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Sample records for pten hamartoma tumor

  1. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome

    NARCIS (Netherlands)

    Nieuwenhuis, M.H.; Kets, C.M.; Murphy-Ryan, M.; Yntema, H.G.; Evans, D.G.; Colas, C.; Moller, P.; Hes, F.J.; Hodgson, S.V.; Olderode-Berends, M.J.; Aretz, S.; Heinimann, K.; Garcia, E.B.; Douglas, F.; Spigelman, A.; Timshel, S.; Lindor, N.M.; Vasen, H.F.

    2014-01-01

    Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hama

  2. Tumor raro em mediastino: hamartoma

    OpenAIRE

    Roberto Saad Júnior; José Donato de Próspero; Roberto Gonçalves; Jorge Henrique Rivaben; Fabiano Alves Squeff

    2013-01-01

    In the present paper we report a case of mediastinal tumor which we believe has never been reported. Since surgical treatment, the patient presented good evolution. We discuss the presentation, differential diagnosis and therapy. Finally, we stress the importance of the pathologic findings.

  3. Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

    OpenAIRE

    Li, Nan; Zhang, Yajie; Han, Xin; Liang, Ke; Wang, Jiadong; Feng, Lin; Wang, Wenqi; Songyang, Zhou; Lin, Chunru; Yang, Liuqing; Yu, Yonghao; Chen, Junjie

    2015-01-01

    Li et al. report ADP-ribosylation as a new post-translational modification of the tumor suppressor PTEN. Tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas.

  4. Hamartoma angiomatoso écrino: um tumor doloroso Eccrine angiomatous hamartoma: a painful tumor

    Directory of Open Access Journals (Sweden)

    Michelle Larissa Zini Lise

    2003-08-01

    Full Text Available O hamartoma angiomatoso écrino (HAE é lesão benigna, em geral, congênita. Apresenta-se na maioria dos casos como nódulo ou placa cor da pele ou eritematosa associada ou não à hiperidrose focal e dor. Localiza-se preferencialmente nos membros inferiores, próximo aos joelhos ou nos artelhos, mas lesões na face, região cervical, sacra e tronco foram descritas. O principal diagnóstico diferencial deve ser feito com o tumor glômico. Em geral, o HAE tem evolução benigna, havendo relatos de remissão espontânea da dor, sem necessidade de remoção. Contudo, foram descritos casos em que a dor levou à exérese da lesão e mesmo à amputação do membro afetado. Os autores relatam um caso de hamartoma angiomatoso écrino de aparecimento tardio, com sintomatologia exuberante e de difícil tratamento.Eccrine angiomatous hamartoma (EAH is a benign lesion usually present at birth. In most cases it presents as a flesh-colored or erythematous nodule or patch. It may or may not be associated with focal hyperhydrosis and pain. It is most commonly located in the lower extremities, near the knee or on the toes, but lesions on the face, sacral and cervical region and trunk have been described. The main differential diagnosis should be made with a glomus tumor. In general, EAH shows benign behavior, and spontaneous remission of pain has been described. Cases have been reported in which the pain led to excision and even to amputation of the affected member. The authors present a case of late onset EAH, with exuberant symptoms, which was difficult to treat.

  5. Role of PTEN in the Tumor Microenvironment

    Science.gov (United States)

    2008-06-01

    mouse mammary tumors. Oncogene 24, 6870-6876. 11. Park ES, Lee JS, Woo HG, Zhan F, Shih JH, Shaughnessy JD Jr, Frederic Mushinski J. (2007...between: Pearson : p-value PTEN and ETS2-P (T72) -0.577 < 0.001 PTEN and AKT-P (S473) -0.552 < 0.001 ETS2-P (T72) and AKT-P (S473) 0.947 < 0.001 50μm

  6. Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth

    Science.gov (United States)

    Li, Nan; Zhang, Yajie; Han, Xin; Liang, Ke; Wang, Jiadong; Feng, Lin; Wang, Wenqi; Songyang, Zhou; Lin, Chunru; Yang, Liuqing; Yu, Yonghao

    2015-01-01

    PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN–AKT pathway that can be explored further for cancer treatment. PMID:25547115

  7. A functional dissection of PTEN N-terminus : Implications in PTEN subcellular targeting and tumor suppressor activity

    NARCIS (Netherlands)

    Gil, Anabel; Rodríguez-Escudero, Isabel; Stumpf, Miriam; Molina, María; Cid, Víctor J.; Pulido, Rafael

    2015-01-01

    Spatial regulation of the tumor suppressor PTEN is exerted through alternative plasma membrane, cytoplasmic, and nuclear subcellular locations. The N-terminal region of PTEN is important for the control of PTEN subcellular localization and function. It contains both an active nuclear localization

  8. Caffeine activates tumor suppressor PTEN in sarcoma cells

    OpenAIRE

    Miwa, Shinji; Sugimoto, Naotoshi; Shirai, Toshiharu; Hayashi, Katsuhiro; Nishida, Hideji; Ohnari, Issei; Takeuchi, Akihiko; Yachie, Akihiro; Tsuchiya, Hiroyuki

    2011-01-01

    The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Akt activation exerts a strong anti-apoptotic effect and inhibits key pro-apoptotic proteins. We investigated the effect of caffeine in the prevention of tumor cell proliferation and induction of cell death. We found that caffeine induced increased intracellular cAMP levels, PTEN activation and Akt inactivation, which to...

  9. Peripheral Tumor with Osteodentin and Cementum-like Material in an Infant: Odontogenic Hamartoma or Odontoma?

    Science.gov (United States)

    Sfakianou, Aikaterini; Emmanouil, Dimitris E; Tosios, Konstantinos I; Sklavounou, Alexandra

    2016-01-01

    The purpose of this report is to describe a peripheral tumor on the mandibular alveolar ridge of a seven-month-old Caucasian boy, consisting of ectomesencymal odontogenic tissues, in particular osteodentin and cementum-like material, in a cellular or loose vascular connective tissue stroma. This case may be considered either a peripheral odontogenic hamartoma or a peripheral odontoma.

  10. Characterization of Heterogeneous Prostate Tumors in Targeted Pten Knockout Mice.

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    Hanneke Korsten

    Full Text Available Previously, we generated a preclinical mouse prostate tumor model based on PSA-Cre driven inactivation of Pten. In this model homogeneous hyperplastic prostates (4-5m developed at older age (>10m into tumors. Here, we describe the molecular and histological characterization of the tumors in order to better understand the processes that are associated with prostate tumorigenesis in this targeted mouse Pten knockout model. The morphologies of the tumors that developed were very heterogeneous. Different histopathological growth patterns could be identified, including intraductal carcinoma (IDC, adenocarcinoma and undifferentiated carcinoma, all strongly positive for the epithelial cell marker Cytokeratin (CK, and carcinosarcomas, which were negative for CK. IDC pattern was already detected in prostates of 7-8 month old mice, indicating that it could be a precursor stage. At more than 10 months IDC and carcinosarcoma were most frequently observed. Gene expression profiling discriminated essentially two molecular subtypes, denoted tumor class 1 (TC1 and tumor class 2 (TC2. TC1 tumors were characterized by high expression of epithelial markers like Cytokeratin 8 and E-Cadherin whereas TC2 tumors showed high expression of mesenchyme/stroma markers such as Snail and Fibronectin. These molecular subtypes corresponded with histological growth patterns: where TC1 tumors mainly represented adenocarcinoma/intraductal carcinoma, in TC2 tumors carcinosarcoma was the dominant growth pattern. Further molecular characterization of the prostate tumors revealed an increased expression of genes associated with the inflammatory response. Moreover, functional markers for senescence, proliferation, angiogenesis and apoptosis were higher expressed in tumors compared to hyperplasia. The highest expression of proliferation and angiogenesis markers was detected in TC2 tumors. Our data clearly showed that in the genetically well-defined PSA-Cre;Pten-loxP/loxP prostate tumor

  11. Reduced Expression of PTEN Protein and Its Prognostic Significance in the Gastrointestinal Stromal Tumor

    Institute of Scientific and Technical Information of China (English)

    张永红; 于冬冬; 李小兰; 胡俊波; 龚建平

    2010-01-01

    Little is reported about the role of PTEN gene in the progression and prognosis of GISTs.This study examined the clinical implications of the tumor suppressor gene PTEN as a prognostic factor in the GISTs.Immunohistological staining and immunoblotting were employed to examine the PTEN protein expression,and its association with clinical measures.Clinicopathological features were reviewed by a retrospective examination of medical records.Reduced PTEN expression was significantly associated with tumor diamete...

  12. Malignant neurocristic hamartoma: a tumor distinct from conventional melanoma and malignant blue nevus.

    Science.gov (United States)

    Linskey, Katy R; Dias-Santagata, Dora; Nazarian, Rosalynn M; Le, Long P; Lam, Quynh; Bellucci, Kirsten S W; Robinson-Bostom, Leslie; Mihm, Martin C; Hoang, Mai P

    2011-10-01

    Neurocristic hamartomas are rare pigmented lesions comprised of melanocytes, Schwann cells, and pigmented dendritic spindle cells that involve the skin and soft tissue. Malignant transformation can rarely arise within neurocristic hamartomas. Up to date, there has been only 1 series of 7 cases of malignant neurocristic hamartomas (MNHs), with 3 cases that developed metastases. We present the histology and clinical course of 3 additional cases of MNH, 2 of which were metastatic. CD117 was strongly positive in all cases with available archival materials--the tumors and background neurocristic hamartoma of 3 cases, and 1 lymph node metastasis; however, KIT sequencing for exons 11, 13, 17, and 18 was negative. Mutational analyses of recurrent mutations of 17 cancer genes, including BRAF and KIT, were also negative. Although our series is small, KIT overexpression in MNH does not seem to correlate with gene mutation. The lack of BRAF, NRAS, GNAQ, and KIT mutations seems to support the notion that MNH may be distinct from conventional melanoma and from other dermal melanomas, such as malignant blue nevi and melanoma arising in congenital nevi.

  13. Nasal chondromesenchymal hamartoma: radiographic and histopathologic analysis of a rare pediatric tumor

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Craig; Esguerra, Jorge; Wurzbach, Douglas [Northeastern Ohio Universities College of Medicine, Canton Affiliated Hospitals, Department of Diagnostic Radiology, Canton, OH (United States); Nagaraj, Usha [Northeastern Ohio Universities College of Medicine, Rootstown, OH (United States); Wasdahl, Daniel [Northeastern Ohio Universities College of Medicine, Canton Affiliated Hospitals, Department of Pathology, Canton, OH (United States)

    2007-01-15

    Nasal chondromesenchymal hamartoma (NCMH) is an extremely rare benign pediatric tumor that was described in 1998. Only 19 cases are reported in the literature. We present a 15-year-old girl with nasal obstruction and recurrent sinusitis. Her medical history was significant for a rare ovarian tumor and pleuropulmonary blastoma. CT demonstrated a partially calcified soft-tissue mass obstructing the nasal cavity. The patient underwent endoscopic surgical excision. Histologic and immunohistochemical analyses of the tumor were consistent with NCMH. The imaging characteristics of the tumor are reviewed. NCMH may be part of a syndrome associated with other pediatric neoplastic and dysplastic disease. (orig.)

  14. PTEN: a default gate-keeping tumor suppressor with a versatile tail

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The tumor suppressor PTEN controls a variety of biological processes including cell proliferation, growth, migration, and death. As a master cellular regulator, PTEN itself is also subjected to deliberated regulation to ensure its proper function. Defects in PTEN regulation have a profound impact on carcinogenesis. In this review, we briefly discuss recent advances concerning PTEN regulation and how such knowledge facilitates our understanding and further exploration of PTEN biology. The carboxyl-tail of PTEN, which appears to be associated with multiple types of posttranslational regulation, will be under detailed scrutiny. Further, a comparative analysis of PTEN and p53 suggests while p53 needs to be activated to suppress tumorigenesis (a dormant gatekeeper), PTEN is probably a constitutive surveillant against cancer development, thus a default gatekeeper.

  15. The mechanism involved in the loss of PTEN expression in NSCLC tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Gang; Zhao, Jingfeng; Peng, Xianjing [Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008 (China); Liang, Jian; Deng, Xin [Ruikang Hospital, Guangxi University of Traditional Chinese Medicine, Nanning 530003 (China); Chen, Yuxiang, E-mail: chenyx008@yahoo.cn [Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008 (China); School of Biological Science and Technology, Central South University, Changsha 410008 (China)

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer Radiation stimulates PTEN reexpression in NSCLC independent of p53 activation. Black-Right-Pointing-Pointer PTEN reexpression is mediated by miR-29b overexpression. Black-Right-Pointing-Pointer miR-29b regulates Dnmts expression in NSCLC tumor cells. Black-Right-Pointing-Pointer Target therapy could be established by overexpressing miR-29b expression. -- Abstract: Loss of PTEN expression is observed in most non-small cell lung cancers (NSCLC). However, the mechanism by which PTEN expression is regulated in NSCLC has not been fully elucidated. In this study, we investigated the role of DNA methyltransferases (Dnmts), microRNA-29b (miR-29b), and anti-miR-29b inhibitor in PTEN promoter methylation and PTEN gene expression in H358 NSCLC cells in vitro and in vivo. PTEN mRNA was measured by RT-PCR. PTEN and Dnmts protein levels were measured by Western blot. miR-29b expression was detected by Northern blot. A xenograft H358 tumor mouse model was established by subcutaneously inoculating H358 cells into the right hind limbs of nude mice. We found that radiation induced cell apoptosis and hypomethylation in PTEN promoter, PTEN and miR-29b expression, and downregulation of Dnmt1, 3a and 3b expression in H358 tumor cells. The effect of radiation on gene expression and apoptosis was blocked by anti-miR-29b inhibitor. In the xenograft H358 tumor model, anti-miR-29b inhibitor reversed radiation-induced tumor growth delay, PTEN reexpression and downregulation of Dnmts expression. Our study suggested that miR-29b is an upstream molecule of PTEN. miR-29b regulates PTEN gene expression through downregulating Dnmts expression and subsequently induces hypomethylation in PTEN promoter. Targeting therapy could be established in NSCLC by upregulating miR-29b expression.

  16. Reprogramming of the Tumor Microenvironment by Stromal Pten-regulated miR-320

    Science.gov (United States)

    Bronisz, A; Godlewski, J; Wallace, JA; Merchant, AS; Nowicki, MO; Mathsyaraja, H; Srinivasan, R; Trimboli, AJ; Martin, CK; Li, F; Yu, L; Fernandez, SA; Pécot, T; Rosol, TJ; Cory, S; Hallett, M; Park, M; Piper, MG; Marsh, CB; Yee, LD; Jimenez, RE; Nuovo, G; Lawler, SE; Chiocca, EA; Leone, G; Ostrowski, MC

    2011-01-01

    Phosphatase and tensin homolog deleted on chromosome ten (Pten) in stromal fibroblasts suppresses epithelial mammary tumors, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2, are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumor angiogenesis and tumor cell invasion. Expression of the Pten-miR-320-Ets2 regulated secretome distinguished human normal breast stroma from tumor stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumor suppressor axis that acts in stromal fibroblasts to reprogram the tumor microenvironment and curtail tumor progression. PMID:22179046

  17. Predominant cartilaginous hamartoma: an unusual variant of chondromatous hamartoma.

    Science.gov (United States)

    Seda, Gilbert; Amundson, Dennis; Lin, Mercury Y

    2010-02-01

    Chondromatous hamartomas are the most common benign lung tumors and the third most common pulmonary nodule. Histologically, they are characteristically composed of hyaline cartilage mixed with fibromyxoid stroma and adipose tissue surrounded by epithelial cells. We report the case of a healthy, 60-year-old woman with an incidentally discovered chondromatous hamartoma that was thorascopically excised. Her pulmonary hamartoma was predominantly cartilaginous, which only occurs in 1% of hamartomas.

  18. PTEN Gene: A Model for Genetic Diseases in Dermatology

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    Corrado Romano

    2012-01-01

    Full Text Available PTEN gene is considered one of the most mutated tumor suppressor genes in human cancer, and it’s likely to become the first one in the near future. Since 1997, its involvement in tumor suppression has smoothly increased, up to the current importance. Germline mutations of PTEN cause the PTEN hamartoma tumor syndrome (PHTS, which include the past-called Cowden, Bannayan-Riley-Ruvalcaba, Proteus, Proteus-like, and Lhermitte-Duclos syndromes. Somatic mutations of PTEN have been observed in glioblastoma, prostate cancer, and brest cancer cell lines, quoting only the first tissues where the involvement has been proven. The negative regulation of cell interactions with the extracellular matrix could be the way PTEN phosphatase acts as a tumor suppressor. PTEN gene plays an essential role in human development. A recent model sees PTEN function as a stepwise gradation, which can be impaired not only by heterozygous mutations and homozygous losses, but also by other molecular mechanisms, such as transcriptional regression, epigenetic silencing, regulation by microRNAs, posttranslational modification, and aberrant localization. The involvement of PTEN function in melanoma and multistage skin carcinogenesis, with its implication in cancer treatment, and the role of front office in diagnosing PHTS are the main reasons why the dermatologist should know about PTEN.

  19. [Inhibitory effects of tumor suppressor gene PTEN on proliferation and metastasis of breast cancer ZR-75-1 cells].

    Science.gov (United States)

    Lin, Guan-Ping; Li, Xiang-Yong; Huang, Jin-Wen; Xiong, Liang; Zhou, Ke-Yuan

    2007-10-01

    Tumor suppressor gene PTEN could not only inhibit the proliferation of cancer cells, but also inhibit their metastasis. However, the mechanism is still unclear. This study was to investigate the effects of PTEN gene on the proliferation and metastasis of human breast cancer ZR-75-1 cells, and explore the mechanisms. Wild-type PTEN (wt-PTEN) plasmid and phosphatase-defective PTEN (G129R-PTEN) plasmid were transfected into ZR-75-1 cells by liposome, respectively. Cell proliferation was detected by MTT assay. Transfected cells were selected by puromycin. The expression of PTEN protein was detected by Western blot. Cell adhesion and invasion were tested by adhesion test and invasion test. The proliferation inhibition rate was significantly higher in wt-PTEN-transfected ZR-75-1 cells than in untransfected cells and G129R-PTEN-transfected cells (42.7% vs. 0% and 2.7%, P0.05). The proliferation inhibition of ZR-75-1 cells was enhanced along with the increase of culture time and concentration of wt-PTEN. wt-PTEN also induced cell apoptosis. PTEN protein was expressed efficiently in the cells transfected with either wt-PTEN or G129R-PTEN. The inhibition rates of adhesion and invasion were significantly higher in wt-PTEN-transfected cells than in G129R-PTEN-transfected cells (65.7% vs. 8.8%, 70.4% vs. 6.9%, PZR-75-1 cells.

  20. Pten in the Breast Tumor Microenvironment: Modeling Tumor-Stroma Co-Evolution

    Science.gov (United States)

    Wallace, Julie A.; Li, Fu; Leone, Gustavo; Ostrowski, Michael C.

    2010-01-01

    Solid human tumors and their surrounding microenvironment are hypothesized to co-evolve in a manner that promotes tumor growth, invasiveness and spread. Mouse models of cancer have focused on genetic changes in the epithelial tumor cells and therefore have not robustly tested this hypothesis. We have recently developed a murine breast cancer model that ablates the PTEN tumor suppressor pathway in stromal fibroblasts. Remarkably, the model resembles human breast tumors both at morphologic and molecular levels. We propose that such models reflect subtypes of tumor-stromal co-evolution relevant to human breast cancer, and will therefore be useful in defining the mechanisms that underpin tumor-stroma crosstalk. Additionally, these models should also aid in molecularly classifying human breast tumors based on both the microenvironment subtypes they contain as well as on the tumor subtype. PMID:21303970

  1. Construction and Expression of Human PTEN Tumor Suppressor Gene Recombinant Adenovirus Vector

    Institute of Scientific and Technical Information of China (English)

    CHEN Qingyong; WANG Chunyou; CHEN Daoda; CHEN Jianying; JIANG Chunfang; ZHENG Hai

    2006-01-01

    The recombinant defective adenovirus vector carrying human PTEN tumor suppres sor gene was constructed by using AdEasy-1 system and its expression was detected in human breast cancer cell line MDA-MB-468. Human PTEN cDNA was cloned into adenovirus shuttle plasmid pAdTrack-CMV to generate a recombinant plasmid pAdTrack-CMV-PTEN, then homologeous recombination was carried out in the E. coli BJ5183 by contransforming linearized shuttle vector with adenovirus backbone plasmid pAdEasy-1. The newly recombined defective adenovirus vector AdPTEN containing green fluorescent protein (GFP) was packaged and propagated in 293 cells. After being purified by cesium chloride gradient centrifugation, the adenovirus was transfected into human breast cancer cell line MDA-MB-468 in vitro. The expression of PTEN mRNA and protein in infected human breast cancer cell line MDA-MB-468 was detected by RT-PCR and Western blot respectively. The recombinant defective adenovirus vector carrying PTEN gene was constructed successfully. The viral titer of purified adenovirus was 2.5×1010 pfu/mL, and about 70 % breast cancer cells were infected with Ad PTEN when multiplicity of infection (MOI) reached 50. The exogenous PTEN mRNA and protein were expressed in MDA-MB-468 cells infected with Ad-PTEN by RT-PCR and Western blot. The recombinant defective adenovirus vector of PTEN gene was constructed successfully using AdEasy-1 system rapidly, which paved a sound foundation for gene study of breast cancer.

  2. In Vitro and In Vivo Effects of Tumor Suppressor Gene PTEN on Endometriosis: An Experimental Study

    Science.gov (United States)

    Lv, Juan; Zhu, Qiaoying; Jia, Xuemei; Yu, Ningzhu; Li, Qian

    2016-01-01

    Background Endometriosis can cause dysmenorrhea and infertility. Its pathogenesis has not yet been clarified and its treatment continues to pose enormous challenges. The protein tyrosine phosphatase (PTEN) gene is a tumor suppressor gene. The aim of this study was to investigate the role and significance of PTEN protein in the occurrence, development, and treatment of endometriosis through changes in apoptosis rate, cell cycle, and angiogenesis. Material/Methods PTEN was overexpressed and silenced in lentiviral vectors and inserted into primary endometrial cells. The changes in cell cycle and apoptosis in the different PTEN expression groups were evaluated using flow cytometry. Vessel growth mimicry was observed using 3-dimensional culture. A human-mouse chimeric endometriosis model was constructed using SCID mice. Hematoxylin and eosin staining and immunohistochemistry were used to detect pathological changes in ectopic endometrial tissues and the expression of VEGF protein in a human-mouse chimeric endometriosis mouse model. Results PTEN overexpression significantly increased apoptosis and inhibited the cell cycle compared with the silenced and control groups. Furthermore, cells expressing low PTEN levels were better able to undergo vasculogenic mimicry, and exhibited significantly increased angiogenesis compared to cells overexpressing PTEN. We found that ectopic foci were more easily formed in the endometrial tissue of SCID mice with low PTEN expression, and the VEGF expression in this group was relatively high. Conclusions PTEN inhibits the occurrence and development of endometriosis by regulating angiogenesis and the apoptosis and cell cycle of endometrial cells; therefore, we propose that the PTEN gene can be used to treat endometriosis. PMID:27744455

  3. Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas.

