl)-2,4-dinitrobenzamide (NTR/CB1954) enzyme/prodrug system is considered as a promising candidate for anti-cancer strategies by gene-directed enzyme prodrug therapy (GDEPT) and has recently entered clinical trials. It requires the genetic modification of tumor cells to express the E. coli enzyme nitroreductase that bioactivates the prodrug CB1954 to a powerful cytotoxin. This metabolite causes apoptotic cell death by DNA interstrand crosslinking. Enhancing the enzymatic NTR activity for CB1954 should improve the therapeutical potential of this enzyme-prodrug combination in cancer gene therapy. We performed de novo synthesis of the bacterial nitroreductase gene adapting codon usage to mammalian preferences. The synthetic gene was investigated for its expression efficacy and ability to sensitize mammalian cells to CB1954 using western blotting analysis and cytotoxicity assays. In our study, we detected cytoplasmic protein aggregates by expressing GFP-tagged NTR in COS-7 cells, suggesting an impaired translation by divergent codon usage between prokaryotes and eukaryotes. Therefore, we generated a synthetic variant of the nitroreductase gene, called ntro, adapted for high-level expression in mammalian cells. A total of 144 silent base substitutions were made within the bacterial ntr gene to change its codon usage to mammalian preferences. The codon-optimized ntro either tagged to gfp or c-myc showed higher expression levels in mammalian cell lines. Furthermore, the ntro rendered several cell lines ten times more sensitive to the prodrug CB1954 and also resulted in an improved bystander effect. Our results show that codon optimization overcomes expression limitations of the bacterial ntr gene in mammalian cells, thereby improving the NTR/CB1954 system at translational level for cancer gene therapy in humans

  10. Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer.

    Science.gov (United States)

    Hussain, Imran; Bhan, Arunoday; Ansari, Khairul I; Deb, Paromita; Bobzean, Samara A M; Perrotti, Linda I; Mandal, Subhrangsu S

    2015-06-01

    HOXC6 is a homeobox-containing gene associated with mammary gland development and is overexpressed in variety of cancers including breast and prostate cancers. Here, we have examined the expression of HOXC6 in breast cancer tissue, investigated its transcriptional regulation via estradiol (E2) and bisphenol-A (BPA, an estrogenic endocrine disruptor) in vitro and in vivo. We observed that HOXC6 is differentially over-expressed in breast cancer tissue. E2 induces HOXC6 expression in cultured breast cancer cells and in mammary glands of Sprague Dawley rats. HOXC6 expression is also induced upon exposure to BPA both in vitro and in vivo. Estrogen-receptor-alpha (ERα) and ER-coregulators such as MLL-histone methylases are bound to the HOXC6 promoter upon exposure to E2 or BPA and that resulted in increased histone H3K4-trimethylation, histone acetylation, and recruitment of RNA polymerase II at the HOXC6 promoter. HOXC6 overexpression induces expression of tumor growth factors and facilitates growth 3D-colony formation, indicating its potential roles in tumor growth. Our studies demonstrate that HOXC6, which is a critical player in mammary gland development, is upregulated in multiple cases of breast cancer, and is transcriptionally regulated by E2 and BPA, in vitro and in vivo. Published by Elsevier B.V.

  11. HPV and high-risk gene expression profiles predict response to chemoradiotherapy in head and neck cancer, independent of clinical factors

    International Nuclear Information System (INIS)

    Jong, Monique C. de; Pramana, Jimmy; Knegjens, Joost L.; Balm, Alfons J.M.; Brekel, Michiel W.M. van den; Hauptmann, Michael; Begg, Adrian C.; Rasch, Coen R.N.

    2010-01-01

    Purpose: The purpose of this study was to combine gene expression profiles and clinical factors to provide a better prediction model of local control after chemoradiotherapy for advanced head and neck cancer. Material and methods: Gene expression data were available for a series of 92 advanced stage head and neck cancer patients treated with primary chemoradiotherapy. The effect of the Chung high-risk and Slebos HPV expression profiles on local control was analyzed in a model with age at diagnosis, gender, tumor site, tumor volume, T-stage and N-stage and HPV profile status. Results: Among 75 patients included in the study, the only factors significantly predicting local control were tumor site (oral cavity vs. Pharynx, hazard ratio 4.2 [95% CI 1.4-12.5]), Chung gene expression status (high vs. Low risk profile, hazard ratio 4.4 [95% CI 1.5-13.3]) and HPV profile (negative vs. Positive profile, hazard ratio 6.2 [95% CI 1.7-22.5]). Conclusions: Chung high-risk expression profile and a negative HPV expression profile were significantly associated with increased risk of local recurrence after chemoradiotherapy in advanced pharynx and oral cavity tumors, independent of clinical factors.