    Science.gov (United States)

    Djordjevic, Bojana; Barkoh, Bedia A; Luthra, Rajyalakshmi; Broaddus, Russell R

    2013-10-01

    Loss of PTEN (phosphatase and tensin homolog) expression and microsatellite instability are two of the more common molecular alterations in endometrial carcinoma. From the published literature, it is controversial as to whether there is a relationship between these different molecular mechanisms. Therefore, a cohort of 187 pure endometrioid and non-endometrioid endometrial carcinomas, carefully characterized as to clinical and pathological features, was examined for PTEN sequence abnormalities and the immunohistochemical expression of PTEN and the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. MLH1 methylation analysis was performed when tumors had loss of MLH1 protein. Mismatch repair protein loss was more frequent in endometrioid carcinomas compared with non-endometrioid carcinomas, a difference primarily attributable to the presence of MLH1 methylation in a greater proportion of endometrioid tumors. Among the non-endometrioid group, mixed endometrioid/non-endometrioid carcinomas were the histotype that most commonly had loss of a mismatch repair protein. In endometrioid tumors, the frequency of PTEN loss measured by immunohistochemistry and mutation did not differ significantly between the mismatch repair protein intact or mismatch repair protein loss groups, suggesting that PTEN loss is independent of mismatch protein repair status in this group. However, in non-endometrioid carcinomas, both intact positive PTEN immunohistochemical expression and PTEN wild type were highly associated with retained positive expression of mismatch repair proteins in the tumor. Relevant to screening endometrial cancers for Lynch Syndrome, an initial PTEN immunohistochemistry determination may be able to replace the use of four mismatch repair immunohistochemical markers in 63% of patients with non-endometrioid endometrial carcinoma. Therefore, PTEN immunohistochemistry, in combination with tumor histotype, is a useful adjunct in the clinical evaluation of endometrial

  4. Hamartoma de la mama Breast hamartoma

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    Mercedes Pérez Vázquez

    2004-06-01

    Full Text Available El hamartoma de la mama o fibroadenolipoma de la mama es una lesión nodular que puede simular un fibroadenoma o un tumor phyllodes . Aparece en las mujeres en la edad media de la vida y se presenta clínicamente como un nódulo bien definido e indoloro. El diagnóstico imagenológico es el que hace pensar en éste, ya que es un tumor poco frecuente. Histológicamente cumple los requisitos generales de un hamartoma: mezcla desordenada de tejidos maduros y especializados. En la mama se puede apreciar estructura ductal y lobulillar con estroma fibroso, tejido adiposo y en ocasiones, tejido muscular liso. En este trabajo se presenta un caso de una paciente de 40 años con un hamartoma de la mama derecha que histológicamente mostraba además, tejido óseo y cartilaginosoBreast hamartoma or breast fibroadenolipoma is a nodular lesion that may resemble a fibroadenoma or phyllodes tumor. It appears in middle-aged women and it clinically presents as a well defined and painless nodule. The imaging diagnosis makes to think about it, since it is an uncommon tumor. From the histological point of view, it fulfills the general requirements of a hamartoma: disarranged combination of mature and specialized tissues. Ductal and lobular structure with fibrous stroma, fat tissue and, on occasions, smooth muscular tissue, may be observed in the breast. A case of a 40-year-old female patient with a hamartoma of the right mamma that histologically showed osteal and cartilaginous tissue is reported

  5. Mulberry Tumors in Retina and Nasal Hamartoma in a Patient With Tuberous Sclerosis

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    S. Reshadat

    2008-10-01

    Full Text Available Introduction: Tuberous Sclerosis (TS is an autosomal dominant disease that affects the brain, skin, eye, heart, kidney even bones. The commonest presentation is seizures in infancy or early childhood (in 80% of cases, mental retardation (in 44%of cases. Characteristic skin lesion includes facial angiofibromas, adenoma sebaceum, hypopigmented macules, shagreen patches ungual ungual fibromas, ash leaf spots, cafe'-au-lait spots.Case Report: A nine years old male was admitted in a pediatric hospital because of the status myoclonic seizures. Seizures had been started since infancy. In physical exam he had some hypopigmented macules, cafe'-au-lait spots and ash leaf lesions, frontal fibrosis and also shagreen patches. Patient was a case of mild mentally retardation with no any focal neurological deficit. Computed tomography scan of brain and MRI imaging revealed sub ependymal tubers with multiple calcification in both sides of parietal region. Electroencephal-ogram recording suggested abnormal spike, sharp wave discharges and lennox-Gastaut pattern. The diagnosis based on the history and physical exam and MRI were tuberous sclerosis. His foundoscopic exam revealed two prominent calcified mass around right optic disc in supratemporal arch, left eye was normal. Retinal angiography revealed the mulberry tumors and right phakoma of retina. Conclusion: Computed tomography also revaled the nasal hamartoma. Histopathologic examination confirmed the diagnosis of angiomyolipoma because the lesion was composed of smooth muscle bundles, mature adipose tissue and blood vessels of different sizes. He remained seizures free after treatment.

  6. [Endobronchial hamartoma revealed by hemoptysis].

    Science.gov (United States)

    Smati, Belhassen; Boudaya, Mohamed Sadok; Mestiri, Taher; Djilani, Habiba; Mezni, Faouzi; Kilani, Tarek

    2005-05-01

    Hamartoma is the most frequent benign tumor of the lung. Its endo bronchial location is rare. We report two cases of endo bronchial hamartoma occurring in 2 men aged 68 and 60 years respectively. The two cases were revealed by hemoptysis. Bronchial fibroscopy showed a bud respectively in the left stump and in the lower left bronchus. Treatment consisted in a pneumonectomy and a lower lobectomy. A histological examination confirmed the diagnosis of endo bronchial hamartoma. Diagnosis of endobronchial hamartoma before surgery is difficult. Pulmonary resections are often necessary because of parenchyma lelions caused bronchial obstruction.

  7. Atypical presentation of myoepithelial hamartoma in the antrum of the stomach, mimicking a gastrointestinal stromal tumor: a case report

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    Nabi Junaid

    2012-11-01

    Full Text Available Abstract Introduction A myoepithelial hamartoma is a very uncommon submucosal tumor of the stomach. In an atypical presentation in our case, it mimicked the clinical presentation of a gastrointestinal stromal tumor. To the best of our knowledge, it is the first case of a hamartoma of the stomach reported from Bangladesh and one of few cases described in the literature. Case presentation We describe the case of a 35-year-old Bengali man with recurrent epigastric pain and occasional vomiting with radiographic findings of a gut mass. An upper gastrointestinal endoscopy revealed a healed duodenal ulcer, deformed ‘D’ bulb and a submucosal swelling in his antrum. Ultrasonography and a contrast-enhanced computed tomography scan confirmed the presence of a well-defined, oval gut mass in his upper abdomen, compressing his duodenum. The mass had a mixed density and was considered to probably be a gastrointestinal stromal tumor. Ultrasonography-guided fine needle aspiration cytology was inconclusive. After resection at laparotomy, a histopathological examination revealed a myoepithelial hamartoma. These tumors are characterized by hypertrophic smooth muscle bands surrounding varied epithelial elements, which may be arranged in diverse patterns such as simple glandular structure, Brunner’s gland, pancreatic ducts and sometimes pancreatic acini. This case report is complemented by a literature review relating to the atypical presentation. Conclusion Gut masses need to be investigated thoroughly and the possibility of rare tumors should not be excluded. Although the recommended treatment for such lesions is limited resection, radical procedures such as a pancreaticoduodenectomy are often performed when the lesion occurs in the periampullary area because of preoperative misdiagnosis as a carcinoma. Therefore, it is essential for clinicians to maintain current knowledge of the lesion to avoid inaccurate diagnosis and prevent unnecessary surgery.

  8. Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau

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    Zhang Xue

    2006-07-01

    Full Text Available Abstract Background Aberrant hyperphosphorylation of tau protein has been implicated in a variety of neurodegenerative disorders. Although a number of protein kinases have been shown to phosphorylate tau in vitro and in vivo, the molecular mechanisms by which tau phosphorylation is regulated pathophysiologically are largely unknown. Recently, a growing body of evidence suggests a link between tau phosphorylation and PI3K signaling. In this study, phosphorylation, aggregation and binding to the microtubule of a mutant frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 tau in the presence of tumor suppressor PTEN, a major regulatory component in PI3K signaling, were investigated. Results Phosphorylation of the human mutant FTDP-17 tau, T40RW, was evaluated using different phospho-tau specific antibodies in the presence of human wild-type or phosphatase activity null mutant PTEN. Among the evaluated phosphorylation sites, the levels of Ser214 and Thr212 phospho-tau proteins were significantly decreased in the presence of wild-type PTEN, and significantly increased when the phosphatase activity null mutant PTEN was ectopically expressed. Fractionation of the mutant tau transfected cells revealed a significantly increased level of soluble tau in cytosol when wild-type PTEN was expressed, and an elevated level of SDS-soluble tau aggregates in the presence of the mutant PTEN. In addition, the filter/trap assays detected more SDS-insoluble mutant tau aggregates in the cells overexpressing the mutant PTEN compared to those in the cells overexpressing wild-type PTEN and control DNA. This notion was confirmed by the immunocytochemical experiment which demonstrated that the overexpression of the phosphatase activity null mutant PTEN caused the mutant tau to form aggregates in the COS-7 cells. Conclusion Tumor suppressor PTEN can alleviate the phosporylation of the mutant FTDP-17 tau at specific sites, and the phosphatase activity

  9. PTEN mutation analysis in two genetic subtypes of high-grade oligodendroglial tumors. PTEN is only occasionally mutated in one of the two genetic subtypes.

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    Jeuken, J W; Nelen, M R; Vermeer, H; van Staveren, W C; Kremer, H; van Overbeeke, J J; Boerman, R H

    2000-05-01

    We recently identified two genetic subtypes of high-grade oligodendroglial tumors (HG-OT): 1p-/19q- HG-OT are characterized by a loss of chromosome 1p32-36 (del(1)(p32-p36) and/or a del(19)(q13. 3); whereas +7/-10 HG-OT harbor a gain of chromosome 7 (+7) and/or a -10 without a loss of 1p32-36 and 19q13.3. Because a -10 and a +7 are most frequently detected in glioblastomas (GBM), the genotype of +7/-10 HG-OT suggests that these tumors are GBM with a prominent oligodendroglial phenotype rather than anaplastic oligodendrogliomas. PTEN is a tumor suppressor gene, located at 10q23.3, which is involved in tumor progression of GBM and other neoplasms. In this study, we screened for PTEN mutations in six low-grade oligodendroglial tumors (LG-OT), five 1p-/19q- HG-OT, seven +7/-10 HG-OT, and nine xenografted GBM. PTEN mutations were detected in none of the LG-OT and 1p-/19q- HG-OT, once in +7/-10 HG-OT, and frequently in GBM. As one of the +7/-10 HG-OT harbored a PTEN mutation, this demonstrates that PTEN can be involved in the oncogenesis of this genetic subtype of HG-OT. The lower frequency of PTEN mutations in +7/-10 HG-OT compared to GBM suggests that these tumors are of a distinct tumor type rather than GBM. Published by Elsevier Science Inc.

  10. Clinical Implications for Germline PTEN Spectrum Disorders.

    Science.gov (United States)

    Ngeow, Joanne; Sesock, Kaitlin; Eng, Charis

    2017-06-01

    Patients with PTEN hamartoma tumor syndrome (PHTS) may present to a variety of different subspecialties with benign and malignant clinical features. They have increased lifetime risks of breast, endometrial, thyroid, renal, and colon cancers, as well as neurodevelopmental disorders such as autism spectrum disorder. Patients and affected family members can be offered gene-directed surveillance and management. Patients who are unaffected can be spared unnecessary investigations. With longitudinal follow-up, we are likely to identify other non-cancer manifestations associated with PHTS such as metabolic, immunologic, and neurologic features. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium.

    Science.gov (United States)

    Grego-Bessa, Joaquim; Bloomekatz, Joshua; Castel, Pau; Omelchenko, Tatiana; Baselga, José; Anderson, Kathryn V

    2016-01-26

    Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of PI3 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis.

  12. Redox regulation of tumor suppressor PTEN in cancer and aging (Review).

    Science.gov (United States)

    Kitagishi, Yasuko; Matsuda, Satoru

    2013-03-01

    Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has been shown to act as a tumor suppressor whose function includes important roles in regulating oxidative stress, indicating a potential role in oxidative damage-associated cancer. Accumulating evidence has revealed that PTEN also acts as a pivotal determinant of cell fate, regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. Cells are continuously exposed to ROS, which represent mutagens and are thought to be a major contributor to cancer and the aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, PTEN and the roles of oxidative stress in phosphoinositide-3 kinase/AKT signaling are summarized with a focus on the links between the pathways and ROS in cancer and aging.

  13. Acquired smooth muscle hamartoma

    Directory of Open Access Journals (Sweden)

    Bari Arfan ul

    2006-01-01

    Full Text Available Smooth muscle hamartoma is an uncommon, usually congenital, cutaneous hyperplasia of the arrectores pilorum muscles. When it is acquired, it may be confused with Becker′s nevus. We report a case of this rare tumor in a 19-year-old man. The disease started several years ago as multiple small skin-colored papules that subsequently coalesced to form a large soft plaque on the back of the left shoulder. The diagnosis of acquired smooth muscle hamartoma was confirmed on histopathology. The patient was reassured about the benign nature of the lesion and was not advised any treatment.

  14. Endobronchial Hamartoma Subtotally Occluding the Right Main Bronchus and Mimicking Bronchial Carcinoid Tumor.

    Science.gov (United States)

    Lococo, Filippo; Galeone, Carla; Lasagni, Luciano; Carbonelli, Cristiano; Tagliavini, Elena; Piro, Roberto; Zucchi, Luigi; Sgarbi, Giorgio

    2016-04-01

    Hamartomas are very rarely identified as an endobronchial lesion. Herein, we describe a peculiar case of a 55-year-old woman with persistent cough and increasing dyspnea and radiological detection of a solid lesion subtotally occluding the main right bronchus. Despite the radiological and radiometabolic (18-fluoro-2-deoxy-d-glucose positron emission tomography/computer tomography scan) features were highly suspected for bronchial carcinoid, the definitive diagnosis after endoscopic removal was indicative of an endobronchial hamartoma. When considering differential diagnosis of an endobronchial lesion, the physicians should take firmly in mind such rare entity and, accordingly, bronchoscopy and bronchoscopic biopsy should be done as first step in management of all cases presenting with endobronchial lesions.

  15. Mechanistic Rationale to Target PTEN-Deficient Tumor Cells with Inhibitors of the DNA Damage Response Kinase ATM.

    Science.gov (United States)

    McCabe, Nuala; Hanna, Conor; Walker, Steven M; Gonda, David; Li, Jie; Wikstrom, Katarina; Savage, Kienan I; Butterworth, Karl T; Chen, Clark; Harkin, D Paul; Prise, Kevin M; Kennedy, Richard D

    2015-06-01

    Ataxia telangiectasia mutated (ATM) is an important signaling molecule in the DNA damage response (DDR). ATM loss of function can produce a synthetic lethal phenotype in combination with tumor-associated mutations in FA/BRCA pathway components. In this study, we took an siRNA screening strategy to identify other tumor suppressors that, when inhibited, similarly sensitized cells to ATM inhibition. In this manner, we determined that PTEN and ATM were synthetically lethal when jointly inhibited. PTEN-deficient cells exhibited elevated levels of reactive oxygen species, increased endogenous DNA damage, and constitutive ATM activation. ATM inhibition caused catastrophic DNA damage, mitotic cell cycle arrest, and apoptosis specifically in PTEN-deficient cells in comparison with wild-type cells. Antioxidants abrogated the increase in DNA damage and ATM activation in PTEN-deficient cells, suggesting a requirement for oxidative DNA damage in the mechanism of cell death. Lastly, the ATM inhibitor KU-60019 was specifically toxic to PTEN mutant cancer cells in tumor xenografts and reversible by reintroduction of wild-type PTEN. Together, our results offer a mechanistic rationale for clinical evaluation of ATM inhibitors in PTEN-deficient tumors.

  16. PTEN loss represses glioblastoma tumor initiating cell differentiation via inactivation of Lgl1.

    Science.gov (United States)

    Gont, Alexander; Hanson, Jennifer E L; Lavictoire, Sylvie J; Parolin, Doris A; Daneshmand, Manijeh; Restall, Ian J; Soucie, Mathieu; Nicholas, Garth; Woulfe, John; Kassam, Amin; Da Silva, Vasco F; Lorimer, Ian A J

    2013-08-01

    Glioblastoma multiforme is an aggressive and incurable type of brain tumor. A subset of undifferentiated glioblastoma cells, known as glioblastoma tumor initiating cells (GTICs), has an essential role in the malignancy of this disease and also appears to mediate resistance to radiation therapy and chemotherapy. GTICs retain the ability to differentiate into cells with reduced malignant potential, but the signaling pathways controlling differentiation are not fully understood at this time. PTEN loss is a very common in glioblastoma multiforme and leads to aberrant activation of the phosphoinositide 3-kinase pathway. Increased signalling through this pathway leads to activation of multiple protein kinases, including atypical protein kinase C. In Drosophila, active atypical protein kinase C has been shown to promote the self-renewal of neuroblasts, inhibiting their differentiation along a neuronal lineage. This effect is mediated by atypical protein kinase c-mediated phosphorylation and inactivation of Lgl, a protein that was first characterized as a tumour suppressor in Drosophila. The effects of the atypical protein kinase C/Lgl pathway on the differentiation status of GTICs, and its potential link to PTEN loss, have not been assessed previously. Here we show that PTEN loss leads to the phosphorylation and inactivation of Lgl by atypical protein kinase C in glioblastoma cells. Re-expression of PTEN in GTICs promoted their differentiation along a neuronal lineage. This effect was also seen when atypical protein kinase C was knocked down using RNA interference, and when a non-phosphorylatable, constitutively active form of Lgl was expressed in GTICs. Thus PTEN loss, acting via atypical protein kinase C activation and Lgl inactivation, helps to maintain GTICs in an undifferentiated state.

  17. Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

    Science.gov (United States)

    Tilot, Amanda K; Gaugler, Mary K; Yu, Qi; Romigh, Todd; Yu, Wanfeng; Miller, Robert H; Frazier, Thomas W; Eng, Charis

    2014-06-15

    PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models.

  18. MUC1 positive, Kras and Pten driven mouse gynecologic tumors replicate human tumors and vary in survival and nuclear grade based on anatomical location.

    Science.gov (United States)

    Tirodkar, Tejas S; Budiu, Raluca A; Elishaev, Esther; Zhang, Lixin; Mony, Jyothi T; Brozick, Joan; Edwards, Robert P; Vlad, Anda M

    2014-01-01

    Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.

  19. Breast cancer risk and clinical implications for germline PTEN mutation carriers.

    Science.gov (United States)

    Ngeow, Joanne; Sesock, Kaitlin; Eng, Charis

    2017-08-01

    PTEN Hamartoma Tumor syndrome (PHTS) encompasses a clinical spectrum of heritable disorders including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and Proteus and Proteus-like syndrome that are associated with germline mutations in the PTEN tumor suppressor gene. Breast cancer risk estimates (67-85 %) for women with germline PTEN mutations are similar to those quoted for patients with germline mutations in the BRCA1/2 genes. With PTEN on several germline gene testing panels, finding PTEN mutations and variants have increased exponentially. PHTS can be differentiated from other hereditary cancer syndromes including Hereditary Breast Ovarian Cancer syndrome, Lynch syndrome, and hamartomatous polyposis syndromes based on personal as well as family history. However, many of the benign features of CS are common in the general population, making the diagnosis of CS challenging. Breast cancer patients with an identified germline PTEN mutation are at increased risk of endometrial, thyroid, renal, and colorectal cancers as well as a second breast cancer. Increased screening for the various component cancers as well as predictive testing in first-degree relatives is recommended. Prophylactic mastectomy may be considered especially if breast tissue is dense or if repeated breast biopsies have been necessary. Management of women with breast cancer suspected of CS who test negative for germline PTEN mutations should be managed as per a mutation carrier if she meets CS diagnostic criteria, and should be offered enrollment in research to identify other predisposition genes.

  20. A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.

    Science.gov (United States)

    de la Rosa, Jorge; Weber, Julia; Friedrich, Mathias Josef; Li, Yilong; Rad, Lena; Ponstingl, Hannes; Liang, Qi; de Quirós, Sandra Bernaldo; Noorani, Imran; Metzakopian, Emmanouil; Strong, Alexander; Li, Meng Amy; Astudillo, Aurora; Fernández-García, María Teresa; Fernández-García, María Soledad; Hoffman, Gary J; Fuente, Rocío; Vassiliou, George S; Rad, Roland; López-Otín, Carlos; Bradley, Allan; Cadiñanos, Juan

    2017-03-20

    The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

  1. C-Myc negatively controls the tumor suppressor PTEN by upregulating miR-26a in glioblastoma multiforme cells

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    Guo, Pin; Nie, Quanmin; Lan, Jin; Ge, Jianwei [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Qiu, Yongming, E-mail: qiuzhoub@hotmail.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China); Mao, Qing, E-mail: maoq@netease.com [Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 (China); Shanghai Institute of Head Trauma, Shanghai 200127 (China)

    2013-11-08

    Highlights: •The c-Myc oncogene directly upregulates miR-26a expression in GBM cells. •ChIP assays demonstrate that c-Myc interacts with the miR-26a promoter. •Luciferase reporter assays show that PTEN is a specific target of miR-26a. •C-Myc–miR-26a suppression of PTEN may regulate the PTEN/AKT pathway. •Overexpression of c-Myc enhances the proliferative capacity of GBM cells. -- Abstract: The c-Myc oncogene is amplified in many tumor types. It is an important regulator of cell proliferation and has been linked to altered miRNA expression, suggesting that c-Myc-regulated miRNAs might contribute to tumor progression. Although miR-26a has been reported to be upregulated in glioblastoma multiforme (GBM), the mechanism has not been established. We have shown that ectopic expression of miR-26a influenced cell proliferation by targeting PTEN, a tumor suppressor gene that is inactivated in many common malignancies, including GBM. Our findings suggest that c-Myc modulates genes associated with oncogenesis in GBM through deregulation of miRNAs via the c-Myc–miR-26a–PTEN signaling pathway. This may be of clinical relevance.

  2. A functional network of the tumor suppressors APC, hDlg, and PTEN, that relies on recognition of specific PDZ-domains.

    Science.gov (United States)

    Sotelo, Natalia S; Valiente, Miguel; Gil, Anabel; Pulido, Rafael

    2012-08-01

    APC and PTEN are tumor suppressor proteins that bind through their C-termini to the PDZ domain containing-hDlg scaffolding protein. We have found that co-expression of PTEN and hDlg enhanced the negative regulation of the PI3K/Akt pathway by PTEN, indicating the physiologic importance of these interactions. APC and PTEN share other PDZ domain containing-interacting partners, including the MAGI scaffolding proteins and the MAST family of protein kinases. Mutational analysis revealed that the C-terminal PDZ-binding motifs from APC and PTEN were differentially recognized by distinct PDZ domains. APC bound to the three PDZ domains from hDlg, whereas PTEN mainly bound to PDZ-2/hDlg. This indicates the existence of overlapping, but distinct PDZ-domain recognition patterns by APC and PTEN. Furthermore, a ternary complex formed by APC, PTEN, and hDlg was detected, suggesting that hDlg may serve as a platform to bring in proximity APC and PTEN tumor suppressor activities. In line with this, tumor-related mutations targeting the PDZ-2/hDlg domain diminished its interaction with APC and PTEN. Our results expand the PDZ-domain counterparts for the tumor suppressor APC, show that APC and PTEN share PDZ-domain partners but have individual molecular determinants for specific recognition of PDZ domains, and suggest the participation of the tumor suppressors APC, PTEN, and hDlg in PDZ-domain interaction networks which may be relevant in oncogenesis.

  3. [Splenic hamartoma. Case report].

    Science.gov (United States)

    Soto-Medina, Carlos Alberto; Mier-Escurra, Erik Antonio; Treviño-Garza, Francisco; Ripa-Galván, Paola

    2014-01-01

    Antecedentes: los hamartomas son tumores benignos mixtos muy raros, de crecimiento lento, que generalmente no provocan síntomas, por lo que es más frecuente encontrarlos como un incidentaloma en autopsias o laparotomías. La incidencia de los hamartomas del bazo es sólo de 0.001% entre la población general. Caso clínico: hombre de 39 años de edad, sin antecedentes relevantes, inició dos meses previos con pirosis y dolor ocasional en el hemiabdomen superior. En un ultrasonido de abdomen se observó una tumoración pseudoquística dependiente del bazo. La resonancia magnética reveló cuatro lesiones en el bazo, una de ellas de gran tamaño en el polo inferior, bilobulada, de 12 × 10 × 9 cm. Se realizó una esplenectomía. El paciente no sufrió complicaciones y fue dado de alta al tercer día. El reporte de patología indicó un hamartoma esplénico. Conclusiones: los hamartomas del bazo y otras localizaciones son lesiones benignas que se encuentran como incidelantomas. El diagnóstico se confirma por medio de estudio histopatólogico y su tratamiento es la esplenectomía, siendo la técnica preferida la transabdominal completa por vía laparoscópica. A pesar de que su baja incidencia en México, es de vital importancia que el médico lo considere como diagnóstico diferencial al evaluar una tumoración.