  12. Bioinformatics analysis of breast cancer bone metastasis related gene-CXCR4

    Institute of Scientific and Technical Information of China (English)

    Heng-Wei Zhang; Xian-Fu Sun; Ya-Ning He; Jun-Tao Li; Xu-Hui Guo; Hui Liu

    2013-01-01

    Objective: To analyze breast cancer bone metastasis related gene-CXCR4. Methods: This research screened breast cancer bone metastasis related genes by high-flux gene chip. Results:It was found that the expressions of 396 genes were different including 165 up-regulations and 231 down-regulations. The expression of chemokine receptor CXCR4 was obviously up-regulated in the tissue with breast cancer bone metastasis. Compared with the tissue without bone metastasis, there was significant difference, which indicated that CXCR4 played a vital role in breast cancer bone metastasis. Conclusions: The bioinformatics analysis of CXCR4 can provide a certain basis for the occurrence and diagnosis of breast cancer bone metastasis, target gene therapy and evaluation of prognosis.

  13. Periostin Expression and Its Prognostic Value for Colorectal Cancer

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    Zewu Li

    2015-05-01

    Full Text Available Integrin is important for cell growth, invasion and metastasis, which are frequently observed in malignant tumors. The periostin (POSTN gene encodes the ligand for integrin, one of the key focal adhesion proteins contributing to the formation of a structural link between the extracellular matrix and integrins. High expression levels of the POSTN gene are correlated with numerous human malignancies. We examined POSTN protein in colorectal cancer specimens from 115 patients by strictly following up using immunohistochemistry. Cytoplasm immunohistochemical staining showed POSTN protein expression in colorectal cancers. The positive expression rate of POSTN protein (59.13%, 68/115 in colorectal cancers was significantly higher than that in adjacent normal colon mucosa (0.47%, 11/109. POSTN over-expression in colorectal cancers was positively correlated with tumor size, differentiation, lymph node metastasis, serosal invasion, clinical stage and five-year survival rates. Further analysis showed that patients with advanced stage colorectal cancer and high POSTN expression levels had lower survival rates than those with early stage colorectal cancer and low POSTN expression levels. Overall, our results showed that POSTN played an important role in the progression of colorectal cancers.

  14. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.

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    Laetitia Marisa

    Full Text Available Colon cancer (CC pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype-like, normal-like, serrated CC phenotype-like, and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II-III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after

  15. Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5'-Aza-2'-deoxycytidine.

    Science.gov (United States)

    Fialova, Barbora; Luzna, Petra; Gursky, Jan; Langova, Katerina; Kolar, Zdenek; Trtkova, Katerina Smesny

    2016-10-01

    The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.

  16. Expression level of novel tumor suppressor gene FATS is associated with the outcome of node positive breast cancer

    Institute of Scientific and Technical Information of China (English)

    ZHANG Jun; GU Lin; ZHAO Lu-jun; ZHANG Xi-feng; QIU Li; LI Zheng

    2011-01-01

    Background Recently, we reported the identification of a previously uncharacterized and evolutionarily conserved gene, fragile-site associated tumor suppressor (FATS), at a frequently deleted region in irradiation (IR)-induced tumors.However, the role of FATS in breast cancer development and its clinical significance has not been defined. The aim of this study was to determine the role of FA7S in breast cancer development and to evaluate its clinical significance in breast cancer.Methods The expression level of FATS mRNA was determined in 106 breast carcinomas and 23 paired normal breast tissues using quantitative real time reverse transcription-polymerase chain reaction (RT-PCR). The relationship between FATS expression and clinicopathological parameters were also analyzed.Results The mRNA level of FATS was down-regulated in breast cancer compared with paired normal tissues. Low expression of FATS was correlated with high nuclear grade. There was a tendency to a favorable outcome for patients with high expression of FATS (P=0.346). However, low expression of FATS was associated with poor outcome of breast cancer patients with node positive (P=0.011). Furthermore, the mRNA level of FATS showed an independent value in predicting the outcome of breast cancer patients with positive lymph nodes.Conclusion FATS is involved in the carcinogenesis and development of breast cancer and could be a potential biomarker and prognostic factor for breast cancer therapy.

  17. Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

    Directory of Open Access Journals (Sweden)

    Yan Ting Chiang

    2014-08-01

    Full Text Available Metastatic prostate cancer is currently incurable. Metastasis is thought to result from changes in the expression of specific metastasis-driving genes in nonmetastatic prostate cancer tissue, leading to a cascade of activated downstream genes that set the metastatic process in motion. Such genes could potentially serve as effective therapeutic targets for improved management of the disease. They could be identified by comparative analysis of gene expression profiles of patient-derived metastatic and nonmetastatic prostate cancer tissues to pinpoint genes showing altered expression, followed by determining whether silencing of such genes can lead to inhibition of metastatic properties. Various hurdles encountered in this approach are discussed, including (i the need for clinically relevant, nonmetastatic and metastatic prostate cancer tissues such as xenografts of patients' prostate cancers developed via subrenal capsule grafting technology and (ii limitations in the currently available methodology for identification of master regulatory genes.

  18. 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

  19. Specific genes involved in synthesis and editing of heparan sulfate proteoglycans show altered expression patterns in breast cancer

    International Nuclear Information System (INIS)

    Fernández-Vega, Iván; García, Olivia; Crespo, Ainara; Castañón, Sonia; Menéndez, Primitiva; Astudillo, Aurora; Quirós, Luis M

    2013-01-01

    The expression of a specific set of genes controls the different structures of heparan sulfate proteoglycans (HSPGs), which are involved in the growth, invasion and metastatic properties of cancerous cells. The purpose of this study is to increase knowledge of HSPG alterations in breast cancer. Twenty-three infiltrating ductal adenocarcinomas (IDCs), both metastatic and non-metastatic were studied. A transcriptomic approach to the structure of heparan sulfate (HS) chains was used, employing qPCR to analyze both the expression of the enzymes involved in their biosynthesis and editing, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate chains, we extended the study to include the genes involved in the biosynthesis of these glycosaminoglycans. Histochemical techniques were also used to analyze tissular expression of particular genes showing significant expression differences, of potential interest. No significant change in transcription was detected in approximately 70% of analyzed genes. However, 13 demonstrated changes in both tumor types (40% showing more intense deregulation in the metastatic), while 5 genes showed changes only in non-metastatic tumors. Changes were related to 3 core proteins: overexpression of syndecan-1 and underexpression of glypican-3 and perlecan. HS synthesis was affected by lower levels of some 3-O-sulfotransferase transcripts, the expression of NDST4 and, only in non metastatic tumors, higher levels of extracellular sulfatases. Furthermore, the expression of chondroitin sulfate also was considerably affected, involving both the synthesis of the saccharidic chains and sulfations at all locations. However, the pro-metastatic enzyme heparanase did not exhibit significant changes in mRNA expression, although in metastatic tumors it appeared related to increased levels of the most stable form of mRNA. Finally, the expression of heparanase 2, which displays anti-metastatic features

  20. Robust multi-tissue gene panel for cancer detection

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    Talantov Dmitri

    2010-06-01

    Full Text Available Abstract Background We have identified a set of genes whose relative mRNA expression levels in various solid tumors can be used to robustly distinguish cancer from matching normal tissue. Our current feature set consists of 113 gene probes for 104 unique genes, originally identified as differentially expressed in solid primary tumors in microarray data on Affymetrix HG-U133A platform in five tissue types: breast, colon, lung, prostate and ovary. For each dataset, we first identified a set of genes significantly differentially expressed in tumor vs. normal tissue at p-value = 0.05 using an experimentally derived error model. Our common cancer gene panel is the intersection of these sets of significantly dysregulated genes and can distinguish tumors from normal tissue on all these five tissue types. Methods Frozen tumor specimens were obtained from two commercial vendors Clinomics (Pittsfield, MA and Asterand (Detroit, MI. Biotinylated targets were prepared using published methods (Affymetrix, CA and hybridized to Affymetrix U133A GeneChips (Affymetrix, CA. Expression values for each gene were calculated using Affymetrix GeneChip analysis software MAS 5.0. We then used a software package called Genes@Work for differential expression discovery, and SVM light linear kernel for building classification models. Results We validate the predictability of this gene list on several publicly available data sets generated on the same platform. Of note, when analysing the lung cancer data set of Spira et al, using an SVM linear kernel classifier, our gene panel had 94.7% leave-one-out accuracy compared to 87.8% using the gene panel in the original paper. In addition, we performed high-throughput validation on the Dana Farber Cancer Institute GCOD database and several GEO datasets. Conclusions Our result showed the potential for this panel as a robust classification tool for multiple tumor types on the Affymetrix platform, as well as other whole genome arrays

  1. Expression of Tyrosine Kinase Syk in Breast Cancer and Their Clinical Significance

    Institute of Scientific and Technical Information of China (English)

    DINGYong-bin; WUZheng-yan; WANGShui; FANPing; ZHAXiao-ming; ZHENGWei; LIUXiao-an

    2004-01-01

    To evaluate the effects of the Syk mRNA expression in human breast cancer on tummor growth and metastasis, and the correlalion of the Syk gene expression with ER, PR, 1)53, and HER2/neu. Methods: Using se~i-RT-PCR,specimens from 40 breast cancer palients( tumor 1issues,adjacent normal tissues),and 15 filmmdenoma were detected for the expression of the Syk gene and level of Syk mRNA. Meanwhile, Eli, PR, P53, llER2/neu were detected in 40 tumor tissues from breast cancer with immunohistoch~mical staining. Resu/ts:Expression of the Syk gene was detected in all normal breast 1issues. Unlike normal breast tissue, 31 out of 40 breast cancer tissues did not show any detectable Syk mRNA expression,and there were significant differences in two groups(P <0.05).The level of Syk mRNA in the primary breast cancer 1issues was significantly lower than that in the adjacent non-cancerous breast tissues and benign fibroadenonm breast tissues( P < 0.05). Furthermore, only two breast cancer tissues in 18 pa ",tights with lymph node metastasis had the Syk mRNA expression. The Syk mRNA expression was negatively correlated to lymph nodemetastasis,HER2/neuproteinexpression(P<0.05). Conc/us/on.. The expression of the Syk gene may play an important role in suppressing growth and metastasis of breast cancer.

  2. Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype

    Science.gov (United States)

    Kanth, Priyanka; Bronner, Mary P.; Boucher, Kenneth M.; Burt, Randall W.; Neklason, Deborah W.; Hagedorn, Curt H.; Delker, Don A.