  4. Tumor Suppressor Pten Inhibits Nuclear Accumulation of β-Catenin and T Cell/Lymphoid Enhancer Factor 1–Mediated Transcriptional Activation

    Science.gov (United States)

    Persad, Sujata; A.Troussard, Armelle; McPhee, Timothy R.; Mulholland, David J.; Dedhar, Shoukat

    2001-01-01

    β-Catenin is a protein that plays a role in intercellular adhesion as well as in the regulation of gene expression. The latter role of β-catenin is associated with its oncogenic properties due to the loss of expression or inactivation of the tumor suppressor adenomatous polyposis coli (APC) or mutations in β-catenin itself. We now demonstrate that another tumor suppressor, PTEN, is also involved in the regulation of nuclear β-catenin accumulation and T cell factor (TCF) transcriptional activation in an APC-independent manner. We show that nuclear β-catenin expression is constitutively elevated in PTEN null cells and this elevated expression is reduced upon reexpression of PTEN. TCF promoter/luciferase reporter assays and gel mobility shift analysis demonstrate that PTEN also suppresses TCF transcriptional activity. Furthermore, the constitutively elevated expression of cyclin D1, a β-catenin/TCF–regulated gene, is also suppressed upon reexpression of PTEN. Mechanistically, PTEN increases the phosphorylation of β-catenin and enhances its rate of degradation. We define a pathway that involves mainly integrin-linked kinase and glycogen synthase kinase 3 in the PTEN-dependent regulation of β-catenin stability, nuclear β-catenin expression, and transcriptional activity. Our data indicate that β-catenin/TCF–mediated gene transcription is regulated by PTEN, and this may represent a key mechanism by which PTEN suppresses tumor progression. PMID:11402061

  5. MUC1 positive, Kras and Pten driven mouse gynecologic tumors replicate human tumors and vary in survival and nuclear grade based on anatomical location.

    Directory of Open Access Journals (Sweden)

    Tejas S Tirodkar

    Full Text Available Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus. Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015, yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.

  6. Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Li; Zhong Tian; Dong-Ying Wu; Bao-Yu Fu; Yan Xin

    2005-01-01

    AIM: To investigate the loss of heterozygosity (LOH) and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions.METHODS: Thirty cases of normal gastric mucosa, advanced and early stage gastric cancer, intestinal metaplasia, atrophic gastritis, and atypical hyperplasia were analyzed for PTEN LOH and mutations within the entire coding region of PTEN gene by PCR-SSCP denaturing PAGE gel electrophoresis,and PTEN mutation was detected by PCR-SSCP sequencing followed by silver staining.RESULTS: LOH rate found in respectively atrophic gastritis was 10% (3/30), intestinal metaplasia 10% (3/30), atypical hyperpiasia 13.3% (4/30), early stage gastric cancer 20%(6/30), and advanced stage gastric cancer 33.3% (9/30),None of the precancerous lesions and early stage gastric cancer showed PTEN mutations, but 10% (3/30) of the advanced stage gastric cancers, which were all positive for LOH, showed PTEN mutation.CONCLUSION: LOH of PTEN gene appears in precancerous lesions, and PTEN mutations are restricted to advanced gastric cancer, LOH and mutation of PTEN gene are closely related to the infiltration and metastasis of gastric cancer.

  7. Gene Expression Analysis of an EGFR Indirectly Related Pathway Identified PTEN and MMP9 as Reliable Diagnostic Markers for Human Glial Tumor Specimens

    Directory of Open Access Journals (Sweden)

    Sergio Comincini

    2009-01-01

    Full Text Available In this study the mRNA levels of five EGFR indirectly related genes, EGFR, HB-EGF, ADAM17, PTEN, and MMP9, have been assessed by Real-time PCR in a panel of 37 glioblastoma multiforme specimens and in 5 normal brain samples; as a result, in glioblastoma, ADAM17 and PTEN expression was significantly lower than in normal brain samples, and, in particular, a statistically significant inverse correlation was found between PTEN and MMP9 mRNA levels. To verify if this correlation was conserved in gliomas, PTEN and MMP9 expression was further investigated in an additional panel of 16 anaplastic astrocytoma specimens and, in parallel, in different human normal and astrocytic tumor cell lines. In anaplastic astrocytomas PTEN expression was significantly higher than in glioblastoma multiforme, but no significant correlation was found between PTEN and MMP9 expression. PTEN and MMP9 mRNA levels were also employed to identify subgroups of specimens within the different glioma malignancy grades and to define a gene expression-based diagnostic classification scheme. In conclusion, this gene expression survey highlighted that the combined measurement of PTEN and MMP9 transcripts might represent a novel reliable tool for the differential diagnosis of high-grade gliomas, and it also suggested a functional link involving these genes in glial tumors.

  8. PTEN at 18: Still Growing.

    Science.gov (United States)

    Gorbenko, Olena; Stambolic, Vuk

    2016-01-01

    Discovered in 1997, PTEN remains one of the most studied tumor suppressors. In this issue of Methods in Molecular Biology, we assembled a series of papers describing various clinical and experimental approaches to studying PTEN function. Due to its broad expression, regulated subcellular localization, and intriguing phosphatase activity, methodologies aimed at PTEN study have often been developed in the context of mutations affecting various aspects of its regulation, found in patients burdened with PTEN loss-driven tumors. PTEN's extensive posttranslational modifications and dynamic localization pose unique challenges for studying PTEN features in isolation and necessitate considerable development of experimental systems to enable controlled characterization. Nevertheless, ongoing efforts towards the development of PTEN knockout and knock-in animals and cell lines, antibodies, and enzymatic assays have facilitated a huge body of work, which continues to unravel the fascinating biology of PTEN.

  9. An Unexpected Cause of Hemoptysis: Endobronchial Lipomatous Hamartoma

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    Sarioglu, Nurhan; Susur, Alev; Goksel, Tuncay; Paksoy, Serpil; Erel, Fuat

    2014-01-01

    ABSTRACT Hamartomas are the most common benign tumors of the lung. Endobnronchial hamartomas are even rarer and infrequently causes hemoptysis. We report a case of endobronchial hamartoma that was originating from a segment bronchus and invisible in chest X-ray. A 63-year-old man was admitted to hospital with hemoptysis. A CT scan revealed endobronchial mass obstructing anterior bronchus of the right lower lob of the right lung. It wasn’t radiographically presented. Flexible bronchoscopy dete...

  10. Kaempferol Promotes Apoptosis in Human Bladder Cancer Cells by Inducing the Tumor Suppressor, PTEN

    Directory of Open Access Journals (Sweden)

    Liqun Zhou

    2013-10-01

    Full Text Available Kaempferol (Kae, a natural flavonoid, is widely distributed in fruits and vegetables. Previous studies have identified Kae as a possible cancer preventive and therapeutic agent. We found Kae to exhibit potent antiproliferation and anti-migration effects in human bladder cancer EJ cells. Kaempferol robustly induced apoptosis in EJ cells in a dose-dependent manner, as evidenced by increased cleavage of caspase-3. Furthermore, we found Kae-induced apoptosis in EJ cells to be associated with phosphatase and the tensin homolog deleted on the chromosome 10 (PTEN/PI3K/Akt pathway. Kae significantly increased PTEN and decreased Akt phosphorylation. Kae-induced apoptosis was partially attenuated in PTEN-knockdown cells. Our findings indicate that Kae could be an alternative medicine for bladder cancer, based on a PTEN activation mechanism.

  11. miR-17 inhibitor suppressed osteosarcoma tumor growth and metastasis via increasing PTEN expression

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Yong, E-mail: gaoyongunion@163.com [Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Luo, Ling-hui [Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Li, Shuai; Yang, Cao [Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China)

    2014-02-07

    Highlights: • miR-17 was increased in OS tissues and cell lines. • Inhibition of miR-17 suppressed OS cell proliferation. • Inhibition of miR-17 suppressed OS cell migration and invasion. • PTEN was a target of miR-17. • miR-17 was negatively correlated with PTEN in OS tissues. - Abstract: MicroRNAs (miRNAs) play essential roles in cancer development and progression. Here, we investigated the role of miR-17 in the progression and metastasis of osteosarcoma (OS). miR-17 was frequently increased in OS tissues and cell lines. Inhibition of miR-17 in OS cell lines substantially suppressed cell proliferation, migration, and invasion. Phosphatase and tensin homolog (PTEN) was identified as a target of miR-17, and ectopic expression of miR-17 inhibited PTEN by direct binding to its 3′-untranslated region (3′-UTR). Expression of miR-17 was negatively correlated with PTEN in OS tissues. Together, these findings indicate that miR-17 acts as an oncogenic miRNA and may contribute to the progression and metastasis of OS, suggesting miR-17 as a potential novel diagnostic and therapeutic target of OS.

  12. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.

    Science.gov (United States)

    Chen, W-T; Zhu, G; Pfaffenbach, K; Kanel, G; Stiles, B; Lee, A S

    2014-10-16

    Glucose-regulated protein 78 (GRP78), a molecular chaperone widely elevated in human cancers, is critical for endoplasmic reticulum (ER) protein folding, stress signaling and PI3K/AKT activation. Genetic knockout models of GRP78 revealed that GRP78 maintains homeostasis of metabolic organs, including liver, pancreas and adipose tissues. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common liver cancers. There is a lack of effective therapeutics for HCC and CC, highlighting the need to further understand liver tumorigenic mechanisms. PTEN (phosphatase and tenson homolog deleted on chromosome 10), a tumor suppressor that antagonizes the PI3K/AKT pathway, is inactivated in a wide range of tumors, including 40-50% of human liver cancers. To elucidate the role of GRP78 in liver cancer, we created a mouse model with biallelic liver-specific deletion of Pten and Grp78 mediated by Albumin-Cre-recombinase (cP(f/f)78(f/f)). Interestingly, in contrast to PTEN, deletion of GRP78 was progressive but incomplete. At 3 months, cP(f/f)78(f/f) livers showed hepatomegaly, activation of lipogenic genes, exacerbated steatosis and liver injury, implying that GRP78 protects the liver against PTEN-null-mediated pathogenesis. Furthermore, in response to liver injury, we observed increased proliferation and expansion of bile duct and liver progenitor cells in cP(f/f)78(f/f) livers. Strikingly, bile duct cells in cP(f/f)78(f/f) livers maintained wild-type (WT) GRP78 level, whereas adjacent areas showed GRP78 reduction. Analysis of signaling pathways revealed selective JNK activation, β-catenin downregulation, along with PDGFRα upregulation, which was unique to cP(f/f)78(f/f) livers at 6 months. Development of both HCC and CC was accelerated and was evident in cP(f/f)78(f/f) livers at 8-9 months, coinciding with intense GRP78 expression in the cancer lesions, and GRP78 expression in adjacent normal areas reverted back to the WT level. In contrast, c78(f/f) livers

  13. PTEN loss and chromosome 8 alterations in Gleason grade 3 prostate cancer cores predicts the presence of un-sampled grade 4 tumor: implications for active surveillance.

    Science.gov (United States)

    Trock, Bruce J; Fedor, Helen; Gurel, Bora; Jenkins, Robert B; Knudsen, B S; Fine, Samson W; Said, Jonathan W; Carter, H Ballentine; Lotan, Tamara L; De Marzo, Angelo M

    2016-07-01

    Men who enter active surveillance because their biopsy exhibits only Gleason grade 3 (G3) frequently have higher grade tumor missed by biopsy. Thus, biomarkers are needed that, when measured on G3 tissue, can predict the presence of higher grade tumor in the whole prostate. We evaluated whether PTEN loss, chromosome 8q gain (MYC) and/or 8p loss (LPL) measured only on G3 cores is associated with un-sampled G4 tumor. A tissue microarray was constructed of prostatectomy tissue from patients whose prostates exhibited only Gleason score 3+3, only 3+4 or only 4+3 tumor (n=50 per group). Cores sampled only from areas of G3 were evaluated for PTEN loss by immunohistochemistry, and PTEN deletion, LPL/8p loss and MYC/8q gain by fluorescence in situ hybridization. Biomarker results were compared between Gleason score 6 vs 7 tumors using conditional logistic regression. PTEN protein loss, odds ratio=4.99, P=0.033; MYC/8q gain, odds ratio=5.36, P=0.010; and LPL/8p loss, odds ratio=3.96, P=0.003 were significantly more common in G3 cores derived from Gleason 7 vs Gleason 6 tumors. PTEN gene deletion was not statistically significant. Associations were stronger comparing Gleason 4+3 vs 6 than for Gleason 3+4 vs 6. MYC/8q gain, LPL/8p loss and PTEN protein loss measured in G3 tissue microarray cores strongly differentiate whether the core comes from a Gleason 6 or Gleason 7 tumor. If validated to predict upgrading from G3 biopsy to prostatectomy these biomarkers could reduce the likelihood of enrolling high-risk men and facilitate safe patient selection for active surveillance.

  14. Estudio de PTEN como supresor tumoral: desarrollo de modelos animales, evaluación de terapias dirigidas e interacción con el proceso inflamatorio

    OpenAIRE

    Mirantes Barbeito, Cristina

    2015-01-01

    Desde su descubrimiento a finales de los 90, PTEN se ha convertido en uno de los genes supresores de tumores más importantes que se conocen. Se sitúa entre los 20 supresores tumorales mutados con mayor frecuencia, un fenómeno que llega a ocurrir hasta en el 80% de los casos, en función del tipo de cáncer. Una de las herramientas esenciales para el estudio de la biología de PTEN y su papel en el proceso tumoral es el empleo de modelos animales modificados genéticamente. Su uso permite estudiar...

  15. High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

    Directory of Open Access Journals (Sweden)

    Jehnan Liu

    2015-03-01

    Conclusion: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

  16. Breast hamartoma with intrathoracic extension in a 13-year-old boy

    Directory of Open Access Journals (Sweden)

    Gupta Shilpi

    2010-01-01

    Full Text Available Breast hamartoma is a rare tumor that has been reported only thrice in a male breast. The pediatric age group is seldom involved. We present a case of breast hamartoma in a 13-year-old boy, which interestingly, extended through but without definite involvement of the chest wall into the thoracic cavity. In view of occasional recurrence and documented malignancy in hamartomas, tumor was excised along with two ribs.

  17. Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice

    Directory of Open Access Journals (Sweden)

    Marcel A. Deken

    2016-12-01

    Full Text Available Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreERT2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in PtenLoxP/LoxP;BrafCA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies.

  18. Placental mesenchymal dysplasia associated with hepatic and pulmonary hamartoma.

    Science.gov (United States)

    Tortoledo, Maria; Galindo, A; Ibarrola, C

    2010-01-01

    This report describes a 31-week stillborn female infant with placental mesenchymal dysplasia (PMD) in association with hepatic mesenchymal hamartoma (HMH) and pulmonary hamartoma. Placental mesenchymal dysplasia was initially misdiagnosed as a partial mole. However, histologically, no trophoblastic proliferation or inclusions were observed. Differential diagnosis of the hepatic mass with similar tumors is discussed. To our knowledge, this is the first case of lung hamartoma reported in a fetus and the first case related to PMD and HMH. A common anomalous development of the mesoderm, a reparative post-injury process and a genetic mechanism, have been proposed to explain their pathogenesis.

  19. [Non-chondromatous hamartoma].

    Science.gov (United States)

    Okubo, T; Shimazaki, T; Shindo, G; Kitashiro, N; Tsukamoto, T

    2008-11-01

    A 69-year-old female visited our hospital because of dyspnea. Chest X-ray showed an abnormal shadow in the right lower lung field. Chest computed tomography (CT) showed a round, well-circumscribed, homogenous subpleural nodle of 8 mm in diameter in the right lower lobe, which had no calcification and no pleural indentation. Bronchofiber scope, abdominal CT, brain magnetic resonance imaging (MRI), bone scintigraphy could not establish definitive diagnosis. Scince the possibility of malignancy could not be excluded throughout, video-assisted thoracoscopic surgery was performed to obtain confirmed diagnosis. Pathological examination revealed non-chondromatous hamartoma of the lung. Non-chondromatous hamartoma should be considered in the differential diagnosis of pulmonary nodles. We report a rare case of non-chondromatous hamartoma.

  20. Laparoscopic Splenectomy for Splenic Hamartoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Andrea Pisani Ceretti

    2012-01-01

    Full Text Available Hamartoma is a rare splenic benign tumor usually accidentally detected as a radiologic finding. Preoperative diagnosis poses a challenge and thus surgery becomes necessary to confirm the clinical suspicion. Laparoscopic splenectomy has gained consensus as a standard surgical procedure particularly for autoimmune hematological diseases. This former experience has allowed this technique to be extended to other splenic pathologies. Here we report a case of total laparoscopic splenectomy for a bulky splenic hamartoma in a young male patient.

  1. Bilateral Multifocal Hamartoma of the Chest Wall in an Infant

    OpenAIRE

    Yilmaz, Erdem; Erol, Oguz Bulent; Pekcan, Melih; Gundogdu, Gokcen; Bilgic, Bilge; Gun, Feryal; Yekeler, Ensar

    2015-01-01

    Summary Background Hamartoma of the thoracic wall is a rare benign tumor that occurs in infancy and can be mistaken for a malignancy due to its clinical and imaging features. Hamartomas are extrapleural soft tissue lesions that cause rib expansion and destruction and appear on imaging as cystic areas with fluid levels and calcification. They can cause scoliosis, pressure on the neighboring lung parenchyma and mediastinal displacement. While conservative treatment is recommended in asymptomati...

  2. [Chest wall mesenchymal hamartoma: a case report].

    Science.gov (United States)

    Morales, Olga Lucía; Valencia, María de la Luz; Gómez, Carolina; Pérez, María del Pilar; Sanín, Emilio; Vásquez, Luz Marina

    2010-01-01

    Chest wall mesenchymal hamartoma is an extremely rare benign tumor. Approximately 80 cases have been reported in the literature. Most tumors are manifested at birth with a painless palpable mass of the chest wall, usually unilateral. Respiratory symptoms result from extrinsic compression of the pulmonary parenchyma, and the severity of the symptoms will depend on the size and location of the lesion. Imaging features are characteristic, but definitive diagnosis is histological. Herein, a case is described of a four month old infant with diagnosis of chest wall mesenchymal hamartoma, manifested at birth. Different treatment options are described, including expectations from tumor management, the possibility of spontaneous regression, and the morbidity associated with the surgical option.

  3. Tumor suppressors in Zebrafish : From TP53 to PTEN and beyond

    NARCIS (Netherlands)

    den Hertog, Jeroen

    2016-01-01

    Zebrafish are increasingly being used to study cancer. Almost all tumor types have been found in zebrafish. However, tumor incidence is relatively low and tumors develop late in life. Functional inactivation of tumor suppressors is a crucial step in cancer progression and more and more tumor

  4. Tumor Suppressors in Zebrafish : From TP53 to PTEN and Beyond

    NARCIS (Netherlands)

    den Hertog, Jeroen

    2016-01-01

    Zebrafish are increasingly being used to study cancer. Almost all tumor types have been found in zebrafish. However, tumor incidence is relatively low and tumors develop late in life. Functional inactivation of tumor suppressors is a crucial step in cancer progression and more and more tumor

  5. Tumor suppressors in Zebrafish : From TP53 to PTEN and beyond

    NARCIS (Netherlands)

    den Hertog, Jeroen

    2016-01-01

    Zebrafish are increasingly being used to study cancer. Almost all tumor types have been found in zebrafish. However, tumor incidence is relatively low and tumors develop late in life. Functional inactivation of tumor suppressors is a crucial step in cancer progression and more and more tumor suppres

  6. WWP1 as a potential tumor oncogene regulates PTEN-Akt signaling pathway in human gastric carcinoma.

    Science.gov (United States)

    Zhang, Li; Wu, Zongyin; Ma, Zhao; Liu, Hongtao; Wu, Yahong; Zhang, Qinxian

    2015-02-01

    Whelming evidence has demonstrated that WW domain containing E3 ubiquitin protein ligase 1 (WWP1) participates in a wide variety of biological processes and is tightly related to the initiation and progression of many tumors. Currently, although mounting evidence supports a role of WWP1 in tumor promotion and tumorigenesis, the potential roles of WWP1 and its biological functions in gastric carcinoma are not fully understood. Here, we found that WWP1 messenger RNA (mRNA) and protein were highly expressed in gastric carcinoma tissues and cells. High WWP1 mRNA and protein levels were tightly related to differentiation status, TNM stage, invasive depth, lymph node metastasis, and poor prognosis in gastric carcinoma. Furthermore, WWP1 siRNA significantly decreased WWP1 protein level in MKN-45 and AGS cells; meanwhile, WWP1 depletion markedly inhibited tumor proliferation in vitro and in vivo, arrested cell cycle at G0/G1 phase, and induced cell apoptosis in MKN-45 and AGS cells. Most notably, WWP1 downregulation both inactivated PTEN-Akt signaling pathway in MKN-45 and AGS cells. Taken altogether, our findings suggest that WWP1 acts as an oncogenic factor and should be considered as a novel interfering molecular target for gastric carcinoma.

  7. Mutant PTEN in Cancer : Worse Than Nothing

    NARCIS (Netherlands)

    Leslie, Nick R; den Hertog, Jeroen

    2014-01-01

    Tumor suppressors block the development of cancer and are often lost during tumor development. Papa et al. show that partial loss of normal PTEN tumor suppressor function can be compounded by additional disruption caused by the expression of inactive mutant PTEN protein. This has significant

  8. Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.

    Directory of Open Access Journals (Sweden)

    Tracy M Covey

    Full Text Available PTEN, a phosphoinositide-3-phosphatase, serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism. Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimposed a vulnerability to other mediators of oxidative stress and inflammation, especially reactive carbonyl species, which are commonly occurring by-products of arachidonic acid peroxidation. Using MCF7 and HEK-293 cells, we report that several reactive aldehydes and ketones, e.g. electrophilic α,β-enals (acrolein, 4-hydroxy-2-nonenal and α,β-enones (prostaglandin A(2, Δ12-prostaglandin J(2 and 15-deoxy-Δ-12,14-prostaglandin J(2 covalently modify and inactivate cellular PTEN, with ensuing activation of PKB/Akt kinase; phosphorylation of Akt substrates; increased cell proliferation; and increased nuclear β-catenin signaling. Alkylation of PTEN by α,β-enals/enones and interference with its restraint of cellular PKB/Akt signaling may accentuate hyperplastic and neoplastic disorders associated with chronic inflammation, oxidative stress, or aging.

  9. PTEN inhibits BMI1 function independently of its phosphatase activity

    Directory of Open Access Journals (Sweden)

    Kapoor Anil

    2009-11-01

    Full Text Available Abstract Background PTEN is the second most mutated tumor suppressor gene other than p53. It suppresses tumorigenesis by dephosphorylating phosphatidylinositol (3,4,5-triphosphate (PIP3 to phosphatidylinositol (4,5-biphosphate (PIP2, thereby directly inhibiting phosphatidylinositol 3 kinase (PI3K-mediated tumorigenic activities. Consistent with this model of action, cytosolic PTEN is recruited to the plasma membrane to dephosphorylate PIP3. While nuclear PTEN has been shown to suppress tumorigenesis by governing genome integrity, additional mechanisms may also contribute to nuclear PTEN-mediated tumor suppression. The nuclear protein BMI1 promotes stem cell self-renewal and tumorigenesis and PTEN inhibits these events, suggesting that PTEN may suppress BMI1 function. Results We investigated whether PTEN inhibits BMI1 function during prostate tumorigenesis. PTEN binds to BMI1 exclusively in the nucleus. This interaction does not require PTEN's phosphatase activity, as phosphatase-deficient PTEN mutants, PTEN/C124S (CS, PTEN/G129E (GE, and a C-terminal PTEN fragment (C-PTEN excluding the catalytic domain, all associate with BMI1. Furthermore, the residues 186-286 of C-PTEN are sufficient for binding to BMI1. This interaction reduces BMI1's function. BMI1 enhances hTERT activity and reduces p16INK4A and p14ARF expression. These effects were attenuated by PTEN, PTEN(CS, PTEN(GE, and C-PTEN. Furthermore, knockdown of PTEN in DU145 cells increased hTERT promoter activity, which was reversed when BMI1 was concomitantly knocked-down, indicating that PTEN reduces hTERT promoter activity via inhibiting BMI1 function. Conversely, BMI1 reduces PTEN's ability to inhibit AKT activation, which can be attributed to its interaction with PTEN in the nucleus, making PTEN unavailable to dephosphorylate membrane-bound PIP3. Furthermore, BMI1 appears to co-localize with PTEN more frequently in clinical prostate tissue samples from patients diagnosed with PIN

  10. Schwann cell hamartoma: case report

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    Bulfamante Gaetano

    2011-06-01

    Full Text Available Abstract Background Colorectal polyps of mesenchymal origin represent a small percentage of gastrointestinal (GI lesions. Nevertheless, they are encountered with increasing frequency since the widespread adoption of colonoscopy screening. Case presentation We report a case of a small colonic polyp that presented as intramucosal diffuse spindle cell proliferation with a benign cytological appearance, strong and diffuse immunoreactivity for S-100 protein, and pure Schwann cell phenotype. Careful morphological, immunohistochemical and clinical evaluation emphasize the differences from other stromal colonic lesions and distinguish it from schwannoma, a circumscribed benign nerve sheath tumor that rarely arises in the GI tract. Conclusion As recently proposed, this lesion was finally described as mucosal Schwann cell hamartoma.