    2016-01-01

    Sessile serrated colon adenoma/polyps (SSA/Ps) are found during routine screening colonoscopy and may account for 20–30% of colon cancers. However, differentiating SSA/Ps from hyperplastic polyps (HP) with little risk of cancer is challenging and complementary molecular markers are needed. Additionally, the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood. RNA sequencing was performed on 21 SSA/Ps, 10 HPs, 10 adenomas, 21 uninvolved colon and 20 control colon specimens. Differential expression and leave-one-out cross validation methods were used to define a unique gene signature of SSA/Ps. Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify a subtype of colon cancers that may develop from SSA/Ps. A total of 1422 differentially expressed genes were found in SSA/Ps relative to controls. Serrated polyposis syndrome (n=12) and sporadic SSA/Ps (n=9) exhibited almost complete (96%) gene overlap. A 51-gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability (MSI-H). A smaller seven-gene panel showed high sensitivity and specificity in identifying BRAF mutant, CpG island methylator phenotype high (CIMP-H) and MLH1 silenced colon cancers. We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway. These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway. PMID:27026680

  3. Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients.

    Science.gov (United States)

    Chang, Jenny C; Makris, Andreas; Gutierrez, M Carolina; Hilsenbeck, Susan G; Hackett, James R; Jeong, Jennie; Liu, Mei-Lan; Baker, Joffre; Clark-Langone, Kim; Baehner, Frederick L; Sexton, Krsytal; Mohsin, Syed; Gray, Tara; Alvarez, Laura; Chamness, Gary C; Osborne, C Kent; Shak, Steven

    2008-03-01

    Previously, we had identified gene expression patterns that predicted response to neoadjuvant docetaxel. Other studies have validated that a high Recurrence Score (RS) by the 21-gene RT-PCR assay is predictive of worse prognosis but better response to chemotherapy. We investigated whether tumor expression of these 21 genes and other candidate genes can predict response to docetaxel. Core biopsies from 97 patients were obtained before treatment with neoadjuvant docetaxel (4 cycles, 100 mg/m2 q3 weeks). Three 10-microm FFPE sections were submitted for quantitative RT-PCR assays of 192 genes that were selected from our previous work and the literature. Of the 97 patients, 81 (84%) had sufficient invasive cancer, 80 (82%) had sufficient RNA for QRTPCR assay, and 72 (74%) had clinical response data. Mean age was 48.5 years, and the median tumor size was 6 cm. Clinical complete responses (CR) were observed in 12 (17%), partial responses in 41 (57%), stable disease in 17 (24%), and progressive disease in 2 patients (3%). A significant relationship (P<0.05) between gene expression and CR was observed for 14 genes, including CYBA. CR was associated with lower expression of the ER gene group and higher expression of the proliferation gene group from the 21 gene assay. Of note, CR was more likely with a high RS (P=0.008). We have established molecular profiles of sensitivity to docetaxel. RT-PCR technology provides a potential platform for a predictive test of docetaxel chemosensitivity using small amounts of routinely processed material.

  4. Gene expression profiling associated with angiotensin II type 2 receptor-induced apoptosis in human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Nana Pei

    Full Text Available Increased expression of angiotensin II type 2 receptor (AT2R induces apoptosis in numerous tumor cell lines, with either Angiotensin II-dependent or Angiotensin II-independent regulation, but its molecular mechanism remains poorly understood. Here, we used PCR Array analysis to determine the gene and microRNA expression profiles in human prostate cancer cell lines transduced with AT2R recombinant adenovirus. Our results demonstrated that AT2R over expression leads to up-regulation of 6 apoptosis-related genes (TRAIL-R2, BAG3, BNIPI, HRK, Gadd45a, TP53BP2, 2 cytokine genes (IL6 and IL8 and 1 microRNA, and down-regulation of 1 apoptosis-related gene TNFSF10 and 2 cytokine genes (BMP6, BMP7 in transduced DU145 cells. HRK was identified as an up-regulated gene in AT2R-transduced PC-3 cells by real-time RT-PCR. Next, we utilized siRNAs to silence the up-regulated genes to further determine their roles on AT2R overexpression mediated apoptosis. The results showed downregulation of Gadd45a reduced the apoptotic effect by ∼30% in DU145 cells, downregulation of HRK reduced AT2R-mediated apoptosis by more than 50% in PC-3 cells, while downregulation of TRAIL-R2 enhanced AT2R-mediated apoptosis more than 4 times in DU145 cells. We also found that the effects on AT2R-mediated apoptosis caused by downregulation of Gadd45a, TRAIL-R2 and HRK were independent in activation of p38 MAPK, p44/42 MAPK and p53. Taken together, our results demonstrated that TRAIL-R2, Gadd45a and HRK may be novel target genes for further study of the mechanism of AT2R-mediated apoptosis in prostate cancer cells.

  5. PRAME gene expression profile in medulloblastoma

    Directory of Open Access Journals (Sweden)

    Tânia Maria Vulcani-Freitas

    2011-02-01

    Full Text Available Medulloblastoma is the most common malignant tumors of central nervous system in the childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, and has limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84% samples. But no statistical association was found between clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas.

  6. Expression of stanniocalcin 1 in thyroid side population cells and thyroid cancer cells.

    Science.gov (United States)

    Hayase, Suguru; Sasaki, Yoshihito; Matsubara, Tsutomu; Seo, Daekwan; Miyakoshi, Masaaki; Murata, Tsubasa; Ozaki, Takashi; Kakudo, Kennichi; Kumamoto, Kensuke; Ylaya, Kris; Cheng, Sheue-yann; Thorgeirsson, Snorri S; Hewitt, Stephen M; Ward, Jerrold M; Kimura, Shioko

    2015-04-01

    Mouse thyroid side population (SP) cells consist of a minor population of mouse thyroid cells that may have multipotent thyroid stem cell characteristics. However the nature of thyroid SP cells remains elusive, particularly in relation to thyroid cancer. Stanniocalcin (STC) 1 and 2 are secreted glycoproteins known to regulate serum calcium and phosphate homeostasis. In recent years, the relationship of STC1/2 expression to cancer has been described in various tissues. Microarray analysis was carried out to determine genes up- and down-regulated in thyroid SP cells as compared with non-SP cells. Among genes up-regulated, stanniocalcin 1 (STC1) was chosen for study because of its expression in various thyroid cells by Western blotting and immunohistochemistry. Gene expression analysis revealed that genes known to be highly expressed in cancer cells and/or involved in cancer invasion/metastasis were markedly up-regulated in SP cells from both intact as well as partial thyroidectomized thyroids. Among these genes, expression of STC1 was found in five human thyroid carcinoma-derived cell lines as revealed by analysis of mRNA and protein, and its expression was inversely correlated with the differentiation status of the cells. Immunohistochemical analysis demonstrated higher expression of STC1 in the thyroid tumor cell line and thyroid tumor tissues from humans and mice. These results suggest that SP cells contain a population of cells that express genes also highly expressed in cancer cells including Stc1, which warrants further study on the role of SP cells and/or STC1 expression in thyroid cancer.

  7. Absence of pepsinogen A3 gene expression in the gastric mucosa of patients with gastric cancer.

    OpenAIRE

    Kuipers, E J; Peña, A S; Crusius, J B; Defize, J; van der Stoop, P; Meuwissen, S G; Pals, G

    1995-01-01

    AIMS--To investigate the expression of pepsinogen A3 (Pg3) encoding genes in the gastric mucosa of normal controls and subjects with atrophic gastritis and gastric cancer. METHODS--One hundred and fifty nine patients underwent upper gastrointestinal endoscopy with sampling of gastric biopsy specimens and serum. Pg3 isoproteins were determined by electrophoresis in serum and gastric mucosal biopsy specimens. Pg3 encoding genes were assessed by PCR in DNA obtained from peripheral blood. RESULTS...

  8. Human small-cell lung cancers show amplification and expression of the N-myc gene

    International Nuclear Information System (INIS)

    Nau, M.M.; Brooks, B.J. Jr.; Carney, D.N.; Gazdar, A.F.; Battey, J.F.; Sausville, E.A.; Minna, J.D.

    1986-01-01

    The authors have found that 6 of 31 independently derived human small-cell lung cancer (SCLC) cell lines have 5- to 170-fold amplified N-myc gene sequences. The amplification is seen with probes from two separate exons of N-myc, which are homologous to either the second or the third exon of the c-myc gene. Amplified N-myc sequences were found in a tumor cell line started prior to chemotherapy, in SCLC tumor samples harvested directly from tumor metastases at autopsy, and from a resected primary lung cancer. Several N-myc-amplified tumor cell lines also exhibited N-myc hybridizing fragments not in the germ-line position. In one patient's tumor, an additional amplitifed N-myc DNA fragment was observed and this fragment was heterogeneously distributed in liver metastases. In contrast to SCLC with neuroendocrine properties, no non-small-cell lung cancer lines examined were found to have N-myc amplification. Fragments encoding two N-myc exons also detect increased amounts of a 3.1-kilobase N-myc mRNA in N-myc-amplified SCLC lines and in one cell line that does not show N-myc gene amplification. Both DNA and RNA hybridization experiments, using a 32 P-labelled restriction probe, show that in any one SCLC cell line, only one myc-related gene is amplified and expressed. They conclude that N-myc amplification is both common and potentially significant in the tumorigenesis or tumor progression of SCLC

  9. In vivo targeting of ADAM9 gene expression using lentivirus-delivered shRNA suppresses prostate cancer growth by regulating REG4 dependent cell cycle progression.

    Directory of Open Access Journals (Sweden)

    Che-Ming Liu

    Full Text Available Cancer cells respond to stress by activating a variety of survival signaling pathways. A disintegrin and metalloproteinase (ADAM 9 is upregulated during cancer progression and hormone therapy, functioning in part through an increase in reactive oxygen species. Here, we present in vitro and in vivo evidence that therapeutic targeting of ADAM9 gene expression by lentivirus-delivered small hairpin RNA (shRNA significantly inhibited proliferation of human prostate cancer cell lines and blocked tumor growth in a murine model of prostate cancer bone metastasis. Cell cycle studies confirmed an increase in the G1-phase and decrease in the S-phase population of cancer cells under starvation stress conditions, which correlated with elevated intracellular superoxide levels. Microarray data showed significantly decreased levels of regenerating islet-derived family member 4 (REG4 expression in prostate cancer cells with knockdown of ADAM9 gene expression. This REG4 downregulation also resulted in induction of expression of p21(Cip1/WAF1, which negatively regulates cyclin D1 and blocks the G1/S transition. Our data reveal a novel molecular mechanism of ADAM9 in the regulation of prostate cancer cell proliferation, and suggests a combined modality of ADAM9 shRNA gene therapy and cytotoxic agents for hormone refractory and bone metastatic prostate cancer.