  11. Centrally-located pulmonary hamartoma diagnosed in a 16-year-old ...

    African Journals Online (AJOL)

    Pulmonary hamartomas are the most common benign tumors of the lung. ... also known as mesenchymomas, are non-neoplastic tumor-like malformations of the lung ... symptoms including recurrent respiratory tract infections, obstructive ...

  12. High-resolution Structures of Protein-Membrane Complexes by Neutron Reflection and MD Simulation: Membrane Association of the PTEN Tumor Suppressor

    Science.gov (United States)

    Lösche, Matthias

    2012-02-01

    The lipid matrix of biomembranes is an in-plane fluid, thermally and compositionally disordered leaflet of 5 nm thickness and notoriously difficult to characterize in structural terms. Yet, biomembranes are ubiquitous in the cell, and membrane-bound proteins are implicated in a variety of signaling pathways and intra-cellular transport. We developed methodology to study proteins associated with model membranes using neutron reflection measurements and showed recently that this approach can resolve the penetration depth and orientation of membrane proteins with ångstrom resolution if their crystal or NMR structure is known. Here we apply this technology to determine the membrane bindung and unravel functional details of the PTEN phosphatase, a key player in the PI3K apoptosis pathway. PTEN is an important regulatory protein and tumor suppressor that performs its phosphatase activity as an interfacial enzyme at the plasma membrane-cytoplasm boundary. Acting as an antagonist to phosphoinositide-3-kinase (PI3K) in cell signaling, it is deleted in many human cancers. Despite its importance in regulating the levels of the phosphoinositoltriphosphate PI(3,4,5)P3, there is little understanding of how PTEN binds to membranes, is activated and then acts as a phosphatase. We investigated the structure and function of PTEN by studying its membrane affinity and localization on in-plane fluid, thermally disordered synthetic membrane models. The membrane association of the protein depends strongly on membrane composition, where phosphatidylserine (PS) and phosphatidylinositol diphosphate (PI(4,5)P2) act synergetically in attracting the enzyme to the membrane surface. Membrane affinities depend strongly on membrane fluidity, which suggests multiple binding sites on the protein for PI(4,5)P2. Neutron reflection measurements show that the PTEN phosphatase ``scoots'' along the membrane surface (penetration protein, ˜ 60 å away from the bilayer surface, in a rather compact

  13. The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein.

    Science.gov (United States)

    Pabona, John Mark P; Dave, Bhuvanesh; Su, Ying; Montales, Maria Theresa E; de Lumen, Ben O; de Mejia, Elvira G; Rahal, Omar M; Simmen, Rosalia C M

    2013-01-01

    Breast cancer is the leading cause of cancer deaths in women. Diet and lifestyle are major contributing factors to increased breast cancer risk. While mechanisms underlying dietary protection of mammary tumor formation are increasingly elucidated, there remains a dearth of knowledge on the nature and precise actions of specific bioactive components present in foods with purported health effects. The 43-amino acid peptide lunasin (LUN) is found in soybeans, is bioavailable similar to the isoflavone genistein (GEN), and thus may mediate the beneficial effects of soy food consumption. Here, we evaluated whether LUN displays common and distinct actions from those of GEN in non-malignant (mouse HC11) and malignant (human MCF-7) mammary epithelial cells. In MCF-7 cells, LUN up-regulated tumor suppressor phosphatase and tensin homolog deleted in chromosome ten (PTEN) promoter activity, increased PTEN transcript and protein levels and enhanced nuclear PTEN localization, similar to that shown for GEN in mammary epithelial cells. LUN-induced cellular apoptosis, akin to GEN, was mediated by PTEN, but unlike that for GEN, was p53-independent. LUN promoted E-cadherin and β-catenin non-nuclear localization similar to GEN, but unlike GEN, did not influence the proliferative effects of oncogene Wnt1 on HC11 cells. Further, LUN did not recapitulate GEN inhibitory effects on expansion of the cancer stem-like/progenitor population in MCF-7 cells. Results suggest the concerted actions of GEN and LUN on cellular apoptosis for potential mammary tumor preventive effects and highlight whole food consumption rather than intake of specific dietary supplements with limited biological effects for greater health benefits.

  14. Bilateral mesenchymal hamartoma of the chest wall in an infant boy.

    Science.gov (United States)

    Li, Rong; Kelly, David; Siegal, Gene P

    2012-12-01

    Mesenchymal chest wall hamartoma is an extremely rare tumor striking neonates and infants. Histologically, the tumor is composed of islands of hyaline cartilage intermixed with mesenchymal-like stroma and hemorrhagic cysts. We present a case of a congenital bilateral mesenchymal chest wall hamartoma (MCWH) in an infant boy. This extremely rare benign entity may be misdiagnosed as malignant tumor and shares features with another tumor of childhood-fibrocartilagenous mesenchymoma of bone.

  15. Subtle variations in Pten dose determine cancer susceptibility.

    Science.gov (United States)

    Alimonti, Andrea; Carracedo, Arkaitz; Clohessy, John G; Trotman, Lloyd C; Nardella, Caterina; Egia, Ainara; Salmena, Leonardo; Sampieri, Katia; Haveman, William J; Brogi, Edi; Richardson, Andrea L; Zhang, Jiangwen; Pandolfi, Pier Paolo

    2010-05-01

    Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes. Here we analyze Pten hypermorphic mice (Pten(hy/+)), expressing 80% normal levels of Pten. Pten(hy/+) mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.

  16. Loss of the tumor suppressor Pten promotes proliferation of Drosophila melanogaster cells in vitro and gives rise to continuous cell lines.

    Science.gov (United States)

    Justiniano, Steven E; Mathew, Anne; Mitra, Sayan; Manivannan, Sathiya N; Simcox, Amanda

    2012-01-01

    In vivo analysis of Drosophila melanogaster has enhanced our understanding of many biological processes, notably the mechanisms of heredity and development. While in vivo analysis of mutants has been a strength of the field, analyzing fly cells in culture is valuable for cell biological, biochemical and whole genome approaches in which large numbers of homogeneous cells are required. An efficient genetic method to derive Drosophila cell lines using expression of an oncogenic form of Ras (Ras(V12)) has been developed. Mutations in tumor suppressors, which are known to cause cell hyperproliferation in vivo, could provide another method for generating Drosophila cell lines. Here we screened Drosophila tumor suppressor mutations to test if they promoted cell proliferation in vitro. We generated primary cultures and determined when patches of proliferating cells first emerged. These cells emerged on average at 37 days in wild-type cultures. Using this assay we found that a Pten mutation had a strong effect. Patches of proliferating cells appeared on average at 11 days and the cultures became confluent in about 3 weeks, which is similar to the timeframe for cultures expressing Ras(V12). Three Pten mutant cell lines were generated and these have now been cultured for between 250 and 630 cell doublings suggesting the life of the mutant cells is likely to be indefinite. We conclude that the use of Pten mutants is a powerful means to derive new Drosophila cell lines.

  17. Loss of the tumor suppressor Pten promotes proliferation of Drosophila melanogaster cells in vitro and gives rise to continuous cell lines.

    Directory of Open Access Journals (Sweden)

    Steven E Justiniano

    Full Text Available In vivo analysis of Drosophila melanogaster has enhanced our understanding of many biological processes, notably the mechanisms of heredity and development. While in vivo analysis of mutants has been a strength of the field, analyzing fly cells in culture is valuable for cell biological, biochemical and whole genome approaches in which large numbers of homogeneous cells are required. An efficient genetic method to derive Drosophila cell lines using expression of an oncogenic form of Ras (Ras(V12 has been developed. Mutations in tumor suppressors, which are known to cause cell hyperproliferation in vivo, could provide another method for generating Drosophila cell lines. Here we screened Drosophila tumor suppressor mutations to test if they promoted cell proliferation in vitro. We generated primary cultures and determined when patches of proliferating cells first emerged. These cells emerged on average at 37 days in wild-type cultures. Using this assay we found that a Pten mutation had a strong effect. Patches of proliferating cells appeared on average at 11 days and the cultures became confluent in about 3 weeks, which is similar to the timeframe for cultures expressing Ras(V12. Three Pten mutant cell lines were generated and these have now been cultured for between 250 and 630 cell doublings suggesting the life of the mutant cells is likely to be indefinite. We conclude that the use of Pten mutants is a powerful means to derive new Drosophila cell lines.

  18. Triple negative breast tumors in African-American and Hispanic/Latina women are high in CD44+, low in CD24+, and have loss of PTEN.

    Directory of Open Access Journals (Sweden)

    Yanyuan Wu

    Full Text Available African-American women have higher mortality from breast cancer than other ethnic groups. The association between poor survival and differences with tumor phenotypes is not well understood. The purpose of this study is to assess the clinical significance of (1 Stem cell-like markers CD44 and CD24; (2 PI3K/Akt pathway associated targets PTEN, activation of Akt, and FOXO1; and (3 the Insulin-like growth factor-1 (IGF-I and IGF binding protein-3 (IGFBP3 in different breast cancer subtypes, and compare the differences between African-American and Hispanic/Latina women who have similar social-economic-status.A total of N=318 African-American and Hispanic/Latina women, with clinically-annotated information within the inclusion criteria were included. Formalin fixed paraffin embedded tissues from these patients were tested for the different markers using immunohistochemistry techniques. Kaplan-Meier survival-curves and Cox-regression analyses were used to assess Relative Risk and Disease-Free-Survival (DFS.The triple-negative-breast-cancer (TNBC receptor-subtype was more prevalent among premenopausal women, and the Hormonal Receptor (HR positive subtype was most common overall. TNBC tumors were more likely to have loss of PTEN, express high Ki67, and have increased CD44+/CD24- expression. TNBC was also associated with higher plasma-IGF-I levels. HR-/HER2+ tumors showed high pAkt, decreased FOXO1, and high CD24+ expression. The loss of PTEN impacted DFS significantly in African Americans, but not in Hispanics/Latinas after adjusted for treatment and other tumor pathological factors. The CD44+/CD24- and CD24+/CD44- phenotypes decreased DFS, but were not independent predictors for DFS. HER2-positive and TNBC type of cancers continued to exhibit significant decrease in DFS after adjusting for the selected biomarkers and treatment.TNBC incidence is high among African-American and Hispanic/Latino women residing in South Los Angeles. Our study also shows for

  19. Multiple pulmonary hamartomas: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Chang Woo; Kim, Jeung Sook; Lee, Hyeon Jae; Lee, Yong Hee [Pochon CHA Univ. College of Medicine, Sungnam (Korea, Republic of)

    1999-07-01

    Hamartomas are the most common benign neoplasms of the lung. However, multiple pulmonary hamartomas are very rare. We describe the radiographic findings of multiple pulmonary hamartomas without Carney's or pulmonary hamartoma syndrome with review the literature describing to this entity.

  20. Dietary Regulation of PTEN Signaling and Mammary Tumor Initiating Cells: Implications for Breast Cancer Prevention

    Science.gov (United States)

    2012-07-01

    the end stages of at least two different lines of genetic evolution. J Pathol 2001;194:165–70. [9] Polyak K. Is breast tumor progression really...Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127: 679–95. [18] Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells...409–418. 7. Polyak ,K. (2007) Breast cancer: origins and evolution. J. Clin. Invest., 117, 3155–3163. 8. Troisi,R. et al. (2007) Exploring the

  1. PPARγ, PTEN, and the Fight against Cancer

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    Teresi, Rosemary E.; Kristin A. Waite

    2008-01-01

    Peroxisome proliferator-activated receptor gamma (PPAR ) is a ligand-activated transcription factor, which belongs to the family of nuclear hormone receptors. Recent in vitro studies have shown that PPAR can regulate the transcription of phosphatase and tensin homolog on chromosome ten (PTEN), a known tumor suppressor. PTEN is a susceptibility gene for a number of disorders, including breast and thyroid cancer. Activation of PPAR through agonists increases functional PTEN protein levels...

  2. Fibromatosis arising in association with neuromuscular hamartoma of the mandible.

    Science.gov (United States)

    Taher, Leena Yaseen; Saleem, Muhammad; Velagapudi, Suresh; Dababo, Anas

    2013-09-01

    Aggressive fibromatosis is a benign but locally-aggressive tumor, which most often affects the muscles of the shoulder, the pelvic girdle, and the thigh. It usually affects adolescents and young adults. Desmoplastic fibroma, considered the bone counterpart of soft tissue fibromatosis, is a rare tumor that usually affects the metaphyseal or diaphyseal portions of long bones or, less commonly, the jaw. Neuromuscular hamartoma, a rare developmental lesion composed of mature elements of both striated muscle and nerve, is usually diagnosed in infants and children and affects large nerve trunks. Rarely, it can affect the head and neck region. Occasional cases showing an association between aggressive fibromatosis and neuromuscular hamartoma have been reported in the literature. Here we present a unique case of an adult patient with desmoplastic fibroma of the mandible in association with neuromuscular hamartoma.

  3. Hamartoma Breast, Chondromatous Type

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    Vidya Bhat

    2011-07-01

    Full Text Available This case report describes an exceedingly rare case of hamartoma of breast with predominantly chondroid stroma. A 45 year old lady presented with a mobile lump in the upper outer quadrant of left breast, clinically diagnosed as fibroadenoma. Mammography and FNAC were not done. She underwent lumpectomy and we received the specimen measuring 7x5x3cm. Cut surface of which revealed grey white nodule with glistening surface. Histopathologically we found a circumscribed lesion with predominantly mature hyaline cartilage separated by fibrocollagenous bands.

  4. MYC acts via the PTEN tumor suppressor to elicit autoregulation and genome-wide gene repression by activation of the Ezh2 methyltransferase

    Science.gov (United States)

    Kaur, Mandeep; Cole, Michael D.

    2012-01-01

    The control of normal cell growth is a balance between stimulatory and inhibitory signals. MYC is a pleiotropic transcription factor that both activates and represses a broad range of target genes and is indispensable for cell growth. While much is known about gene activation by MYC, there is no established mechanism for the majority of MYC repressed genes. We report that MYC transcriptionally activates the PTEN tumor suppressor in normal cells to inactivate the PI3K pathway, thus suppressing AKT activation. Suppression of AKT enhances the activity of the EZH2 histone methyltransferase, a subunit of the epigenetic repressor Polycomb Repressive Complex 2 (PRC2), while simultaneously stabilizing the protein. MYC mediated enhancement in EZH2 protein level and activity results in local and genome-wide elevation in the repressive H3K27me3 histone modification, leading to widespread gene repression including feedback autoregulation of the MYC gene itself. Depletion of either PTEN or EZH2 and inhibition of the PI3K/AKT pathway leads to gene derepression. Importantly, expression of a phospho-defective EZH2 mutant is sufficient to recapitulate nearly half of all MYC-mediated gene repression. We present a novel epigenetic model for MYC-mediated gene repression and propose that PTEN and MYC exist in homeostatic balance to control normal growth which is disrupted in cancer cells. PMID:23135913

  5. Surgical Treatment for Pulmonary Hamartomas

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    Funda Ižncekara

    2015-11-01

    Full Text Available Aim: In this study, we evaluated the patients operated for hamartoma and treated endobronchially and the diagnostic value of this approach has been examined. Material and Method: 59 patients (24 females, 35 males; mean age 53 years, range 28-78 years which were operated and endobronchial treated for hamartoma in our clinic between January 2003 - January 2013 were analyzed retrospectively. Patient age, sex, symptoms, histopathological, surgical procedures and treatment outcomes were evaluated. Results: The most common complaint was shortness of breath, while 25 patients were asymptomatic. Thoracotomy and mass enucleation in 29 patients (%49,15, thoracotomy and wedge resection in 18 patients (%30.5, VATS and wedge resection in 4 patients (%6.77, thoracotomy and upper lobectomy in 4 patients (%6.77, thoracotomy and lower lobectomy in 2 patients (%3.38 and left upper lobe segmentectomy in 1 patient (%1.69 and right upper bronchial sleeve resection in 1 patient were performed. The postoperative pathology of lesions examined and diagnosis were chondroid hamartoma in 28 , pulmonary hamartoma in 20 , hamartoma chondrolypomatous in 11 and the bronchial hamartoma in 2 . No mortality was observed intraoperatively. Discussion: Although hamartomas are benign , diagnosis should be made because it can be confused with lung cancer. Definitive diagnosis and treatment can be performed successfully through VATS in primarily appropriate cases with minimal morbidity or thoracotomy or endobronchial treatment.

  6. Hereditary breast cancer associated with Cowden syndrome-related PTEN mutation with Lhermitte-Duclos disease.

    Science.gov (United States)

    Kimura, Fuyo; Ueda, Ai; Sato, Eiichi; Akimoto, Jiro; Kaise, Hiroshi; Yamada, Kimito; Hosonaga, Mari; Kawai, Yuko; Teraoka, Saeko; Okazaki, Miki; Ishikawa, Takashi

    2017-12-01

    Cowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease. We describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed. Herein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

  7. Genomic rearrangements of PTEN in prostate cancer

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    Sopheap ePhin

    2013-09-01

    Full Text Available The phosphatase and tensin homolog gene on chromosome 10q23.3 (PTEN is a negative regulator of the PIK3/Akt survival pathway and is the most frequently deleted tumor suppressor gene in prostate cancer. Monoallelic loss of PTEN is present in up to 60% of localized prostate cancers and complete loss of PTEN in prostate cancer is linked to metastasis and androgen independent progression. Studies on the genomic status of PTEN in prostate cancer initially used a two-color fluorescence in-situ hybridization (FISH assay for PTEN copy number detection in formalin fixed paraffin embedded tissue preparations. More recently, a four-color FISH assay containing two additional control probes flanking the PTEN locus with a lower false-positive rate was reported. Combined with the detection of other critical genomic biomarkers for prostate cancer such as ERG, AR, and MYC, the evaluation of PTEN genomic status has proven to be invaluable for patient stratification and management. Although less frequent than allelic deletions, point mutations in the gene and epigenetic silencing are also known to contribute to loss of PTEN function, and ultimately to prostate cancer initiation. Overall, it is clear that PTEN is a powerful biomarker for prostate cancer. Used as a companion diagnostic for emerging therapeutic drugs, FISH analysis of PTEN is promisingly moving human prostate cancer closer to more effective cancer management and therapies.

  8. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress

    Science.gov (United States)

    Bassi, C; Ho, J; Srikumar, T; Dowling, RJO; Gorrini, C; Miller, SJ; Mak, TW; Neel, BG; Raught, B; Stambolic, V

    2016-01-01

    Loss of function of the Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the Phosphatidylinositol 3′ kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase Ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, while PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors. PMID:23888040

  9. PTEN degradation after ischemic stroke: a double-edged sword.

    Science.gov (United States)

    Li, W; Huang, R; Chen, Z; Yan, L-J; Simpkins, J W; Yang, S-H

    2014-08-22

    Tumor suppressor phosphatase and tensin homolog (PTEN) is highly expressed in neurons and PTEN inhibition has been reported to be neuroprotective against ischemic stroke in experimental models. On the other hand, PTEN deletion has been shown to lead to cognitive impairment. In the current study, we examined the expression and functions of PTEN in an ischemic stroke rodent model. We found rapid S-nitrosylation and degradation of PTEN after cerebral ischemia/reperfusion injury. PTEN degradation leads to activation of Akt. PTEN partial deletion or PTEN inhibition increased the expression of GABAA receptor (GABAAR) γ2 subunit and enhanced GABAA receptor current. After cerebral ischemia, increased expression of GABAAR γ2 subunit was observed in the ischemia region and the penumbra area. We also observed PTEN loss in astrocytes after cerebral ischemia. Astrocytic PTEN partial knockout increased astrocyte activation and exacerbated ischemic damage. We speculated that ischemic stroke induced neuronal PTEN degradation, hence enhanced GABAA receptor-medicated neuronal activity inhibition which could attenuate excitotoxicity and provide neuroprotection during the acute phase after stroke, while inhibiting long-term functional recovery and contributing to vascular cognitive impairment after stroke. On the other hand, ischemic stroke induced astrocytic PTEN loss and enhanced ischemic damage and astrogliosis. Taken together, our study indicates that ischemic stroke induces rapid PTEN degradation in both neurons and astrocytes which play both protective and detrimental action in a spatiotemporal- and cell-type-dependent manner. Our study provides critical insight for targeting PTEN signaling pathway for stroke treatment.

  10. Eccrine angiomatous hamartoma: report of five congenital cases.

    Science.gov (United States)

    Larralde, Margarita; Bazzolo, Eleonora; Boggio, Paula; Abad, María Eugenia; Santos Muñoz, Andrea

    2009-01-01

    Eccrine angiomatous hamartoma is a rare entity characterized histologically by the combination of proliferative eccrine and vascular elements. It generally arises before puberty, as solitary or multiple lesions, with a heterogeneous clinical appearance, affecting predominantly the distal extremities, with or without associated pain or hyperhidrosis. It may require surgical treatment due to cosmetic concern, progressive enlargement or the presence of pain or excessive hyperhidrosis. We report five congenital cases of eccrine angiomatous hamartoma, emphasizing a clinically uncommon tumor-like appearance, with numerous telangiectasias on their surfaces resembling vascular lesions, in two of them.

  11. [Mesenchymal hamartoma of the liver in an elderly man].

    Science.gov (United States)

    Giunippero, Alejandro; Maya, Antonio M; Gallo, Antonio; Bazzana, María S; Cosentino, Valeria; Aulet, Francisco J

    2009-01-01

    The mesenchymal hamartoma of the liver is a non frequent benign tumor with a ductal plate malformation, consisting of myxoid mesenchymal tissue and abnormal bile ducts in different proportion. Usually it presents as multiple liver cyst formations without communication with the principal bile duct. They are frequent in children, being rare in adults. The first case was reported by Yamamura et al in 1976, and very few cases are reported in the bibliography. We present the case of an elder 87 year old male who presented a 20 cm mesenchymal hamartoma liver cyst.

  12. Cutaneous hamartoma with pagetoid cells.

    Science.gov (United States)

    Piérard-Franchimont, C; Dosal, F L; Estrada, J A; Piérard, G E

    1991-04-01

    We report an unusual cutaneous hamartoma with pagetoid cells characterized by the presence of intraepidermal cells resembling Toker's cells of the nipple. These cells were EMA positive and could be related to the histogenesis of some Paget's disease.

  13. Giant endobronchial hamartoma resected by fiberoptic bronchoscopy electrosurgical snaring

    Directory of Open Access Journals (Sweden)

    Cavallari Vittorio

    2011-08-01

    Full Text Available Abstract Less than 1% of lung neoplasms are represented by benign tumors. Among these, hamartomas are the most common with an incidence between 0.025% and 0.32%. In relation to the localization, hamartomas are divided into intraparenchymal and endobronchial. Clinical manifestation of an endobronchial hamartoma (EH results from tracheobronchial obstruction or bleeding. Usually, EH localizes in large diameter bronchus. Endoscopic removal is usually recommended. Bronchotomy or parenchimal resection through thoracotomy should be reserved only for cases where the hamatoma cannot be approached through endoscopy, or when irreversible lung functional impairment occurred after prolonged airflow obstruction. Generally, when endoscopic approach is used, this is through rigid bronchoscopy, laser photocoagulation or mechanical resection. Here we present a giant EH occasionally diagnosed and treated by fiberoptic bronchoscopy electrosurgical snaring.