  10. Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

    Directory of Open Access Journals (Sweden)

    Alnawaz Rehemtulla

    2002-01-01

    Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

  11. The Islamic Perspective of Spiritual Intervention Effectiveness on Bio-Psychological Health Displayed by Gene Expression in Breast Cancer Patients.

    Science.gov (United States)

    Hosseini, Leili; Lotfi Kashani, Farah; Akbari, Somayeh; Akbari, Mohammad Esmaeil; Sarafraz Mehr, Saeedeh

    2016-04-01

    During the last two decades, there have been spiritual/religious interventions in cancer patients to prevent or treat a range of physical problems, including managing chronic pain, coping with the disease, boosting hope and mental health. Although societies are of different faiths and belief systems, what they all share is spirituality. Upon this we put forward the hypothesis of changes in gene receptor expressions as a result of spiritual intervention for the first time in the world. In this study, the spiritual intervention was conducted on 57 volunteer females with early breast cancer involvement. Blood samples were collected prior to and after the spiritual intervention to analyze the changes in dopamine gene receptor expressions as the main site of effect. In order to administer the spiritual intervention backed by Quran, Islam and international standards, issues, with emphasis on peace, human growth and perfection, accepting God as an eternal source of power and kindness to build trust and reduce stress, were selected. They included prayer, patience, reliance, self-sacrifice and forgiveness, altruism and kindness, remission and repentance, thankfulness, zikr (mantra), meditation, and death concept. Obtained results from peripheral blood mononuclear cell samples analyzed by real time-PCR showed significant reduction in dopamine gene receptor (DRD1-5) expressions in comparison with those of pre-test scores and the control group. Spiritual intervention based on Islamic principals can bring back mental health, increase hope and quality of life and eventually change dopamine gene receptor expressions resulting in reduction of cell proliferation, thus better prevention and management in breast cancer patients compared to other forms of treatment.

  12. MicroRNA expression profiling to identify and validate reference genes for relative quantification in colorectal cancer.

    LENUS (Irish Health Repository)

    Chang, Kah Hoong

    2010-01-01

    BACKGROUND: Advances in high-throughput technologies and bioinformatics have transformed gene expression profiling methodologies. The results of microarray experiments are often validated using reverse transcription quantitative PCR (RT-qPCR), which is the most sensitive and reproducible method to quantify gene expression. Appropriate normalisation of RT-qPCR data using stably expressed reference genes is critical to ensure accurate and reliable results. Mi(cro)RNA expression profiles have been shown to be more accurate in disease classification than mRNA expression profiles. However, few reports detailed a robust identification and validation strategy for suitable reference genes for normalisation in miRNA RT-qPCR studies. METHODS: We adopt and report a systematic approach to identify the most stable reference genes for miRNA expression studies by RT-qPCR in colorectal cancer (CRC). High-throughput miRNA profiling was performed on ten pairs of CRC and normal tissues. By using the mean expression value of all expressed miRNAs, we identified the most stable candidate reference genes for subsequent validation. As such the stability of a panel of miRNAs was examined on 35 tumour and 39 normal tissues. The effects of normalisers on the relative quantity of established oncogenic (miR-21 and miR-31) and tumour suppressor (miR-143 and miR-145) target miRNAs were assessed. RESULTS: In the array experiment, miR-26a, miR-345, miR-425 and miR-454 were identified as having expression profiles closest to the global mean. From a panel of six miRNAs (let-7a, miR-16, miR-26a, miR-345, miR-425 and miR-454) and two small nucleolar RNA genes (RNU48 and Z30), miR-16 and miR-345 were identified as the most stably expressed reference genes. The combined use of miR-16 and miR-345 to normalise expression data enabled detection of a significant dysregulation of all four target miRNAs between tumour and normal colorectal tissue. CONCLUSIONS: Our study demonstrates that the top six most

  13. MicroRNA expression profiling to identify and validate reference genes for relative quantification in colorectal cancer

    LENUS (Irish Health Repository)