  14. Brunner gland hamartoma masquerading as malignancy; a rare case report.

    Science.gov (United States)

    Sen, Rajeev; Gupta, Veena; Sharma, Nisha; Chawla, Nitika; Kumar, Sanjay; Malik, Shivani

    2014-10-01

    Brunner's gland hamartoma is a rare benign tumour of the duodenum. It was first described by Cruveilhier in 1835. Presently around 200 cases have been reported in literature. No sex predilection is seen. Patients usually present in the fifth to sixth decades of life. They may be clinically silent or may present with variable symptoms and occasionally obstructive symptoms and chronic pancreatitis. Endoscopic presentation can be nodular, polypoid or diffuse glandular proliferation with thickening of duodenal wall and hence can be misdiagnosed as malignancy. We describe a case of duodenal tumor reported outside (on biopsy) as well differentiated adenocarcinoma which out as Brunner gland hamartoma upon complete resection. Brunner gland hamartoma may sometimes have a very unusual presentation. Extensive pre-operative evaluation is necessity to avoid radical surgical procedure.

  15. In MMTV-Her-2/neu transgenic mammary tumors the absence of caveolin-1-/- alters PTEN and NHERF1 but not β-catenin expression.

    Science.gov (United States)

    Cuello-Carrión, F Darío; Cayado-Gutiérrez, Niubys; Natoli, Anthony L; Restall, Christina; Anderson, Robin L; Nadin, Silvina; Alvarez-Olmedo, Daiana; Castro, Gisela N; Gago, Francisco E; Fanelli, Mariel A; Ciocca, Daniel R

    2013-09-01

    In a recent study, we have shown that in mammary tumors from mice lacking the Cav-1 gene, there are alterations in specific heat shock proteins as well as in tumor development. With this in mind, we have now investigated other proteins in the same mammary mouse tumor model (Her-2/neu expressing mammary tumors from Cav-1 wild type and Cav-1 null mice), to further comprehend the complex tumor-stroma mechanisms involved in regulating stress responses during tumor development. In this tumor model the cancer cells always lacked of Cav-1, so the KO influenced the Cav-1 in the stroma. By immunohistochemistry, we have found a striking co-expression of β-catenin and Her-2/neu in the tumor cells. The absence of Cav-1 in the tumor stroma had no effect on expression or localization of β-catenin and Her-2/neu. Both proteins appeared co-localized at the cell surface during tumor development and progression. Since Her-2/neu activation induces MTA1, we next evaluated MTA1 in the mouse tumors. Although this protein was found in numerous nuclei, the absence of Cav-1 did not alter its expression level. In contrast, significantly more PTEN protein was noted in the tumors lacking Cav-1 in the stroma, with the protein localized mainly in the nuclei. P-Akt levels were relatively low in tumors from both Cav-1 WT and Cav-1 KO mice. There was also an increase in nuclear NHERF1 expression levels in the tumors arising from Cav-1 KO mice. The data obtained in the MMTV-neu model are consistent with a role for Cav-1 in adjacent breast cancer stromal cells in modulating the expression and localization of important proteins implicated in tumor cell behavior.

  16. A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response.

    Science.gov (United States)

    Xiao, Zhan; Carrasco, Rosa A; Schifferli, Kevin; Kinneer, Krista; Tammali, Ravinder; Chen, Hong; Rothstein, Ray; Wetzel, Leslie; Yang, Chunning; Chowdhury, Partha; Tsui, Ping; Steiner, Philipp; Jallal, Bahija; Herbst, Ronald; Hollingsworth, Robert E; Tice, David A

    2016-04-01

    HER3/ERBB3 is a kinase-deficient member of the EGFR family receptor tyrosine kinases (RTK) that is broadly expressed and activated in human cancers. HER3 is a compelling cancer target due to its important role in activation of the oncogenic PI3K/AKT pathway. It has also been demonstrated to confer tumor resistance to a variety of cancer therapies, especially targeted drugs against EGFR and HER2. HER3 can be activated by its ligand (heregulin/HRG), which induces HER3 heterodimerization with EGFR, HER2, or other RTKs. Alternatively, HER3 can be activated in a ligand-independent manner through heterodimerization with HER2 in HER2-amplified cells. We developed a fully human mAb against HER3 (KTN3379) that efficiently suppressed HER3 activity in both ligand-dependent and independent settings. Correspondingly, KTN3379 inhibited tumor growth in divergent tumor models driven by either ligand-dependent or independent mechanisms in vitro and in vivo Most intriguingly, while investigating the mechanistic underpinnings of tumor response to KTN3379, we discovered an interesting dichotomy in that PTEN loss, a frequently occurring oncogenic lesion in a broad range of cancer types, substantially blunted the tumor response in HER2-amplified cancer, but not in the ligand-driven cancer. To our knowledge, this represents the first study ascertaining the impact of PTEN loss on the antitumor efficacy of a HER3 mAb. KTN3379 is currently undergoing a phase Ib clinical trial in patients with advanced solid tumors. Our current study may help us optimize patient selection schemes for KTN3379 to maximize its clinical benefits. Mol Cancer Ther; 15(4); 689-701. ©2016 AACR.

  17. PTEN function: the long and the short of it.

    Science.gov (United States)

    Hopkins, Benjamin D; Hodakoski, Cindy; Barrows, Douglas; Mense, Sarah M; Parsons, Ramon E

    2014-04-01

    Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a phosphatase that is frequently altered in cancer. PTEN has phosphatase-dependent and -independent roles, and genetic alterations in PTEN lead to deregulation of protein synthesis, the cell cycle, migration, growth, DNA repair, and survival signaling. PTEN localization, stability, conformation, and phosphatase activity are controlled by an array of protein-protein interactions and post-translational modifications. Thus, PTEN-interacting and -modifying proteins have profound effects on the tumor suppressive functions of PTEN. Moreover, recent studies identified mechanisms by which PTEN can exit cells, via either exosomal export or secretion, and act on neighboring cells. This review focuses on modes of PTEN protein regulation and ways in which perturbations in this regulation may lead to disease.

  18. A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel.

    Science.gov (United States)

    Smyth, Lillian M; Monson, Kelsey R; Jhaveri, Komal; Drilon, Alexander; Li, Bob T; Abida, Wassim; Iyer, Gopa; Gerecitano, John F; Gounder, Mrinal; Harding, James J; Voss, Martin H; Makker, Vicky; Ho, Alan L; Razavi, Pedram; Iasonos, Alexia; Bialer, Philip; Lacouture, Mario E; Teitcher, Jerrold B; Erinjeri, Joseph P; Katabi, Nora; Fury, Matthew G; Hyman, David M

    2017-03-09

    Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with

  19. Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.

    Science.gov (United States)

    Kohnoh, Takashi; Hashimoto, Naozumi; Ando, Akira; Sakamoto, Koji; Miyazaki, Shinichi; Aoyama, Daisuke; Kusunose, Masaaki; Kimura, Motohiro; Omote, Norihito; Imaizumi, Kazuyoshi; Kawabe, Tsutomu; Hasegawa, Yoshinori

    2016-01-01

    Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial-mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus. Our study strengthens the therapeutic possibility that

  20. Hamartoma cístico retrorretal Retrorectal cystic hamartoma

    Directory of Open Access Journals (Sweden)

    Cleverson Winston de Liz Medeiros

    2002-08-01

    Full Text Available A 32-year-old woman was referred to our institution for a pelvic mass. She was asymptomatic and was found to have a mass on rectal examination. Magnetic resonance showed a large solid-cystic mass and the patient underwent complete surgical excision with pathologic findings suggesting retrorectal cyst-hamartoma. Tailgut cysts (or retrorectal cystic hamartomas are rare congenital lesions settled in the retrorectal (presacral space. They are made up of cysts lined by multiple types of epithelium, often predominantly mucin-secreting. The lesion requires complete surgical excision to prevent complications of recurrence, infection or carcinomatous degeneration.

  1. Hamartoma mesenquimatoso hepático en un anciano Mesenchymal hamartoma of the liver in an elderly man

    Directory of Open Access Journals (Sweden)

    Alejandro Giunippero

    2009-10-01

    Full Text Available El hamartoma mesenquimatoso hepático es un tumor benigno poco frecuente, formado por alteraciones de la placa hiliar y compuesto por tejidos mixomatoso, mesenquimático y conductos biliares anormales en proporciones variables. Habitualmente son formaciones hepáticas múltiples, quísticas y sin comunicación con la vía biliar. Es más frecuente en niños, es raro en adultos. El primer caso fue publicado por Yamamura et al en 1976, y se encuentran pocos en la bibliografía. Presentamos el caso de un paciente de 87 años con un hamartoma hepático quístico de 20 cm.The mesenchymal hamartoma of the liver is a non frequent benign tumor with a ductal plate malformation, consisting of myxoid mesenchymal tissue and abnormal bile ducts in different proportion. Usually it presents as multiple liver cyst formations without communication with the principal bile duct. They are frequent in children, being rare in adults. The first case was reported by Yamamura et al in 1976, and very few cases are reported in the bibliography. We present the case of an elder 87 year old male who presented a 20 cm mesenchymal hamartoma liver cyst.

  2. Gelastic epilepsy: Beyond hypothalamic hamartomas

    Directory of Open Access Journals (Sweden)

    Reinaldo Uribe-San-Martin

    2015-01-01

    Full Text Available Gelastic epilepsy or laughing seizures have been historically related to children with hypothalamic hamartomas. We report three adult patients who had gelastic epilepsy, defined as the presence of seizures with a prominent laugh component, including brain imaging, surface/invasive electroencephalography, positron emission tomography, and medical/surgical outcomes. None of the patients had hamartoma or other hypothalamic lesion. Two patients were classified as having refractory epilepsy (one had biopsy-proven neurocysticercosis and the other one hippocampal sclerosis and temporal cortical dysplasia. The third patient had no lesion on MRI and had complete control with carbamazepine. Both lesional patients underwent resective surgery, one with complete seizure control and the other one with poor outcome. Although hypothalamic hamartomas should always be ruled out in patients with gelastic epilepsy, laughing seizures can also arise from frontal and temporal lobe foci, which can be surgically removed. In addition, we present the first case of gelastic epilepsy due to neurocysticercosis.

  3. PTEN, Longevity and Age-Related Diseases

    Directory of Open Access Journals (Sweden)

    Izak S. Tait

    2013-12-01

    Full Text Available Since the discovery of PTEN, this protein has been shown to be an effective suppressor of cancer and a contributor to longevity. This report will review, in depth, the associations between PTEN and other molecules, its mutations and regulations in order to present how PTEN can be used to increase longevity. This report will collect recent research of PTEN and use this to discuss PTEN’s role in caloric restriction, antioxidative defense of DNA-damage and the role it plays in suppressing tumors. The report will also discuss that variety of ways that PTEN can be compromised, through mutations, complete loss of alleles and its main antagonist, the PI3K/AKT pathway.

  4. 抑癌基因PTEN蛋白在肾癌细胞中的表达及病变评估中的意义%Expression of Tumor Suppressor Gene PTEN in Renal Cell Carcinoma and Its Significance

    Institute of Scientific and Technical Information of China (English)

    李金雨; 谢庆祥; 韩聪祥; 赵力; 林吓聪

    2012-01-01

    [Objective]To explore the expression of tumor suppressor gene PTEN in renal cell carcinoma (RCC) and its impact on cell cycle. [Methods] Totally 44 cases of RCC tissues confirmed by pathology after operation, 15 cases of adjacent normal renal cell tissues and 10 cases of non-tumor normal renal tissues were collected. Immunohistochemical SP method was used to detect PTEN protein. Fifteen RCC tissues were selected respectively from renal tissues with positive and negative PTEN protein. Flow cytometry was used to examine the cell cycle. [Results]The expression of PTEN protein mostly located in the renal cell cytoplasm. The positive expression of PTEN protein in RCC tissues was 36. 3% , which was prominently lower than those in the adjacent normal tissues(77. 3%) and the normal tissues(100%) ( P <0. 01). The expression of PTEN in RCC tissues with stage I and H were much higher than those in RCC tissues with stage HI and IV ( P <0. 05). The percentage of Go/Gi phase in renal cancer with positive expression of PTEN protein was mush higher than that in renal cancer with negative expression of PTEN protein( P <0. 01) , but the percentage of G2/M and S phase in renal cancer with positive expression of PTEN protein was mush lower than that in renal cancer with negative expression of PTEN protein( P <0. 01). [Conclusion]The positive expression of PTEN protein in RCC tissues significantly decreases. PTEN protein may suppress renal carcinoma through inducing the cell cycle to be arrested in G0/G1 phase. The expression of PTEN protein can evaluate the development and prognosis of RCC.%[目的]探讨肾细胞癌(renal cell carcinoma,RCC)中的抑癌基因PTEN蛋白的表达及其对肾癌细胞周期的影响.[方法]收集44例手术后并经病理学检查证实的RCC组织、15 例癌旁非癌肾组织及10例非瘤正常肾组织,采用免疫组化SP法进行PTEN蛋白检测,按PTEN蛋白阴、阳性各选15例RCC组织,用流式细胞仪检测细胞周期.[结果]PTEN蛋白

  5. The effect of intense intermittent training with and without taking vitamin E on mRNA expression of p53/PTEN tumor suppressing genes in prostate glands of male rats

    Directory of Open Access Journals (Sweden)

    Mohammad Esmaeil Afzalpour

    2016-11-01

    Full Text Available Physical activity and diet are the most important modifiable determinants of cancer risk. The objective of this study was to examine the effect of intense intermittent training with and without taking vitamin E on expression of p53 and PTEN tumor suppressing genes in the prostate gland of male rats. For this purpose, 50 Sprague-Dawley male rats were randomly assigned into 5 groups: [1] control (CON, n = 10, [2] sham (S, n = 10, [3] intense intermittent training (IIT, n = 10, [4] intense intermittent training + vitamin E (IIT + VE, n = 10, [5] vitamin E (VE, n = 10. Protocol of this study was implemented for 6 days per week for 6 weeks, with observing the overload principle on the motorized treadmill. After implementing training protocol, expression rate of p53 and PTEN genes reduced significantly (p<0.000, p<0.031, respectively. Taking vitamin E with intermittent training caused significant reduction in p53 expression (p<0.013, while it caused significant increase in expression of PTEN (p<0.035. These results showed that intense intermittent training reduces expression of p53 and PTEN tumor suppressing genes and taking supplementation vitamin E along with this type of training could cause different effects in expression of these tumor suppressor genes.

  6. Strain-Specific Spontaneous and NNK-Mediated Tumorigenesis in Pten+/− Mice

    Directory of Open Access Journals (Sweden)

    Mary Christine Hollander

    2008-08-01

    Full Text Available Pten is a negative regulator of the Akt pathway, and its inactivation is believed to be an etiological factor in many tumor types. Pten+/- mice are susceptible to a variety of spontaneous tumor types, depending on strain background. Pten+/- mice, in lung tumor-sensitive and -resistant background strains, were treated with a tobacco carcinogen, 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK, to determine whether allelic Pten deletion can cooperate with NNK in carcinogenesis in lung or other tissues. In lung tumor-resistant C57BL/6 Pten+/- or +/+ mice, NNK treatment did not lead to any lung tumors and did not increase the incidence or severity of tumors previously reported for this strain. In contrast, in a lung tumor-susceptible pseudo-A/J strain, there was a dose-dependent increase in lung tumor size in Pten+/- compared with +/+ mice, although there was no increase in multiplicity. No other tumor types were observed in pseudo-A/J Pten+/- mice regardless of NNK treatment. Lung tumors from these Pten+/- mice had K-ras mutations, retained Pten expression and had similar Akt pathway activation as lung tumors from +/+ mice. Therefore, deletion of a single copy of Pten does not substantially add to the lung tumor phenotype conferred by mutation of K-ras by NNK, and there is likely no selective advantage for loss of the second Pten allele in lung tumor initiation.

  7. Binding of PTEN to specific PDZ domains contributes to PTEN protein stability and phosphorylation by microtubule-associated serine/threonine kinases.

    Science.gov (United States)

    Valiente, Miguel; Andrés-Pons, Amparo; Gomar, Beatriz; Torres, Josema; Gil, Anabel; Tapparel, Caroline; Antonarakis, Stylianos E; Pulido, Rafael

    2005-08-12

    The tumor suppressor phosphatase PTEN is a key regulator of cell growth and apoptosis that interacts with PDZ domains from regulatory proteins, including MAGI-1/2/3, hDlg, and MAST205. Here we identified novel PTEN-binding PDZ domains within the MAST205-related proteins, syntrophin-associated serine/threonine kinase and MAST3, characterized the regions of PTEN involved in its interaction with distinctive PDZ domains, and analyzed the functional consequences on PTEN of PDZ domain binding. Using a panel of PTEN mutations, as well as PTEN chimeras containing distinct domains of the related protein TPTE, we found that the PTP and C2 domains of PTEN do not affect PDZ domain binding and that the C-terminal tail of PTEN (residues 350-403) provides selectivity to recognize specific PDZ domains from MAGI-2, hDlg, and MAST205. Binding of PTEN to the PDZ-2 domain from MAGI-2 increased PTEN protein stability. Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. Our results suggest an important role for the C-terminal region of PTEN in the selective association with scaffolding and/or regulatory molecules and provide evidence that PDZ domain binding stabilizes PTEN and targets this tumor suppressor for phosphorylation by microtubule-associated serine/threonine kinases.

  8. PTEN function, the long and the short of it

    Science.gov (United States)

    Hopkins, Benjamin D.; Hodakoski, Cindy; Barrows, Doug; Mense, Sarah; Parsons, Ramon E.

    2014-01-01

    Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a phosphatase that is frequently altered in cancer. PTEN has phosphatase-dependent and - independent roles; and genetic alterations in PTEN lead to deregulation of protein synthesis, cell cycle, migration, growth, DNA repair, and survival signaling. PTEN localization, stability, conformation, and phosphatase activity are controlled by an array of protein-protein interactions and post-translational modifications. Thus, PTEN-interacting and modifying proteins have profound effects on PTEN’s tumor suppressive functions. Moreover, recent studies identified mechanisms by which PTEN can exit cells, either via exosomal export or secretion, and act on neighboring cells. This review focuses on modes of PTEN protein regulation and ways in which perturbations in this regulation may lead to disease. PMID:24656806

  9. A unified nomenclature and amino acid numbering for human PTEN

    NARCIS (Netherlands)

    Pulido, Rafael; Baker, Suzanne J; Barata, Joao T; Carracedo, Arkaitz; Cid, Victor J; Chin-Sang, Ian D; Davé, Vrushank; den Hertog, Jeroen; Devreotes, Peter; Eickholt, Britta J; Eng, Charis; Furnari, Frank B; Georgescu, Maria-Magdalena; Gericke, Arne; Hopkins, Benjamin; Jiang, Xeujun; Lee, Seung-Rock; Lösche, Mathias; Malaney, Prerna; Matias-Guiu, Xavier; Molina, María; Pandolfi, Pier Paolo; Parsons, Ramon; Pinton, Paolo; Rivas, Carmen; Rocha, Rafael M; Rodríguez, Manuel S; Ross, Alonzo H; Serrano, Manuel; Stambolic, Vuk; Stiles, Bangyan; Suzuki, Akira; Tan, Seong-Seng; Tonks, Nicholas K; Trotman, Lloyd C; Wolff, Nicolas; Woscholski, Rudiger; Wu, Hong; Leslie, Nicholas R

    2014-01-01

    The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line

  10. A unified nomenclature and amino acid numbering for human PTEN

    NARCIS (Netherlands)

    Pulido, Rafael; Baker, Suzanne J; Barata, Joao T; Carracedo, Arkaitz; Cid, Victor J; Chin-Sang, Ian D; Davé, Vrushank; den Hertog, Jeroen; Devreotes, Peter; Eickholt, Britta J; Eng, Charis; Furnari, Frank B; Georgescu, Maria-Magdalena; Gericke, Arne; Hopkins, Benjamin; Jiang, Xeujun; Lee, Seung-Rock; Lösche, Mathias; Malaney, Prerna; Matias-Guiu, Xavier; Molina, María; Pandolfi, Pier Paolo; Parsons, Ramon; Pinton, Paolo; Rivas, Carmen; Rocha, Rafael M; Rodríguez, Manuel S; Ross, Alonzo H; Serrano, Manuel; Stambolic, Vuk; Stiles, Bangyan; Suzuki, Akira; Tan, Seong-Seng; Tonks, Nicholas K; Trotman, Lloyd C; Wolff, Nicolas; Woscholski, Rudiger; Wu, Hong; Leslie, Nicholas R

    2014-01-01

    The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line

  11. Identification of novel PTEN-binding partners: PTEN interaction with fatty acid binding protein FABP4.

    Science.gov (United States)

    Gorbenko, O; Panayotou, G; Zhyvoloup, A; Volkova, D; Gout, I; Filonenko, V

    2010-04-01

    PTEN is a tumor suppressor with dual protein and lipid-phosphatase activity, which is frequently deleted or mutated in many human advanced cancers. Recent studies have also demonstrated that PTEN is a promising target in type II diabetes and obesity treatment. Using C-terminal PTEN sequence in pEG202-NLS as bait, yeast two-hybrid screening on Mouse Embryo, Colon Cancer, and HeLa cDNA libraries was carried out. Isolated positive clones were validated by mating assay and identified through automated DNA sequencing and BLAST database searches. Sequence analysis revealed a number of PTEN-binding proteins linking this phosphatase to a number of different signaling cascades, suggesting that PTEN may perform other functions besides tumor-suppressing activity in different cell types. In particular, the interplay between PTEN function and adipocyte-specific fatty-acid-binding protein FABP4 is of notable interest. The demonstrable tautology of PTEN to FABP4 suggested a role for this phosphatase in the regulation of lipid metabolism and adipocyte differentiation. This interaction was further studied using coimmunoprecipitation and gel-filtration assays. Finally, based on Biacore assay, we have calculated the K(D) of PTEN-FABP4 complex, which is around 2.8 microM.

  12. Hamartoma mamario gigante: dos casos de una entidad rara

    Directory of Open Access Journals (Sweden)

    T.A. Gomes-Rodrigues

    2014-09-01

    Full Text Available El hamartoma gigante de la mama es una entidad clínico-patológica inusual que tiende a confundirse con otros tumores. A pesar del avance en las técnicas diagnósticas, su diagnóstico clínico es difícil y normalmente solo se confirma cuando se analiza toda la pieza de resección. El diagnóstico diferencial debe incluir entidades como el fibroadenoma, lipoma, tumor phyllodes y diversos tipos de carcinomas. Presentamos 2 casos de hamartoma gigante de mama en mujeres de edad media, de los cuales uno fue tratado mediante mastectomía conservadora de complejo pezónareola y reconstrucción con prótesis y el otro con biopsia escisional y remodelación con patrón de pexia mamaria.

  13. DIAGNOSIS AND TREATMENT OF PULMONARY HAMARTOMA

    Institute of Scientific and Technical Information of China (English)

    戈烽; 佟凤山; 李泽坚

    1998-01-01

    From 1970 to 1997, 67 patients with pulmonary hemartocna were operated on in our hospital. There were 38 men and 29 women with a M/F ratio of 1.3 : 1. The mean age seas 47 years (range 21 to 82 years). The peak incidence was 40 to 60 years. 39% patients had pulmonary symptomst;hemoptysis,cough, phlegm and chest pain. All were solitary. 68. 7% tumors were located in right lung and 64.2% in upper or middle lobe. 80. 6% hemartomas were less than 3 cm in transverse diameter. On chest films, the opacity was homogeneous in 79.1% cases, heterogeneous in 20. 9% and calcifications in 9.0%. The vast majority of shadows were heterogeneous on CT films. Operation is the best treamumt for hamartomas.Postoperative mortality was 1.5% There was none recurrences and canceration during the follow-up (mean 14 years).

  14. Mucosal Schwann cell "Hamartoma": A new entity?

    Institute of Scientific and Technical Information of China (English)

    Paola Pasquini; Andrea Baiocchini; Laura Falasca; Dante Annibali; Guido Gimbo; Francesco Pace; Franca Del Nonno

    2009-01-01

    Schwannoma is a well-described, benign nerve sheath tumor of the soft tissue, but is rare in the gastrointestinal tract. Gastrointestinal schwannomas are often incidentally discovered as small polypoid intraluminal lesions. In this report, we describe the clinicopathologic and immunohistochemical features of a distinctive neural mucosal polyp composed of a diffuse cellular proliferation of uniform bland spindled cells in the lamina propria that entraps the colonic crypts. Immunohistochemical analysis revealed strong and diffuse positivity for the S-100 protein. To avoid confusion of these solitary colorectal polyps containing pure spindled Schwann cell proliferation in the lamina propria with neural lesions that have significant association with inherited syndromes, it is better to use the designation "mucosal Schwann hamartoma".