    Chang, Kah Hoong

    2010-04-29

    Abstract Background Advances in high-throughput technologies and bioinformatics have transformed gene expression profiling methodologies. The results of microarray experiments are often validated using reverse transcription quantitative PCR (RT-qPCR), which is the most sensitive and reproducible method to quantify gene expression. Appropriate normalisation of RT-qPCR data using stably expressed reference genes is critical to ensure accurate and reliable results. Mi(cro)RNA expression profiles have been shown to be more accurate in disease classification than mRNA expression profiles. However, few reports detailed a robust identification and validation strategy for suitable reference genes for normalisation in miRNA RT-qPCR studies. Methods We adopt and report a systematic approach to identify the most stable reference genes for miRNA expression studies by RT-qPCR in colorectal cancer (CRC). High-throughput miRNA profiling was performed on ten pairs of CRC and normal tissues. By using the mean expression value of all expressed miRNAs, we identified the most stable candidate reference genes for subsequent validation. As such the stability of a panel of miRNAs was examined on 35 tumour and 39 normal tissues. The effects of normalisers on the relative quantity of established oncogenic (miR-21 and miR-31) and tumour suppressor (miR-143 and miR-145) target miRNAs were assessed. Results In the array experiment, miR-26a, miR-345, miR-425 and miR-454 were identified as having expression profiles closest to the global mean. From a panel of six miRNAs (let-7a, miR-16, miR-26a, miR-345, miR-425 and miR-454) and two small nucleolar RNA genes (RNU48 and Z30), miR-16 and miR-345 were identified as the most stably expressed reference genes. The combined use of miR-16 and miR-345 to normalise expression data enabled detection of a significant dysregulation of all four target miRNAs between tumour and normal colorectal tissue. Conclusions Our study demonstrates that the top six most

  14. Integrative analysis of copy number and gene expression in breast cancer using formalin-fixed paraffin-embedded core biopsy tissue: a feasibility study.

    Science.gov (United States)

    Iddawela, Mahesh; Rueda, Oscar; Eremin, Jenny; Eremin, Oleg; Cowley, Jed; Earl, Helena M; Caldas, Carlos

    2017-07-11

    An absence of reliable molecular markers has hampered individualised breast cancer treatments, and a major limitation for translational research is the lack of fresh tissue. There are, however, abundant banks of formalin-fixed paraffin-embedded (FFPE) tissue. This study evaluated two platforms available for the analysis of DNA copy number and gene expression using FFPE samples. The cDNA-mediated annealing, selection, extension, and ligation assay (DASL™) has been developed for gene expression analysis and the Molecular Inversion Probes assay (Oncoscan™), were used for copy number analysis using FFPE tissues. Gene expression and copy number were evaluated in core-biopsy samples from patients with breast cancer undergoing neoadjuvant chemotherapy (NAC). Forty-three core-biopsies were evaluated and characteristic copy number changes in breast cancers, gains in 1q, 8q, 11q, 17q and 20q and losses in 6q, 8p, 13q and 16q, were confirmed. Regions that frequently exhibited gains in tumours showing a pathological complete response (pCR) to NAC were 1q (55%), 8q (40%) and 17q (40%), whereas 11q11 (37%) gain was the most frequent change in non-pCR tumours. Gains associated with poor survival were 11q13 (62%), 8q24 (54%) and 20q (47%). Gene expression assessed by DASL correlated with immunohistochemistry (IHC) analysis for oestrogen receptor (ER) [area under the curve (AUC) = 0.95], progesterone receptor (PR)(AUC = 0.90) and human epidermal growth factor type-2 receptor (HER-2) (AUC = 0.96). Differential expression analysis between ER+ and ER- cancers identified over-expression of TTF1, LAF-4 and C-MYB (p ≤ 0.05), and between pCR vs non-pCRs, over-expression of CXCL9, AREG, B-MYB and under-expression of ABCG2. This study was an integrative analysis of copy number and gene expression using FFPE core biopsies and showed that molecular marker data from FFPE tissues were consistent with those in previous studies using fresh-frozen samples. FFPE tissue can provide

  15. Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue.

    Science.gov (United States)

    Mina, Lida; Soule, Sharon E; Badve, Sunil; Baehner, Fredrick L; Baker, Joffre; Cronin, Maureen; Watson, Drew; Liu, Mei-Lan; Sledge, George W; Shak, Steve; Miller, Kathy D

    2007-06-01

    Primary chemotherapy provides an ideal opportunity to correlate gene expression with response to treatment. We used paraffin-embedded core biopsies from a completed phase II trial to identify genes that correlate with response to primary chemotherapy. Patients with newly diagnosed stage II or III breast cancer were treated with sequential doxorubicin 75 mg/M2 q2 wks x 3 and docetaxel 40 mg/M2 weekly x 6; treatment order was randomly assigned. Pretreatment core biopsy samples were interrogated for genes that might correlate with pathologic complete response (pCR). In addition to the individual genes, the correlation of the Oncotype DX Recurrence Score with pCR was examined. Of 70 patients enrolled in the parent trial, core biopsies samples with sufficient RNA for gene analyses were available from 45 patients; 9 (20%) had inflammatory breast cancer (IBC). Six (14%) patients achieved a pCR. Twenty-two of the 274 candidate genes assessed correlated with pCR (p < 0.05). Genes correlating with pCR could be grouped into three large clusters: angiogenesis-related genes, proliferation related genes, and invasion-related genes. Expression of estrogen receptor (ER)-related genes and Recurrence Score did not correlate with pCR. In an exploratory analysis we compared gene expression in IBC to non-inflammatory breast cancer; twenty-four (9%) of the genes were differentially expressed (p < 0.05), 5 were upregulated and 19 were downregulated in IBC. Gene expression analysis on core biopsy samples is feasible and identifies candidate genes that correlate with pCR to primary chemotherapy. Gene expression in IBC differs significantly from noninflammatory breast cancer.