  15. Phosphorylation of PTEN at STT motif is associated with DNA damage response

    Energy Technology Data Exchange (ETDEWEB)

    Misra, Sandip; Mukherjee, Ananda; Karmakar, Parimal, E-mail: pkarmakar_28@yahoo.co.in

    2014-12-15

    Highlights: • Phosphorylation PTEN at the C-terminal STT motif is necessary for DNA repair. • DNA damage induces phosphorylation of STT motif of PTEN. • Phospho-PTEN translocates to nucleus after DNA damage. • Phospho-PTEN forms nuclear foci after DNA damage which co localized with γH2AX. - Abstract: Phosphatase and tensin homolog deleted on chromosome Ten (PTEN), a tumor suppressor protein participates in multiple cellular activities including DNA repair. In this work we found a relationship between phosphorylation of carboxy (C)-terminal STT motif of PTEN and DNA damage response. Ectopic expression of C-terminal phospho-mutants of PTEN, in PTEN deficient human glioblastoma cells, U87MG, resulted in reduced viability and DNA repair after etoposide induced DNA damage compared to cells expressing wild type PTEN. Also, after etoposide treatment phosphorylation of PTEN increased at C-terminal serine 380 and threonine 382/383 residues in PTEN positive HEK293T cells and wild type PTEN transfected U87MG cells. One-step further, DNA damage induced phosphorylation of PTEN was confirmed by immunoprecipitation of total PTEN from cellular extract followed by immunobloting with phospho-specific PTEN antibodies. Additionally, phospho-PTEN translocated to nucleus after etoposide treatment as revealed by indirect immunolabeling. Further, phosphorylation dependent nuclear foci formation of PTEN was observed after ionizing radiation or etoposide treatment which colocalized with γH2AX. Additionally, etoposide induced γH2AX, Mre11 and Ku70 foci persisted for a longer period of times in U87MG cells after ectopic expression of PTEN C-terminal phospho-mutant constructs compared to wild type PTEN expressing cells. Thus, our findings strongly suggest that DNA damage induced phosphorylation of C-terminal STT motif of PTEN is necessary for DNA repair.

  16. Hamartomas of the tuber cinereum

    Energy Technology Data Exchange (ETDEWEB)

    Diebler, C.; Ponsot, G.

    1983-05-01

    The hamartoma of the tuber cinereum, a midline dysraphic syndrome, corresponds to a mass of normal neuronal tissue implanted in the area of the mamillary bodies. It has no evolutionary potential, but association to other cerebral malformations has been observed. On the basis of 18 personal cases and a review of the literature, the authors evaluate the actual diagnostic criteria and the incidence of different clinical signs such as precocious isosexual puberty, seizures, and mental impairment.

  17. CHEST WALL HAMARTOMA : Case Report

    OpenAIRE

    Gülden DİNİZ; Ortaç, Ragıp; Aktaş, Safiye; TEMİR, Günyüz; HOŞGÖR, Münevver; Karaca, İrfan

    2005-01-01

    A case of four-month – old girl diagnosed as chest wall hamartoma is presented. This entity is an extremely rare but characteristic lesion of the ribs usually presenting in the neonate or infant with a mass or respiratory symptoms. Complete sponraneous regression of the lesion has been reported. Recently conservative management of asymptomatic childiren was recommended. Although rare, this condition ought to be kept in mind while dealing with infantile chest wall masses to avoid an errone...

  18. CHEST WALL HAMARTOMA : Case Report

    OpenAIRE

    Gülden DİNİZ; Ortaç, Ragıp; Aktaş, Safiye; HOŞGÖR, Günyüz TEMİR2Münevver; Karaca, İrfan

    2005-01-01

    A case of four-month – old girl diagnosed as chest wall hamartoma is presented. This entity is an extremely rare but characteristic lesion of the ribs usually presenting in the neonate or infant with a mass or respiratory symptoms. Complete sponraneous regression of the lesion has been reported. Recently conservative management of asymptomatic childiren was recommended. Although rare, this condition ought to be kept in mind while dealing with infantile chest wall masses to avoid...

  19. Focus on PTEN regulation

    Directory of Open Access Journals (Sweden)

    Miriam eBermudez-Brito

    2015-07-01

    Full Text Available The role of PTEN as a tumour suppressor has been for a long time attributed to its lipid phosphatase activity against PI(3,4,5P3, the phospholipid product of the class I PI3Ks. Besides its traditional role as a lipid phosphatase at the plasma membrane, a wealth of data has shown that PTEN can function independently of its phosphatase activity and that PTEN also exists and plays a role in the nucleus, in cytoplasmic organelles and extracellularly. Accumulating evidence has shed light on diverse physiological functions of PTEN which are accompanied by a complex regulation of its expression and activity. PTEN levels and function are regulated transcriptionally, post-transcriptionally and post-translationally. PTEN is also sensitive to regulation by its interacting proteins and its localization. Herein, we summarize the current knowledge on mechanisms that regulate the expression and enzymatic activity of PTEN and its role in human diseases.

  20. A Novel PTEN/Mutant p53/c-Myc/Bcl-XL Axis Mediates Context-Dependent Oncogenic Effects of PTEN with Implications for Cancer Prognosis and Therapy

    Directory of Open Access Journals (Sweden)

    Xiaoping Huang

    2013-08-01

    Full Text Available Phosphatase and tensin homolog located on chromosome 10 (PTEN is one of the most frequently mutated tumor suppressors in human cancer including in glioblastoma. Here, we show that PTEN exerts unconventional oncogenic effects in glioblastoma through a novel PTEN/mutant p53/c-Myc/Bcl-XL molecular and functional axis. Using a wide array of molecular, genetic, and functional approaches, we demonstrate that PTEN enhances a transcriptional complex containing gain-of-function mutant p53, CBP, and NFY in human glioblastoma cells and tumor tissues. The mutant p53/CBP/NFY complex transcriptionally activates the oncogenes c-Myc and Bcl-XL, leading to increased cell proliferation, survival, invasion, and clonogenicity. Disruption of the mutant p53/c-Myc/Bcl-XL axis or mutant p53/CBP/NFY complex reverses the transcriptional and oncogenic effects of PTEN and unmasks its tumor-suppressive function. Consistent with these data, we find that PTEN expression is associated with worse patient survival than PTEN loss in tumors harboring mutant p53 and that a small molecule modulator of p53 exerts greater antitumor effects in PTEN-expressing cancer cells. Altogether, our study describes a new signaling pathway that mediates context-dependent oncogenic/tumor-suppressive role of PTEN. The data also indicate that the combined mutational status of PTEN and p53 influences cancer prognosis and anticancer therapies that target PTEN and p53.

  1. Effects of Tumor Suppressor Gene PTEN on Migration and Proliferation of Human Airway Smooth Muscle Cells%肿瘤抑制基因 PTEN对人气道平滑肌细胞迁移和增殖的影响

    Institute of Scientific and Technical Information of China (English)

    蓝海兵; 罗雅玲; 赖文岩; 龚园其

    2015-01-01

    ABSTRACT:Objective To investigate the mechanism for the effect of tumor suppressor gene PTEN on migration and proliferation of human airway smooth muscle cells (HASMCs).Methods HASMCs were transfected with recombinant adenoviruses encoding human wild-type PTEN cDNA (Ad-PTEN group),GFP-labeled adenovirus vectors (Ad-GFP group)and mock adenoviru-ses (MOCK group),respectively.Cell proliferation was assessed by MTS assay.Cell migration was analyzed using Transwell chamber apparatus.The rearrangement of cell actin cytoskeleton was observed by laser scanning confocal microscope.The protein expression of PTEN,p-Akt, Akt,p-FAK and FAK were measured by Western blotting.Results Compared with Ad-GFP group or MOCK group,the absorbance value,number of migrated cells per unit area and levels of p-Akt and p-FAK protein significantly decreased in Ad-PTEN group (P 0.05).In addition,Ad-PTEN transfection diminished cell outline and reduced the pseudopodium and stress fibers.However,cells in Ad-GFP group and MOCK group had a small amount of short and thin stress fibers with few filiform pseudopodia.Conclusion The overex-pression of PTEN gene inhibits the migration and proliferation of HASMCs through down-regu-lating the expression of p-Akt and p-FAK.Therefore,PTEN may be involved in the regulation of airway remodeling in asthma.%目的:观察肿瘤抑制基因 PTEN 对人气道平滑肌细胞(HASMCs)迁移和增殖的影响机制。方法用重组PTEN 腺病毒转染体外培养的 HASMCs(Ad-PTEN 组),并与携带绿色荧光蛋白(GFP)的腺病毒空载体(Ad-GFP组)和空白对照(MOCK)组对比,采用 MTS 测定细胞增殖、Transwell 法观察细胞迁移、共聚焦显微镜观测细胞骨架的变化、免疫印迹法检测 PTEN、p-Akt、Akt、p-FAK、FAK 蛋白的表达。结果Ad-PTEN 组的吸光度(A)值和每单位面积迁移的细胞数显著低于 Ad-GFP 及 MOCK 组(均 P <0.05),Ad-GFP 和 MOCK 两对照组间

  2. Genetic and cell biological aspects of PTEN in prostate cancer

    NARCIS (Netherlands)

    P.W. van Duijn (Petra)

    2008-01-01

    textabstractThe dual specific phosphatase PTEN (Phosphatase and TENsin homolog deleted on chromosome 10) is one of the most extensively studied proteins of the last decade. It was the first phosphatase identified as a tumor suppressor and in sporadic cancers PTEN is one of the most frequently altere

  3. Pten function in zebrafish : Anything but a fish story

    NARCIS (Netherlands)

    Stumpf, Miriam; Choorapoikayil, Suma; den Hertog, J.

    2015-01-01

    Zebrafish is an excellent model system for the analysis of gene function. We and others use zebrafish to investigate the function of the tumor suppressor, Pten, in tumorigenesis and embryonic development. Zebrafish have two pten genes, ptena and ptenb. The recently identified N-terminal extension of

  4. Identification of nucleolus-localized PTEN and its function in regulating ribosome biogenesis.

    Science.gov (United States)

    Li, Pingdong; Wang, Danni; Li, Haiyang; Yu, Zhenkun; Chen, Xiaohong; Fang, Jugao

    2014-10-01

    The tumor suppressor PTEN is a lipid phosphatase that is found mutated in different types of human cancers. PTEN suppresses cell proliferation by inhibiting the PI3K-Akt signaling pathway at the cell membrane. However, PTEN is also demonstrated to localize in the cell nucleus where it exhibits tumor suppressive activity via a different, unknown mechanism. In this study we report that PTEN also localizes to the nucleolus and that nucleolar PTEN plays an important role in regulating nucleolar homeostasis and maintaining nucleolar morphology. Overexpression of nuclear PTEN in PTEN null cells inhibits Akt phosphorylation and reduces cell size. Knockdown of PTEN in PTEN positive cells leads to nucleolar morphologic changes and an increase in the proportion of cells with a greater number of nucleoli. In addition, knockdown of PTEN in PTEN positive cells increased ribosome biogenesis. These findings expand current understanding of function and relevance of nuclear localized PTEN and provide a foundation for the development of novel therapies targeting PTEN.

  5. A Case of Eccrine Angiomatous Hamartoma Associated with Verrucous Hemangioma

    Science.gov (United States)

    Cheong, Seung Hyun; Lim, Ji Yeon; Kim, So Young; Choi, You Won; Choi, Hae Young

    2009-01-01

    Eccrine angiomatous hamartomas are benign vascular and eccrine malformations often accompanied by hyperhidrosis or pain, increased eccrine glands, and aggregates of vessels. Verrucous hemangiomas are congenital vascular malformations presenting as unilateral grouped papules. Histologically, they show verrucous epidermal change and proliferation of capillaries in the dermis. We report a case of a 47-year-old woman with a red keratotic patch overlying a bluish plaque on the right sole, which had been present since birth. It was accompanied by pain and hyperhidrosis. Histologically, there were verrucous changes in the epidermis, numerous dilated capillaries in the papillary dermis, and increased eccrine glands with angiomatous foci in the deep dermis. The epithelial cells of the eccrine glands were positive for CEA, and the endothelial cells were positive for CD31 and GLUT-1. Eccrine angiomatous hamartomas have been reported in conjunction with other vascular tumors in only a few instances. We report an interesting case of an eccrine angiomatous hamartoma associated with a verrucous hemangioma. PMID:20523811

  6. WWP2 and its association with PTEN in endometrial cancer

    Directory of Open Access Journals (Sweden)

    Aine E. Clements

    2015-08-01

    We found that in tumors with low PTEN protein but normal mRNA expression there were significantly higher levels of WWP2 expression (p = 0.0017. Increased WWP2 expression was not associated with clinical prognostic factors including lymphovascular space invasion, ≥50% myometrial invasion, grade, stage or recurrence. WWP2 expression was not different statistically between tumors and normal controls (p = NS. Therefore, in this cohort, tumors with low PTEN protein but normal mRNA expression had elevated levels of WWP2 expression. This suggests that WWP2 may be playing a role in PTEN degradation in endometrial cancer.

  7. Suppression of gastric cancer growth by adenovirus-mediated transfer of the PTEN gene

    Institute of Scientific and Technical Information of China (English)

    Ying Hang; Yong-Chen Zheng; Yan Cao; Qing-Shan Li; Yu-Jie Sui

    2005-01-01

    AIM: To investigate the tumor-suppressive effect of the phosphatase and tensin homologue deleted from chromosome (PTEN) in human gastric cancer cells th atwere wild type for PTEN.METHODS: Adenoviruses expressing PTEN or luciferase as a control were introduced into gastric cancer cells.The effect of exogenous PTEN gene on the growth and apoptosis of gastric cancer cells that are wtPTEN were examined in vitro and in vivo.RESULTS: Adenovirus-mediated transfer of PTEN (AdPTEN) suppressed cell growth and induced apoptosis significantly in gastric cancer cells (MGC-803, SGC-7901)carrying wtPTEN in comparison with that in normal gastric epithelial cells (GES-1) carrying wtPTEN. This suppression was induced through downregulation of the Akt/PKB pathway, dephosphorylation of focal adhesion kinase and mitogen-activated protein kinase and cell-cycle arrest at the G2/M phase but not at the G1 phase. Furthermore,treatment of human gastric tumor xenografts (MGC-803,SGC-7901) with Ad-PTEN resulted in a significant (P<0.01)suppression of tumor growth.CONCLUSION: These results indicate a significant tumorsuppressive effect of Ad-PTEN against human gastric cancer cells. Thus, Ad-PTEN may be used as a potential therapeutic strategy for treatment of gastric cancers.

  8. Imaging findings of biliary hamartomas

    Institute of Scientific and Technical Information of China (English)

    Rong-Qin Zheng; Bo Zhang; Masatoshi Kudo; Hirokazu Onda; Tatsuo Inoue

    2005-01-01

    AIM: To evaluate the imaging findings of biliary hamartomas (von Meyenburg complexes, VMCs) and discuss the differential diagnosis with other related diseases.METHODS: Imaging findings of biliary hamartomas on ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), MR cholangiopancreatography (MRCP)and hepatobiliary scintigraphy were retrospectively analyzed in six patients.RESULTS: On ultrasound images, five of the six cases showed multiple small hyper- and hypo-echoic lesions with comet-tail echoes, especially when magnified by US with the usage of zoom function. In all the six cases,multiple tiny hypodense lesions less than 10 mm in diameter were revealed as scattered throughout the liver with no enhancement on CT. These tiny lesions were demonstrated to be hyper- and hypo-intensity on T2- and TI-weighed images, respectively, in three patients who underwent MRI examinations. MRCP was performed in two patients, and clearly showed multiple tiny irregular- and round-shaped hyper-intensity lesions.MRCP and hepatobiliary scintigraphy showed normal appearances of intra- and extra-hepatic bile ducts in two and one patients, respectively.CONCLUSION: Imaging modalities are useful in the diagnosis and differential diagnosis of VMCs. A correct diagnosis might be obtained when typical imaging findings are present even without a histological confirmation.

  9. PTEN stabilizes TOP2A and regulates the DNA decatenation.

    Science.gov (United States)

    Kang, Xi; Song, Chang; Du, Xiao; Zhang, Cong; Liu, Yu; Liang, Ling; He, Jinxue; Lamb, Kristy; Shen, Wen H; Yin, Yuxin

    2015-12-10

    PTEN is a powerful tumor suppressor that antagonizes the cytoplasmic PI3K-AKT pathway and suppresses cellular proliferation. PTEN also plays a role in the maintenance of genomic stability in the nucleus. Here we report that PTEN facilitates DNA decatenation and controls a decatenation checkpoint. Catenations of DNA formed during replication are decatenated by DNA topoisomerase II (TOP2), and this process is actively monitored by a decatenation checkpoint in G2 phase. We found that PTEN deficient cells form ultra-fine bridges (UFBs) during anaphase and these bridges are generated as a result of insufficient decatenation. We show that PTEN is physically associated with a decatenation enzyme TOP2A and that PTEN influences its stability through OTUD3 deubiquitinase. In the presence of PTEN, ubiquitination of TOP2A is inhibited by OTUD3. Deletion or deficiency of PTEN leads to down regulation of TOP2A, dysfunction of the decatenation checkpoint and incomplete DNA decatenation in G2 and M phases. We propose that PTEN controls DNA decatenation to maintain genomic stability and integrity.

  10. PTEN Interacts with Histone H1 and Controls Chromatin Condensation

    Directory of Open Access Journals (Sweden)

    Zhu Hong Chen

    2014-09-01

    Full Text Available Chromatin organization and dynamics are integral to global gene transcription. Histone modification influences chromatin status and gene expression. PTEN plays multiple roles in tumor suppression, development, and metabolism. Here, we report on the interplay of PTEN, histone H1, and chromatin. We show that loss of PTEN leads to dissociation of histone H1 from chromatin and decondensation of chromatin. PTEN deletion also results in elevation of histone H4 acetylation at lysine 16, an epigenetic marker for chromatin activation. We found that PTEN and histone H1 physically interact through their C-terminal domains. Disruption of the PTEN C terminus promotes the chromatin association of MOF acetyltransferase and induces H4K16 acetylation. Hyperacetylation of H4K16 impairs the association of PTEN with histone H1, which constitutes regulatory feedback that may reduce chromatin stability. Our results demonstrate that PTEN controls chromatin condensation, thus influencing gene expression. We propose that PTEN regulates global gene transcription profiling through histones and chromatin remodeling.

  11. A case of fibrolipomatous hamartoma of the median nerve with macrodactyly

    Directory of Open Access Journals (Sweden)

    Sathish Arakeri

    2012-07-01

    Full Text Available Fibrolipomatous hamartoma of nerve is a tumor-like lipomatous process principally involving affecting young persons. The median nerve is most commonly affectedinvolved. The lesion is characterized by a soft slowly growing mass, surrounding and infiltrating major nerves and their branches. It may cause symptoms of compression neuropathy and is associated with macrodactyly in one third of cases. Here, we present a case of Fibrolipomatous hamartoma of nerve in the wrist of a young man arising from median nerve. Debulking of the tumour was performed.

  12. Retrorectal Cystic Hamartoma: A Problematic 'Tail'

    African Journals Online (AJOL)

    hamartoma occurred in a 2‑year‑old child and very few cases have been ... only dermoid cysts contain dermal appendages (hair follicles, sweat glands, and tooth buds). Dermoid cysts ... Retrorectal developmental cysts in adults: Clinical and.

  13. Resection of endobronchial hamartoma causing recurrent hemoptysis by electrocautery and cryotherapy

    Science.gov (United States)

    Ucar, N; Akpinar, S; Aktas, Z; Sipit, T; Ozaydin, E

    2014-01-01

    Background: Pulmonary hamartomas are rare benign tumors of the lung with an incidence of 0.025%-0.32%. Endobronchial benign lesions can cause bronchial obstruction and recurrent respiratory infections or obstructive pneumonia and recurrent hemopthysis. Case report: A 66-year-old male with recurrent hemoptysis and pneumonias for a year, was referred to our department for an endoscopic resection of an endobronchial hamartoma. Initially he refused any intervention but, as he suffered additional episodes of hemoptysis and chest infections during a year on follow up, he finally underwent interventional bronchoscopy and the lesion was cauterized using snare electrocautery probe and removed with cryoextraction. The patient has been followed for two years in our outpatient clinic, with no further problems. Conclusion: Endoscopic treatment with flexible bronchoscope, electrocautery and cryotherapy provides an excellent outcome. Surgical therapy, should be reserved for the hamartomas that cannot be approached through endoscopy. Hippokratia 2014; 18 (4): 355-356. PMID:26052204

  14. Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma.

    Directory of Open Access Journals (Sweden)

    Robert C Castellino

    Full Text Available BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.

  15. Hamartoma fibroso infantil: lesão volumosa com envolvimento de plexo braquil Children's fibrous hamartoma: extensive injury involving brachial plexus

    Directory of Open Access Journals (Sweden)

    Lisieux Eyer de Jesus

    2006-01-01

    Full Text Available OBJETIVO: Apresentar um caso de hamartoma fibroso da infância em lactente ressecado tardiamente e se apresentando como lesão extensa, com envolvimento de elementos vasculares e neurais do plexo braquial. MÉTODOS: Estudo de caso clínico e revisão de literatura pertinente. RESULTADOS: Criança do sexo masculino, com massa tumoral axilar direita, irregular surgida aos 2 meses de idade e relacionada à administração da vacina BCG, sendo tratada com agentes anti-tuberculosos, sem resposta. Mediante biópsia a lesão foi diagnosticada como hamartoma fibroso infantil, e, após sofrer período de crescimento rápido, foi submetida à exérese cirúrgica completa. CONCLUSÃO: O hamartoma fibroso juvenil é um tumor benigno raro, tipicamente se apresentando no primeiro ano de vida em meninos, com localização mais comum no oco axilar. O diagnóstico diferencial se faz com tumores de partes moles em geral e, em casos de apresentação na axila direita, com adenopatias axilares causadas por reação à BCG. O tratamento é exerese completa da lesão e o prognóstico é favorável.OBJECTIVE: To present a case of fibrous hamartoma in a late-dried infant presenting as an extensive injury, involving vascular and neural elements of brachial plexus. METHODS: Clinical case study and pertinent literature review. RESULTS: Male child, with right axillary irregular tumoral mass, of which onset occurred at 2 months of age and related to BCG vaccine application, being treated with anti-tuberculosis agents, not responding to therapy. Upon biopsy, the injury was diagnosed as children’s fibrous hamartoma, and, after a fast growing period, was submitted to total surgical exeresis. CONCLUSION: The juvenile fibrous hamartoma is a rare benign tumor, typically occurring within the first year of life in boys, most commonly located at axillary gap. The differential diagnosis is performed with soft parts tumors in general, and, in right axillary location cases, with

  16. Neurological complications after gamma-knife radiosurgery for hypothalamic hamartoma.

    Science.gov (United States)

    Butragueño Laiseca, Laura; Oikonomopoulou, Niki; Miranda Herrero, María Concepción; Barredo Valderrama, Estíbaliz; Vázquez López, María; Jiménez de Domingo, Ana; Aguado Del Hoyo, Alejandra; García-Leal, Roberto; Meiriño, Rosa M

    2016-09-01

    The Gamma-knife technique is a safe and effective option for the treatment of hypothalamic hamartomas that produce epileptic seizures refractory to medical treatment and/or serious behavioral disorders. After this type of radiosurgery, an adequate symptomatic control is normally achieved, with notable decrease or even disappearance of the seizures. Radiological changes, such as a decrease in the size of the tumor or adjacent edema secondary to non-necrotizing radioinduced inflammatory reaction are unusual consequences. Side effects and neurological complications are also rare events. This report describes an unusual case of complete radiological resolution of a hypothalamic hamartoma as well as neurological complications after Gamma-knife surgery (receiving 13 Gy to the 85% isodose line, 1 cm(3) of tumor volume) in a 8-year-old boy who suffered from severe refractory seizures. After radiosurgery, the patient experienced a notable improvement in his symptoms, achieving seizure cessation within 3 months. However, 4 months after the procedure he presented drowsiness, fever and decreased level of consciousness due to a direct effect on the hypothalamus with local and regional edema secondary to the radiosurgery that was performed. He was successfully treated with corticosteroids (with a total duration of 11 months), and twelve months after the surgery, complete disappearance of both the nodular lesion and the secondary edema was observed. The patient remains seizure-free in the last 16 months, with remarkable changes in his behavior. The present case shows that complete radiological resolution of a hypothalamic hamartoma after Gamma-knife technique is unusual but possible, without long-term neurological consequences. Nevertheless, despite its low incidence, if a patient presents neurological symptoms, primarily during the first year after intervention, possible complications of this type of surgery must be taken into account. Copyright © 2016 European Paediatric

  17. Spontaneous rupture of splenic hamartoma in a patient with hepatitis C virus-related cirrhosis and portal hypertension: A case report and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Yasuji Seyama; Nobutaka Tanaka; Yoshio Suzuki; Motoki Nagai; Takatoshi Furuya; Yukihiro Nomura; Jimpei Ishii; Masakazu Nobori

    2006-01-01

    Spontaneous rupture is a rare complication of splenic hamartoma. A review of the literature revealed only four such cases. To the best of our knowledge, this is the first report of spontaneous rupture of splenic hamartoma associated with liver cirrhosis and portal hypertension.A 53-year-old woman, who was followed up for aortic dissection and hepatitis C virus (HCV)-related liver cirrhosis, was referred with sudden left chest and shoulder pain. An abdominal ultrasound showed intraabdominalbleeding, and computed tomography indicated rupture of a splenic tumor. Emergent splenectomy was carried out. The postoperative course was uneventful, and the patient was discharged on the 13th postoperative day.Pathology revealed the tumor to be a ruptured splenic hamartoma. The non-tumorous splenic parenchyma revealed congestive changes. We consider that the presence of liver cirrhosis and portal hypertension are risk factors for spontaneous rupture of the splenic hamartoma.

  18. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

  19. Phosphorylation of PTEN at STT motif is associated with DNA damage response.

    Science.gov (United States)

    Misra, Sandip; Mukherjee, Ananda; Karmakar, Parimal

    2014-12-01

    Phosphatase and tensin homolog deleted on chromosome Ten (PTEN), a tumor suppressor protein participates in multiple cellular activities including DNA repair. In this work we found a relationship between phosphorylation of carboxy (C)-terminal STT motif of PTEN and DNA damage response. Ectopic expression of C-terminal phospho-mutants of PTEN, in PTEN deficient human glioblastoma cells, U87MG, resulted in reduced viability and DNA repair after etoposide induced DNA damage compared to cells expressing wild type PTEN. Also, after etoposide treatment phosphorylation of PTEN increased at C-terminal serine 380 and threonine 382/383 residues in PTEN positive HEK293T cells and wild type PTEN transfected U87MG cells. One-step further, DNA damage induced phosphorylation of PTEN was confirmed by immunoprecipitation of total PTEN from cellular extract followed by immunobloting with phospho-specific PTEN antibodies. Additionally, phospho-PTEN translocated to nucleus after etoposide treatment as revealed by indirect immunolabeling. Further, phosphorylation dependent nuclear foci formation of PTEN was observed after ionizing radiation or etoposide treatment which colocalized with γH2AX. Additionally, etoposide induced γH2AX, Mre11 and Ku70 foci persisted for a longer period of times in U87MG cells after ectopic expression of PTEN C-terminal phospho-mutant constructs compared to wild type PTEN expressing cells. Thus, our findings strongly suggest that DNA damage induced phosphorylation of C-terminal STT motif of PTEN is necessary for DNA repair. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Fat-Containing Giant Hamartoma of the Stomach

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ye Lim; Choi, Jae Woong; Lee, Jong Mee; Lee, Chang Hee; Kim, Kyeong Ah; Park, Cheol Min [Guro Hospital, University of Korea, Seoul (Korea, Republic of); Park, Sung Soo [Anam Hospital, University of Korea, Seoul (Korea, Republic of); Lee, Ju Han [Ansan Hospital, Korea University, Ansan (Korea, Republic of)

    2010-10-15

    Gastric hamartoma is considered to be a rare disease entity, usually associated with polyposis syndrome. We report a case of unique and distinguishable fat containing unusually large gastric hamartoma and gastrointestinal bleeding. The patient had no history of polyposis syndrome.

  1. Hepatic Mesenchymal Hamartoma Combined with Infantile Hepatic Hemangioendothelioma in an Infant

    Directory of Open Access Journals (Sweden)

    Kuang-Hung Hsiao

    2007-01-01

    Full Text Available Hepatic mesenchymal hamartoma is a rare benign tumor in children, and infantile hepatic hemangioendothelioma is also a rare liver neoplasm. We report a female newborn with an abdominal mass noted by the regular maternal ultrasound at 32 weeks of gestation. After birth, a liver mass was detected by computed tomography and magnetic resonance cholangiopancreatography. Frequent postprandial vomiting and progressive abdominal distension occurred 4 months later. Three tumor masses were detected this time, and the serum alpha-fetoprotein (AFP was 6700 ng/mL. Segmental resection was performed initially and complete resection of these tumors and left lobectomy were performed 21 days later. Pathologic examination of these liver masses revealed mesenchymal hamartoma combined with infantile hepatic hemangioendothelioma. After half a year of regular follow-up, the AFP level decreased gradually to 79.5 ng/mL, without evidence of tumor recurrence. [J Formos Med Assoc 2007;106(3 Suppl:S1-S4

  2. Giant solid-cystic hypothalamic hamartoma. Case report.

    Science.gov (United States)

    Dorfer, Christian; Kasprian, Gregor; Mühlebner, Angelika; Czech, Thomas

    2011-02-01

    Hypothalamic hamartomas are rare lesions for which different classification schemes have been proposed. The authors report on an exceptionally large solid-cystic hamartoma that led to hydrocephalus, precocious puberty, and intractable gelastic seizures. They discuss potential mechanisms of the development of hypothalamic hamartomas.

  3. Subtle variations in Pten dose determine cancer susceptibility

    Science.gov (United States)

    Alimonti, Andrea; Carracedo, Arkaitz; Clohessy, John G; Trotman, Lloyd C; Nardella, Caterina; Egia, Ainara; Salmena, Leonardo; Sampieri, Katia; Haveman, William J; Brogi, Edi; Richardson, Andrea L; Zhang, Jiangwen; Pandolfi, Pier Paolo

    2010-01-01

    Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG)1. It has been hypothesized that subtle variations in TSG expression can promote cancer development2,3. However, this hypothesis has not yet been definitively supported in vivo. PTEN is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes4. Here, we analyze Pten hypermorphic mice (Ptenhy/+), expressing 80% normal levels of Pten. Ptenhy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosis. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner. PMID:20400965

  4. Soy peptide lunasin induces pten-mediated apoptosis in human breast cancer cells

    Science.gov (United States)

    The tumor suppressor PTEN inhibits the AKT signaling pathway whose unrestrained activity underlies many human malignancies. Previously we showed that dietary intake of soy protein isolate (SPI) enhanced PTEN expression in mammary tissue of rats with lower NMU-induced mammary tumor incidence relative...

  5. Paravertebral vascular hamartoma - radiological findings; Hamartoma vascular paravertebral - relato de um caso

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Maria Cristina Soares dos; Dinoa, Vanessa de Albuquerque; Borges, Aurea Valeria Rosa Mohana; Teixeira, Sonia [Hospital Universitario Antonio Pedro (HUAP), Niteroi, RJ (Brazil). Secao de Radiologia; Marchiori, Edson [Universidade Federal Fluminense, Niteroi, RJ (Brazil). Dept. de Radiologia; Monteiro, Elio [Universidade Federal Fluminense, Niteroi, RJ (Brazil). Dept. de Cirurgia

    1997-01-01

    Hamartomas are benign tumours that can occur in different organs and tissues. They consist of an abnormal increase of cells and tissues common to the organ from which they arise. When they occur in lymphatic and blood vessels they are called vascular hamartomas. These tumours are frequent in the central nervous system, giving rise to hemorrhages. The authors report a case of vascular hamartoma in the right paravertebral gutter with an intradural component that caused a spinal cord compression and paraplegia. A malignant lesion was suggested based on the clinical and radiological findings. (author) 14 refs., 4 figs.

  6. PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan, E-mail: quan_haotj@126.com

    2014-02-07

    Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer.

  7. PTEN-PDZ domain interactions: Binding of PTEN to PDZ domains of PTPN13.

    NARCIS (Netherlands)

    Sotelo, N.S.; Schepens, J.T.G.; Valiente, M.; Hendriks, W.J.A.J.; Pulido, R.

    2015-01-01

    Protein modular interactions mediated by PDZ domains are essential for the establishment of functional protein networks controlling diverse cellular functions. The tumor suppressor PTEN possesses a C-terminal PDZ-binding motif (PDZ-BM) that is recognized by a specific set of PDZ domains from scaffol

  8. Nuclear trafficking of Pten after brain injury leads to neuron survival not death.

    Science.gov (United States)

    Goh, Choo-Peng; Putz, Ulrich; Howitt, Jason; Low, Ley-Hian; Gunnersen, Jenny; Bye, Nicole; Morganti-Kossmann, Cristina; Tan, Seong-Seng

    2014-02-01

    There is controversy whether accumulation of the tumor suppressor PTEN protein in the cell nucleus under stress conditions such as trauma and stroke causes cell death. A number of in vitro studies have reported enhanced apoptosis in neurons possessing nuclear PTEN, with the interpretation that its nuclear phosphatase activity leads to reduction of the survival protein phospho-Akt. However, there have been no in vivo studies to show that nuclear PTEN in neurons under stress is detrimental. Using a mouse model of injury, we demonstrate here that brain trauma altered the nucleo-cytoplasmic distribution of Pten, resulting in increased nuclear Pten but only in surviving neurons near the lesion. This event was driven by Ndfip1, an adaptor and activator of protein ubiquitination by Nedd4 E3 ligases. Neurons next to the lesion with nuclear PTEN were invariably negative for TUNEL, a marker for cell death. These neurons also showed increased Ndfip1 which we previously showed to be associated with neuron survival. Biochemical assays revealed that overall levels of Pten in the affected cortex were unchanged after trauma, suggesting that Pten abundance globally had not increased but rather Pten subcellular location in affected neurons had changed. Following experimental injury, the number of neurons with nuclear Pten was reduced in heterozygous mice (Ndfip1(+/-)) although lesion volumes were increased. We conclude that nuclear trafficking of Pten following injury leads to neuron survival not death.

  9. Hamartoma: Diagnostic Procedure of Unspecific Clinical Appearance in the Oral Cavity

    Directory of Open Access Journals (Sweden)

    Ahmad Ronal

    2012-12-01

    Full Text Available Hamartoma is a benign tumor-like lesion composed of overgrowth of mature cells and tissues. Along with its unspecific appearance, it may occur in the oral cavity and bear resemblance to the other lesions. In this report we describes the clini-cal appearance of hamartoma as well as the diagnosis method in the case of a 37-year-old-man. The patient explained that he already has redness plaque lesion on his skin left cheek region since he was born. The lesion was sensed to grow and discomfort at the age of 22. A surgical therapy had been performed to reduce the size of lesion one year after, but the red-ness plaque still existed. Thirteen years following the operation, white lesion appeared on the inner left cheek 10 x 8.5 x 6 cm of size and extended onto lower lips within half a year. Diagnostic procedure was carried out such as biopsy, CT-scan and radiography with neuroma as an initial conclusion. New histopathological examination confirmed the diagnosis of hamartoma. It is concluded that adequate and appropriate biopsy procedure along with sufficient clinical information are needed to develop a proper diagnosis to distinguish hamartoma from other oral lesions.DOI: 10.14693/jdi.v17i3.38

  10. What controls PTEN and what it controls (in prostate cancer)

    Institute of Scientific and Technical Information of China (English)

    Paramita M Ghosh

    2012-01-01

    The standard of care for metastatic prostate cancer (PCa) is androgen deprivation therapy since almost all PCa growth is initially reliant on the androgen receptor (AR).However,almost all patients develop resistance to this therapy within 18-24months,and current treatment for castration-resistant prostate cancer (CRPC) is extremely limited,despite the advent of new drugs that target the AR,such as ahiraterone and MDV3100.1 Multiple studies have associated the loss of phosphatase and tensin homolog deleted on chromosome 10(PTEN),a dual lipid and protein phosphatase that is frequently lost in prostate cancer,with the development of CRPC.2,3 Yet,multiple studies have shown that at least 20%-40%of primary PCa,which are almost always androgen sensitive,experience a loss of PTEN,4,5 while as many as 30% of CRPC tumors are PTEN-positive.6 The broad questions then facing researchers are:(i) How does PTEN loss cause CRPC?;(ii) What is the mechanism of CRPC development in PTEN+/+ tumors?;and (iii) How can CRPC tumors be inhibited in PTEN-null cells?Three new publications in recent times have come up with mechanisms that answer these questions.7-9 Two of these,both in Cancer Cell eadier this year,from the laboratories of Dr Charles Sawyers and Dr Hong Wu,address a novel negative feedback regulation between AR and PTEN,and all three,including the one from Dr Damu Tang,show that the loss of PTEN function is likely the first step towards the development of CRPC.

  11. Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN

    OpenAIRE

    Makoto Nakakido; Zhenzhong Deng; Takehiro Suzuki; Naoshi Dohmae; Yusuke Nakamura; Ryuji Hamamoto

    2015-01-01

    Phosphatase and tensin homologue (PTEN), one of the well-characterized tumor suppressor proteins, counteracts the phosphatidylinositol 3-kinase-AKT pathway through its unique lipid phosphatase activity. The functions of PTEN are regulated by a variety of posttranslational modifications such as acetylation, oxidation, ubiquitylation, phosphorylation, and SUMOylation. However, methylation of PTEN has not been reported so far. In this study, we demonstrated that the oncogenic protein lysine meth...

  12. Evolution of Gelastic Epilepsy with Hypothalamic Hamartoma

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2003-11-01

    Full Text Available The patterns of clinical presentation, evolution of the epilepsy, and electoclinical diagnostic features of hypothalamic hamartoma (HH in 19 patients (8 children and 11 adults, seen between 1991 and 2001, were evaluated at Kings College Hospital and the Institute of Epileptology, London, UK.

  13. MRI of hypothalamic hamartomas in children

    Energy Technology Data Exchange (ETDEWEB)

    Barral, V.; Brunelle, F.; Brauner, R.; Rappaport, R.; Lallemand, D.

    1988-09-01

    The purpose of this paper is to study the MRI characteristics of hypothalamic hamartomas of which only one case has been reported to our knowledge. Radiological studies were normal X-ray studies of the skull and sella turcica and CT studies.

  14. Expression and significance of tumor suppressor gene PTEN in colorectal cancer%抑癌基因PTEN在人大肠癌中的表达及其意义

    Institute of Scientific and Technical Information of China (English)

    郑国宝; 王元和; 高春芳; 王红阳; 万兴望

    2003-01-01

    目的阐明抑癌基因PTEN在大肠癌的发生发展及转移过程中的作用.方法应用Nothern blot和免疫组化的方法检测47例人大肠癌及癌旁组织中PTEN mRNA和蛋白的表达,分析其与大肠癌的临床病理学分期、分级及其与大肠癌肝转移的关系.结果 PTEN mRNA在大肠癌组织内的表达水平显著低于相应的癌旁组织,在癌组织内,PTEN mRNA表达水平与大肠癌的恶性程度分级、Dukes分期及血清中癌胚抗原(CEA)水平呈显著负相关,PTEN蛋白在大肠癌旁组织中表达阳性率为100%,在大肠癌组织中表达阳性率为76.6%,PTEN在大肠癌组织中表达的降低与大肠癌的Dukes分期、淋巴结转移及血清中CEA水平呈显著负相关.结论抑癌基因PTEN表达的降低在大肠癌的发生和转移过程中起重要作用.

  15. Fibrolipomatous hamartoma: pathognomonic on MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Marom, E.M.; Helms, C.A. [Duke University Medical Center, Department of Radiology, Durham, NC 27710 (United States)

    1999-05-01

    Purpose. To assess the MR imaging characteristics, presenting symptoms, age and nerve distribution of fibrolipomatous hamartoma. Design. A computer search was performed of the term fibrolipomatous hamartoma through the musculoskeletal section MR imaging results at our institution from June 7, 1996 to January 21, 1998 followed by a search of the terms lipomatous hamartoma, median nerve, surrounding fat, increased fatty signal, coaxial, and neuroma. MR images and medical files were retrospectively reviewed by two experienced musculoskeletal radiologists for imaging characteristics, nerve and age distribution as well as for history of trauma. In addition three consultation cases from outside institutions were added for determination of image characteristics. Results. Ten fibrolipomatous hamartomas were identified: eight in the median nerve, one in the ulnar nerve and one in the sciatic nerve. Mean age was 32.3 years (range 4-75 years, SD 21 years). Imaging characteristics were serpiginous low-intensity structures representing thickened nerve fascicles, surrounded by evenly distributed fat, high signal intensity on T1-weighted sequences and low signal intensity on T2-weighted sequences. The amount of fat varied; however, distribution in eight cases (80%) was predominantly between nerve fibers rather than surrounding them peripherally. All had a coaxial-cable-like appearance on axial planes and a spaghetti-like appearance on coronal planes that was not seen in any other type of median nerve abnormality imaged during the study period. Conclusion. The MR imaging characteristics of fibrolipomatous hamartoma are pathognomonic, obviating the need for biopsy for diagnosis. (orig.) With 3 figs., 1 tab., 18 refs.

  16. Characterization of a novel PTEN mutation in MDA-MB-453 breast carcinoma cell line

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    Singh Gobind

    2011-11-01

    cisplatinum when re-expressed in Pten-/- MEFS. Conclusions Mutation at codon 307 in PTEN C2 loop alters its subcellular distribution with greater membrane localization while being excluded from the cell nucleus. This mutation may predispose breast epithelial cells to malignant transformation. Also, tumor cells harboring this mutation may be less susceptible to the cytotoxic effects of chemotherapeutics.

  17. CLINICOPATHOLOGICAL SIGNIFICANCE OF PTEN AND CASPASE-3 EXPRESSIONS IN BREAST CANCER

    Institute of Scientific and Technical Information of China (English)

    Xue-fei Yang; Yan Xin; Li-li Mao

    2008-01-01

    Objective To investigate the expressions of PTEN and Caspase-3 proteins in human breast carcinoma, and to evaluate their clinicopathological implications during the tumorigenesis and progression of breast cancer.Methods The expressions of PTEN and Caspase-3 proteins in 95 cases of breast cancer and 15 cases of benignbreast diseases were investigated immunohistochemically. Correlations between the expression of PTEN protein,Caspase-3 protein, and clinicopathological features of breast cancers were analyzed.Results The loss expression rate of PTEN protein in tumor tissues was significantly higher than that in benignbreast diseases (33.7% vs. 0, P 0. 05). In addition,the expression of PTEN protein had significantly positive correlation with the expression of Caspase-3 protein in breast cancer (P <0.01 ).Conclusion The combination detection of PTEN and Caspase-3 may serve as an important index to estimate the pathobiological behavior and pognosis of breast cancer.

  18. Cystic Brunner's gland hamartoma in the duodenum: A case report

    Institute of Scientific and Technical Information of China (English)

    Beom Jin Park; Min Ju Kim; Jeong Hyeon Lee; Sung-Soo Park; Deuk Jae Sung; Sung Bum Cho

    2009-01-01

    Cystic Brunner's gland hamartoma in the duodenum is exceedingly rare, although microscopic examination may sometimes reveal a Brunner's gland hamartoma containing dilated ducts in the duodenum. We present a case of large cystic Brunner's gland hamartoma in the duodenum with a long stalk, which is described in light of multidetector-row computed tomography, magnetic resonance imaging, and a modified small bowel series, together with pathologic correlation and differential diagnosis.

  19. Congenital fibrous hamartoma of the knee

    Energy Technology Data Exchange (ETDEWEB)

    Arioni, Cesare; Bellini, Carlo; Risso, Francesco Maria; Scopesi, Fabio; Serra, Giovanni [University of Genoa, Neonatal Pathology Service, Department of Paediatrics, Institute G. Gaslini, Genoa (Italy); Oddone, Mauro; Toma, Paolo [Institute G. Gaslini, Radiology Service, Genoa (Italy); Nozza, Paolo [Institute G. Gaslini, U. O. di Anatomia Patologica, Genoa (Italy)

    2006-05-15

    A full-term male infant presented at birth with a hard swelling of the left knee. The lemon-sized lesion was fixed to the underlying knee muscles, while the overlying skin was stretched and shiny; there was no bruit. Radiography, sonography and MRI suggested a soft-tissue tumour. After surgical excision, histology showed the presence of fibrous and mesenchymal tissue, with mature adipose tissue. Fibrous hamartoma of infancy was diagnosed. Among soft-tissue tumours, fibrous hamartoma of infancy is a rare and benign lesion, occurring in the first 2 years of life. The tumour mainly affects the trunk, axilla, and upper extremities. This infant had unique involvement of the knee. The treatment of choice is local excision. (orig.)

  20. [Cowden's disease or the multiple hamartoma syndrome].

    Science.gov (United States)

    Crickx, B; Sigal, M; Pastel, A; Vissuzaine, C; Grossin, M; Maurer, F; Morinière, B; Belaich, S

    1984-06-01

    Cowden's disease, also called multiple hamartoma syndrome, is a clinical entity characterized by hamartomatous tumours of endodermal, mesodermal and ectodermal origin. Although extremely rare, the disease must be known to all internists. A case of Cowden's disease in a 36-year old male patient is reported. The authors insist on the high incidence of digestive disorders and the risk of malignant degeneration of mammary and thyroid tumours. They also describe the cutaneous and mucosal lesions characteristic of the disease.

  1. The drug-resistance to gefitinib in PTEN low expression cancer cells is reversed by irradiation in vitro

    Directory of Open Access Journals (Sweden)

    Zhao Lu-Jun

    2009-09-01

    Full Text Available Abstract Background Despite of the recent success of EGFR inhibitory agents, the primary drug-resistant becomes a major challenge for EGFR inhibitor therapies. PTEN gene is an important positive regulatory factor for response to EGFR inhibitor therapy. Low-expression of PTEN is clearly one of the important reasons why tumor cells resisted to tyrosine kinase inhibitors. Methods To investigate the drug-resistance reversal to gefitinb and the mechanism in PTEN low expression cells which radiated with X-rays in vitro, We demonstrated that H-157 lung cancer cells (low-expression of PTEN but phospho-EGFR overexpressed tumor cells exposed to X-rays. The PTEN expressions and radiosensitizing effects of tyrosine kinase inhibitor before and after irradiation were observed. The cell-survival rates were evaluated by colony-forming assays. The cell apoptosis was investigated using FCM. The expressions of phospho-EGFR and PTEN were determined by Western blot analysis. Results The results showed that the PTEN expressions were significantly enhanced by X-rays. Moreover, the cell growth curve and survival curve were down-regulated in the gefitinib-treated groups after irradiation. Meanwhile, the radiation-induced apoptosis of tumor cells was increased by inhibition of the EGFR through up-regulation of PTEN. Conclusion These results suggested that PTEN gene is an important regulator on TKI inhibition, and the resistance to tyrosine kinase inhibitors might be reversed by irradiation in PTEN low expression cancer cells.

  2. Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance

    Directory of Open Access Journals (Sweden)

    Baksh Shairaz

    2007-02-01

    Full Text Available Abstract Background The PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten tumor suppressor gene is frequently mutated or deleted in a wide variety of solid tumors, and these cancers are generally more aggressive and difficult to treat than those possessing wild type PTEN. While PTEN lies upstream of the phosphoinositide-3 kinase signaling pathway, the mechanisms that mediate its effects on tumor survival remain incompletely understood. Renal cell carcinoma (RCC is associated with frequent treatment failures (~90% in metastatic cases, and these tumors frequently contain PTEN abnormalities. Results Using the ACHN cell line containing wild type PTEN, we generated a stable PTEN knockdown RCC cell line using RNA interference. We then used this PTEN knockdown cell line to show that PTEN attenuation increases resistance to cisplatin-induced apoptosis, a finding associated with increased levels of the cyclin kinase inhibitor p21. Elevated levels of p21 result from stabilization of the protein, and they are dependent on the activities of phosphoinositide-3 kinase and Akt. More specifically, the accumulation of p21 occurs preferentially in the cytosolic compartment, which likely contributes to both cell cycle progression and resistance to apoptosis. Conclusion Since p21 regulates a decision point between repair and apoptosis after DNA damage, our data suggest that p21 plays a key role in mechanisms used by PTEN-deficient tumors to escape chemotherapy. This in turn raises the possibility to use p21 attenuators as chemotherapy sensitizers, an area under active continuing investigation in our laboratories.