  16. ICan: an integrated co-alteration network to identify ovarian cancer-related genes.

    Science.gov (United States)

    Zhou, Yuanshuai; Liu, Yongjing; Li, Kening; Zhang, Rui; Qiu, Fujun; Zhao, Ning; Xu, Yan

    2015-01-01

    Over the last decade, an increasing number of integrative studies on cancer-related genes have been published. Integrative analyses aim to overcome the limitation of a single data type, and provide a more complete view of carcinogenesis. The vast majority of these studies used sample-matched data of gene expression and copy number to investigate the impact of copy number alteration on gene expression, and to predict and prioritize candidate oncogenes and tumor suppressor genes. However, correlations between genes were neglected in these studies. Our work aimed to evaluate the co-alteration of copy number, methylation and expression, allowing us to identify cancer-related genes and essential functional modules in cancer. We built the Integrated Co-alteration network (ICan) based on multi-omics data, and analyzed the network to uncover cancer-related genes. After comparison with random networks, we identified 155 ovarian cancer-related genes, including well-known (TP53, BRCA1, RB1 and PTEN) and also novel cancer-related genes, such as PDPN and EphA2. We compared the results with a conventional method: CNAmet, and obtained a significantly better area under the curve value (ICan: 0.8179, CNAmet: 0.5183). In this paper, we describe a framework to find cancer-related genes based on an Integrated Co-alteration network. Our results proved that ICan could precisely identify candidate cancer genes and provide increased mechanistic understanding of carcinogenesis. This work suggested a new research direction for biological network analyses involving multi-omics data.

  17. A longitudinal study of gene expression in healthy individuals

    Directory of Open Access Journals (Sweden)

    Tessier Michel

    2009-06-01

    Full Text Available Abstract Background The use of gene expression in venous blood either as a pharmacodynamic marker in clinical trials of drugs or as a diagnostic test requires knowledge of the variability in expression over time in healthy volunteers. Here we defined a normal range of gene expression over 6 months in the blood of four cohorts of healthy men and women who were stratified by age (22–55 years and > 55 years and gender. Methods Eleven immunomodulatory genes likely to play important roles in inflammatory conditions such as rheumatoid arthritis and infection in addition to four genes typically used as reference genes were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR, as well as the full genome as represented by Affymetrix HG U133 Plus 2.0 microarrays. Results Gene expression levels as assessed by qRT-PCR and microarray were relatively stable over time with ~2% of genes as measured by microarray showing intra-subject differences over time periods longer than one month. Fifteen genes varied by gender. The eleven genes examined by qRT-PCR remained within a limited dynamic range for all individuals. Specifically, for the seven most stably expressed genes (CXCL1, HMOX1, IL1RN, IL1B, IL6R, PTGS2, and TNF, 95% of all samples profiled fell within 1.5–2.5 Ct, the equivalent of a 4- to 6-fold dynamic range. Two subjects who experienced severe adverse events of cancer and anemia, had microarray gene expression profiles that were distinct from normal while subjects who experienced an infection had only slightly elevated levels of inflammatory markers. Conclusion This study defines the range and variability of gene expression in healthy men and women over a six-month period. These parameters can be used to estimate the number of subjects needed to observe significant differences from normal gene expression in clinical studies. A set of genes that varied by gender was also identified as were a set of genes with elevated

  18. Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Rems Miran

    2009-08-01

    Full Text Available Abstract Background Despite identification of the major genes and pathways involved in the development of colorectal cancer (CRC, it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Therefore we wanted to improve our understanding of the genetic mechanisms of CRC development. Methods We used microarrays to identify novel genes involved in the development of CRC. Real time PCR was used for mRNA expression as well as to search for chromosomal abnormalities within candidate genes. The correlation between the expression obtained by real time PCR and the presence of the KRAS mutation was investigated. Results We detected significant previously undescribed underexpression in CRC for genes SLC26A3, TPM1 and DCN, with a suggested tumour suppressor role. We also describe the correlation between TPM1 and DCN expression and the presence of KRAS mutations in CRC. When searching for chromosomal abnormalities, we found deletion of the TPM1 gene in one case of CRC, but no deletions of DCN and SLC26A3 were found. Conclusion Our study provides further evidence of decreased mRNA expression of three important tumour suppressor genes in cases of CRC, thus implicating them in the development of this type of cancer. Moreover, we found underexpression of the TPM1 gene in a case of CRCs without KRAS mutations, showing that TPM1 might serve as an alternative path of development of CRC. This downregulation could in some cases be mediated by deletion of the TPM1 gene. On the other hand, the correlation of DCN underexpression with the presence of KRAS mutations suggests that DCN expression is affected by the presence of activating KRAS mutations, lowering the amount of the important tumour suppressor protein decorin.

  19. Transcriptome analysis of recurrently deregulated genes across multiple cancers identifies new pan-cancer biomarkers

    DEFF Research Database (Denmark)

    Kaczkowski, Bogumil; Tanaka, Yuji; Kawaji, Hideya

    2016-01-01

    Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression (CAGE) profiles from 225 different cancer cell lines and 339 corresponding primary cell...