  3. Function of PTEN during the formation and maintenance of neuronal circuits in the brain.

    Science.gov (United States)

    van Diepen, Michiel T; Eickholt, Britta J

    2008-01-01

    PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor that can inhibit proliferation and migration and controls apoptosis in a number of cell types, mainly through inhibition of the phosphoinositide 3-kinase (PI3K) signaling pathway. Patients carrying inactivating mutations of PTEN show a prevalence to develop tumors that can coincide with neurological defects such as mental retardation, ataxia and seizures. A number of in vitro and in vivo studies were instrumental in uncovering a direct correlation between deregulated PI3K/PTEN signaling and changes in neuronal morphogenesis, which is likely to have profound bearings upon the pathogenesis of neurological symptoms. This review outlines recent work on the function of PTEN during vertebrate brain development and the current understanding of the signaling pathways downstream of PTEN that control neuronal connectivity in the brain.

  4. Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control?

    Science.gov (United States)

    Gutilla, Erin A; Steward, Oswald

    2016-08-01

    The limited ability for injured adult axons to regenerate is a major cause for limited functional recovery after injury to the nervous system, motivating numerous efforts to uncover mechanisms capable of enhancing regeneration potential. One promising strategy involves deletion or knockdown of the phosphatase and tensin (PTEN) gene. Conditional genetic deletion of PTEN before, immediately following, or several months after spinal cord injury enables neurons of the corticospinal tract (CST) to regenerate their axons across the lesion, which is accompanied by enhanced recovery of skilled voluntary motor functions mediated by the CST. Although conditional genetic deletion or knockdown of PTEN in neurons enables axon regeneration, PTEN is a well-known tumor suppressor and mutations of the PTEN gene disrupt brain development leading to neurological abnormalities including macrocephaly, seizures, and early mortality. The long-term consequences of manipulating PTEN in the adult nervous system, as would be done for therapeutic intervention after injury, are only now being explored. Here, we summarize evidence indicating that long-term deletion of PTEN in mature neurons does not cause evident pathology; indeed, cortical neurons that have lived without PTEN for over 1 year appear robust and healthy. Studies to date provide only a first look at potential negative consequences of PTEN deletion or knockdown, but the absence of any detectable neuropathology supports guarded optimism that interventions to enable axon regeneration after injury are achievable.

  5. Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control?

    Directory of Open Access Journals (Sweden)

    Erin A Gutilla

    2016-01-01

    Full Text Available The limited ability for injured adult axons to regenerate is a major cause for limited functional recovery after injury to the nervous system, motivating numerous efforts to uncover mechanisms capable of enhancing regeneration potential. One promising strategy involves deletion or knockdown of the phosphatase and tensin (PTEN gene. Conditional genetic deletion of PTEN before, immediately following, or several months after spinal cord injury enables neurons of the corticospinal tract (CST to regenerate their axons across the lesion, which is accompanied by enhanced recovery of skilled voluntary motor functions mediated by the CST. Although conditional genetic deletion or knockdown ofPTEN in neurons enables axon regeneration, PTEN is a well-known tumor suppressor and mutations of the PTEN gene disrupt brain development leading to neurological abnormalities including macrocephaly, seizures, and early mortality. The long-term consequences of manipulating PTEN in the adult nervous system, as would be done for therapeutic intervention after injury, are only now being explored. Here, we summarize evidence indicating that long-term deletion of PTEN in mature neurons does not cause evident pathology; indeed, cortical neurons that have lived without PTEN for over 1 year appear robust and healthy. Studies to date provide only a first look at potential negative consequences of PTEN deletion or knockdown, but the absence of any detectable neuropathology supports guarded optimism that interventions to enable axon regeneration after injury are achievable.

  6. Molecular cloning and characterization of PTEN in the orange-spotted grouper (Epinephelus coioides).

    Science.gov (United States)

    Luo, Sheng-Wei; Wang, Wei-Na; Xie, Ren-Chong; Xie, Fu-Xing; Kong, Jing-Rong; Xiao, Yu-Chao; Huang, Di; Sun, Zuo-Ming; Liu, Yuan; Wang, Cong

    2016-11-01

    PTEN is a key tumor suppressor gene that can play a regulatory role in the cellular proliferation, survival and apoptosis. In this study, the full-length PTEN (EcPTEN) was obtained, containing a 5'UTR of 745 bp, an ORF of 1269 bp and a 3'UTR of 106 bp. The EcPTEN gene encoded a polypeptide of 422 amino acids with an estimated molecular mass of 49.14 KDa and a predicted isoelectric point (pI) of 6.34. The deduced amino acid sequence analysis showed that EcPTEN comprised the conserved residues and the characteristic domains known to the critical functionality of PTEN. qRT-PCR analysis revealed that EcPTEN mRNA was broadly expressed in all the examined tissues, while the highest expression level was observed in liver, followed by the expression in blood, kidney, spleen, heart, gill, muscle and intestine. The groupers challenged with Vibrio alginolyticus showed a sharp increase of EcPTEN mRNA expression in immune tissues. In addition, western blotting analysis confirmed that the up-regulation of EcPTEN protein expression was steadily induced in liver. Subcellular localization analysis indicated that EcPTEN was localized in both nucleus and cytoplasm. Overexpression of EcPTEN can activate the apoptotic cascade and abrogate NF-kB, AP-1, Stat3 and Myc promoter activity in Hela cells. These results indicated that EcPTEN harboring highly-conserved domains with a close sequence similarity to those of PTP superfamily may disrupt the mammalian signalings and play a regulatory role in the apoptotic process.

  7. PTEN encoding product: a marker for tumorigenesis and progression of gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Lin Yang; Li-Ge Kuang; Hua-Chuan Zheng; Jin-Yi Li; Dong-Ying Wu; Su-Min Zhang; Yan Xin

    2003-01-01

    AIM: To detect the expression of PTEN encoding productin normal mucosa, intestinal metaplasia (IM), dysplasia andcarcinoma of the stomach, and to investigate its clinicalimplication in tumorigenesis and progression of gastriccarcinoma.METHODS: Formalin-fixed paraffin embedded specimens from184 cases of gastric carcinoma, their adjacent normal mucosa,IM and dysplasia were evaluated for PTEN protein expressionby SABC immunohistochemistry. PTEN expression wascompared with tumor stage, lymph node metastasis, Lauren'sand WHO's histological classification of gastric carcinoma.Expression of VEGF was also detected in 60 cases of gastriccarcinoma and its correlation with PTEN was concerned.RESULTS: The positive rates of PTEN protein were 100 %(102/102), 98.5 %(65/66), 66.7 % (4/6) and 47.8 %(88/184)in normal mucosa, IM, dysplasia and carcinoma of the stomach,respectively. The positive rates in dysplasia and carcinomawere lower than in normal mucosa and IM (P<0.01).Advanced gastric cancers expressed less frequent PTEN thanearly gastric cancer (42.9 % v567.6 %, P<0.01). The positiverate of PTEN protein was lower in gastric cancer with thanwithout lymph node metastasis (40.3 % v563.3 %, P<0.01).PTEN was less expressed in diffuse-type than in intestinal-type gastric cancer (41.5 % v557.8 %,P<0.05). Signet ringcell carcinoma showed the expression of PTEN at the lowestlevel (25.0 %, 7/28); less than well and moderatelydifferentiated ones (P<0.01). Expression of PTEN was notcorrelated with expression of VEGF (P>0.05).CONCLUSION: Loss or reduced expression of PTEN proteinoccures commonly in tumorigenesis and progression of gastriccarcinoma. It is suggested that PTEN can be an objective markerfor pathologically biological behaviors of gastric carcinoma.

  8. Atypical Presentation of Fibrolipomatous Hamartoma of Superficial Peroneal Nerve.

    Science.gov (United States)

    Dhinsa, Baljinder Singh; Lidder, Surjit; Abbasian, Ali

    2016-01-01

    Fibrolipomatous hamartoma is a rare presentation in the foot. An accurate diagnosis is key, with magnetic resonance imaging findings considered definitive. The management is dependent on the symptoms. We present an atypical presentation of fibrolipomatous hamartoma of the superficial peroneal nerve and discuss the current published data.

  9. Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens

    Energy Technology Data Exchange (ETDEWEB)

    Puxeddu, Efisio [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Zhao Guisheng [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Stringer, James R. [Department of Molecular Genetics, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Medvedovic, Mario [Center for Biostatistic Service, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Moretti, Sonia [Dipartimento di Medicina Interna, Universita degli Studi di Perugia, Via E. dal Pozzo, Perugia 06126, (Italy); Fagin, James A. [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States)]. E-mail: james.fagin@uc.edu

    2005-02-15

    The two main forms of RET rearrangement in papillary thyroid carcinomas (PTC) arise from intrachromosomal inversions fusing the tyrosine kinase domain of RET with either the H4 (RET/PTC1) or the ELE1/RFG genes (RET/PTC3). PTEN codes for a dual-specificity phosphatase and maps to chromosome 10q22-23. Germline mutations confer susceptibility to Cowden syndrome whereas somatic mutations or deletions are common in several sporadic human tumors. Decreased PTEN expression has been implicated in thyroid cancer development. We report the characterization of a new chromosome 10 rearrangement involving H4 and PTEN. The initial H4/PTEN rearrangement was discovered as a non-specific product of RT-PCR for RET/PTC1 in irradiated thyroid cell lines. Sequencing revealed a transcript consisting of exon 1 and 2 of H4 fused with exons 3-6 of PTEN. Nested RT-PCR with specific primers bracketing the breakpoints confirmed the H4/PTEN rearrangements in irradiated KAT-1 and KAT-50 cells. Additional H4/PTEN variants, generated by recombination of either exon 1 or exon 2 of H4 with exon 6 of PTEN, were found in non-irradiated KAK-1, KAT-50, ARO and NPA cells. Their origin through chromosomal recombination was confirmed by detection of the reciprocal PTEN/H4 product. H4/PTEN recombination was not a clonal event in any of the cell lines, as Southern blots with appropriate probes failed to demonstrate aberrant bands, and multicolor FISH of KAK1 cells with BAC probes for H4 and PTEN did not show a signal overlap in all cells. Based on PCR of serially diluted samples, the minimal frequency of spontaneous recombination between these loci was estimated to be approximately 1/10{sup 6} cells. H4/PTEN products were found by nested RT-PCR in 4/14 normal thyroid tissues (28%) and 14/18 PTC (78%) (P < 0.01). H4/PTEN is another example of recombination involving the H4 locus, and points to the high susceptibility of thyroid cells to intrachromosomal gene rearrangements. As this also represents a

  10. Interaction of IGF2 and PTEN in ( M alignant Breast T issues

    Directory of Open Access Journals (Sweden)

    Preetha J Shetty

    2012-07-01

    Full Text Available Background: Breast Cancer (BC is one of the leading malignancies affecting women worldwide. Epigenetic mechanisms regulate gene expression playing an important role in the pathophysiology of cancer. In the present study IGF2 and PTEN genes in AKT pathway were selected for evaluation. Objective: To investigate the role of methylation and interaction of IGF2 and PTEN and in the pathoetiology of BC. Methods: Paraffin embedded archival breast tumor and adjacent normal tissue samples were used for carrying out PCR based methylation assay, genomic PCR, immunohistochemistry and qRT PCR. Results: In-Silico study indicated the absence of hormone responsive elements in the promoters of the selected genes. Methylation results indicated significant loss of methylation in IGF2 exon 9 CpG cluster and significant gain of PTEN promoter methylation in tumors. Immunohistochemistry revealed enhanced cytoplasmic expression o f IGF2 protein (p< 0.0001 and decreased nuclear localization of PTEN protein (p=0.0069 in the breast tumors. RT-PCR results indicated an increased IGF2 (p=0.024 and decreased PTEN transcripts (p<0.0001 in the tumors. Conclusion: Increased IGF2 in normal tissues increases PTEN which acts as a negative regulator of AKT pathway in the cytoplasm controlling excessive proliferation while in tumors this regulation is lost. PTEN acts as a negative regulator of MAPK pathway in the nucleus, plays an important role in cell cycle arrest in normal breast tissue. Reduction of PTEN in tumor tissue affects this pathway leading to cell survival. IGF2 and PTEN have a role in breast cancer and these molecular factors can be used for targeting therapy in future.

  11. Opening the conformation is a master switch for the dual localization and phosphatase activity of PTEN

    Science.gov (United States)

    Nguyen, Hoai-Nghia; Yang, Jr-Ming; Miyamoto, Takafumi; Itoh, Kie; Rho, Elmer; Zhang, Qiang; Inoue, Takanari; Devreotes, Peter N.; Sesaki, Hiromi; Iijima, Miho

    2015-01-01

    Tumor suppressor PTEN mainly functions at two subcellular locations, the plasma membrane and the nucleus. At the plasma membrane, PTEN dephosphorylates the tumorigenic second messenger PIP3, which drives cell proliferation and migration. In the nucleus, PTEN controls DNA repair and genome stability independently of PIP3. Whereas the concept that a conformational change regulates protein function through post-translational modifications has been well established in biology, it is unknown whether a conformational change simultaneously controls dual subcellular localizations of proteins. Here, we discovered that opening the conformation of PTEN is the crucial upstream event that determines its key dual localizations of this crucial tumor suppressor. We identify a critical conformational switch that regulates PTEN’s localization. Most PTEN molecules are held in the cytosol in a closed conformation by intramolecular interactions between the C-terminal tail and core region. Dephosphorylation of the tail opens the conformation and exposes the membrane-binding regulatory interface in the core region, recruiting PTEN to the membrane. Moreover, a lysine at residue 13 is also exposed and when ubiquitinated, transports PTEN to the nucleus. Thus, opening the conformation of PTEN is a key mechanism that enhances its dual localization and enzymatic activity, providing a potential therapeutic strategy in cancer treatments. PMID:26216063

  12. The PTEN/NRF2 Axis Promotes Human Carcinogenesis

    DEFF Research Database (Denmark)

    Rojo, Ana I; Rada, Patricia; Mendiola, Marta;

    2014-01-01

    UNLABELLED: Abstract Aims: A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 1...

  13. Folliculosebaceous Cystic Hamartoma With Spindle Cell Lipoma-Like Stromal Features.

    Science.gov (United States)

    Nguyen, Catherine M; Skupsky, Hadas; Cassarino, David

    2015-12-01

    Folliculosebaceous cystic hamartoma is a distinctive cutaneous hamartoma composed of follicular, sebaceous, and mesenchymal components. The lesions are most commonly found on the face and scalp of young adults, with approximately 30% occurring in the nasal or paranasal regions of the face. The clinical differential diagnoses are extensive and include epidermoid cyst, dermal nevus, soft fibroma, and adnexal tumors including sebaceous neoplasms. Here, the authors present a case of a 24-year-old man who presented for evaluation of an asymptomatic growth on the nose, which had slowly enlarged over 9 years. On examination, there was a 0.6 cm dome-shaped flesh-colored papule on the nasal bridge. The clinical differential included dermatofibroma versus intradermal nevus. A shave biopsy was performed, and histological examination of the sections showed a proliferation of multiple enlarged and irregular-appearing sebaceous glands attached to a cystic follicular structure. The associated dermal mesenchymal component consisted of numerous mature-appearing adipocytes associated with a fibromyxoid stroma, prominent collections of mucin, and bundles of ropey collagen resembling a spindle cell lipoma. This combination of a folliculosebaceous cystic hamartoma with a spindle cell lipoma-like mesenchymal proliferation is unusual and has not been previously reported.

  14. Folliculosebaceous Cystic Hamartoma With Spindle Cell Lipoma-Like Stromal Features

    Science.gov (United States)

    Skupsky, Hadas; Cassarino, David

    2015-01-01

    Abstract: Folliculosebaceous cystic hamartoma is a distinctive cutaneous hamartoma composed of follicular, sebaceous, and mesenchymal components. The lesions are most commonly found on the face and scalp of young adults, with approximately 30% occurring in the nasal or paranasal regions of the face. The clinical differential diagnoses are extensive and include epidermoid cyst, dermal nevus, soft fibroma, and adnexal tumors including sebaceous neoplasms. Here, the authors present a case of a 24-year-old man who presented for evaluation of an asymptomatic growth on the nose, which had slowly enlarged over 9 years. On examination, there was a 0.6 cm dome-shaped flesh-colored papule on the nasal bridge. The clinical differential included dermatofibroma versus intradermal nevus. A shave biopsy was performed, and histological examination of the sections showed a proliferation of multiple enlarged and irregular-appearing sebaceous glands attached to a cystic follicular structure. The associated dermal mesenchymal component consisted of numerous mature-appearing adipocytes associated with a fibromyxoid stroma, prominent collections of mucin, and bundles of ropey collagen resembling a spindle cell lipoma. This combination of a folliculosebaceous cystic hamartoma with a spindle cell lipoma-like mesenchymal proliferation is unusual and has not been previously reported. PMID:26588344

  15. Hamartoma cístico retro-retal: relato de 2 casos e revisão da literatura

    Directory of Open Access Journals (Sweden)

    Gabriella Oliveira Fernandes

    2006-06-01

    Full Text Available Tumores retro-retais são aqueles localizados no espaço retro-retal, de diferentes origens embriológicas e que podem exercer compressão extrínsica no reto e canal anal. São lesões raras, geralmente assintomáticas e mais comuns em mulheres. O hamartoma cístico (tailgut cyst é um tipo de tumor retro-retal congênito, formado a partir de remanescentes embrionários do intestino posterior. Este trabalho traz uma revisão sobre os tumores retro-retais, dando ênfase às lesões císticas e relata 02 casos de pacientes com hamartoma cístico retro-retal, tratados no Hospital Geral de Goiânia,com lesões evidentes ao toque retal e exames de imagem mostrando lesões císticas no espaço pré-sacral. Utilizou-se a incisão de Parks na abordagem das lesões, uma delas associada 'a via abdominal. A histopatologia foi compatível com hamartoma cístico. As lesões císticas do espaço retro-retal possuem bom prognóstico e a abordagem cirúrgica dependerá das características da lesão, principalmente sua altura em relação à margem anal e relação com estruturas adjacentes no espaço pré-sacral.Retrorectal tumors are those located in the retrorectal space, derived from germinal layers and may exert extrinsic compression of rectum and anal canal. They are uncommon lesions, usually asymptomatic and more frequent in females than in males. Cystic hamartoma (tailgut cyst is a congenital retrorectal tumor, derived from embryonic remnants of the posterior gut. The present work makes a review on retrorectal tumors giving emphasis to the cystic lesions and reports two cases of patients suffering from retrorectal cystic hamartoma treated at the Hospital Geral de Goiânia , with evident lesions on rectal examination and imaging showing cystic lesions in the presacral space. The resection of the mass was accomplished by means of a posterior approach (Parks approach associated with abdominal approach in one of the cases. Mycroscopic section showed cystic

  16. Eccrine angiomatous hamartoma: Late onset facial presentation

    Directory of Open Access Journals (Sweden)

    Chinmay Halder

    2014-01-01

    Full Text Available Eccrine angiomatous hamartoma (EAH is a very rare benign neoplastic condition characterized by hamartomatous proliferation of eccrine glands and accompanying blood vessels and lymphatics. These lesions are more often present at birth or appear during early infancy and childhood and present as solitary nodule or plaque with occasional pain and sweating. They are generally present on the extremities, mostly the palms and soles. We report here a case of EAH in a 20-year-old female who presented with a solitary angiomatous plaque close to the lower eyelid of the right eye with occasional pain and sweating for its rarity.

  17. Mesenchymal hamartoma: prenatal diagnosis by MRI

    Energy Technology Data Exchange (ETDEWEB)

    Chu, Leysia [The Hospital for Sick Children, Department of Diagnostic Imaging, Toronto (Canada); Seed, Mike [The Hospital for Sick Children, Division of Cardiology, Department of Paediatrics, Toronto (Canada); Howse, Erica; Ryan, Greg [University of Toronto, Fetal Medicine Unit, Mount Sinai Hospital, Toronto (Canada); Grosse-Wortmann, Lars [The Hospital for Sick Children, Department of Diagnostic Imaging, Toronto (Canada); The Hospital for Sick Children, Division of Cardiology, Department of Paediatrics, Toronto (Canada)

    2011-06-15

    The clinical presentation of thoracic mesenchymal hamartomas varies from an asymptomatic chest wall mass to severe respiratory distress resulting from compression of the airways and lungs. We present the findings on fetal US and MRI of a histologically confirmed case. Following surgical resection, pathological examination corresponded to the cross-sectional imaging features with haemorrhagic, cystic and calcified components. An awareness of the characteristic imaging findings will allow accurate diagnosis of this condition, even prenatally, and thus facilitate appropriate perinatal management and surgical planning. (orig.)

  18. Nasal chondromesenchymal hamartoma with no nasal symptoms.

    LENUS (Irish Health Repository)

    Uzomefuna, Vincent

    2012-01-01

    The authors present a case of nasal chondromesenchymal hamartoma (NCMH) in an 8-year-old boy with a 4-month history of frontal headache and no symptoms of nasal obstruction, rhinorrhoea or postnasal drip. An ENT examination as well as ophthalmology assessment presented normal results. CT scan showed a lesion involving the sphenoid and ethmoid sinuses. The patient had an endoscopic resection of the lesion that was confirmed histologically to be a NCMH. Though NCMH is known to present usually in infants with obstructing nasal mass, an unusual presentation of a patient with throbbing headache without any nasal symptoms is reported here.

  19. EFFECTS OF MUTATION AND EXPRESSION OF PTEN GENE mRNA ON TUMORIGENESIS AND PROGRESSION OF EPITHELIAL OVARIAN CANCER

    Institute of Scientific and Technical Information of China (English)

    陈颖; 郑华川; 杨雪飞; 孙丽梅; 辛彦

    2004-01-01

    Objective To investigate the mutation and expression of tumor suppressor gene-PTEN mRNA and explore their roles in tumorigenesis and progression of ovarian cancer. Methods Mutated exon 5 of PTEN gene was examined in normal ovary (n = 5), ovarian cyst (n =5), ovarian borderline tumor (n=9), epithelial ovarian cancer (n=60), and ovarian cancer cell line (n= 1)by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). mRNA expression of PTEN gene was evaluated in corresponding tissues and cell line by reverse transcription polymerase chain reaction(RT-PCR). The mutation and mRNA expression of PTEN gene were compared with clinicopathological features of ovarian cancer. Results Mutated exon 5 of PTEN gene was detected only in 5 (7.1%) cases of epithelial ovarian cancer. mRNA expression level of PTEN gene in ovarian borderline tumor or ovarian cancer was lower than that in normal ovary or ovarian cyst (P < 0.05). The level of PTEN gene mRNA expression was negatively correlated with clinicopathological staging of ovarian cancer, whereas positively correlated with histological differentiation (P < 0.05). mRNA expression level of PTEN gene in ovarian endometrioid cancer was significantly lower than that in ovarian serous or mucinous cancer (P < 0.05). Conclusions Mutation of PTEN gene occurs in ovarian cancer. Down-regulated expression of PTEN is probably an important molecular event in tumorigenesis of ovarian cancer. Abnormal expression of PTEN gene is involved in progression of ovarian cancer. Reduced expression of PTEN gene is closely associated with tumorigenesis and pathobiological behaviors of ovarian endometrioid cancer.

  20. PTEN inhibition and axon regeneration and neural repair

    Institute of Scientific and Technical Information of China (English)

    Yosuke Ohtake; Umar Hayat; Shuxin Li

    2015-01-01

    The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog (PTEN) appears critical to con-trol the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in con-ditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Im-portantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury.

  1. Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling.

    Science.gov (United States)

    Oviedo, Néstor J; Pearson, Bret J; Levin, Michael; Sánchez Alvarado, Alejandro

    2008-01-01

    We have identified two genes, Smed-PTEN-1 and Smed-PTEN-2, capable of regulating stem cell function in the planarian Schmidtea mediterranea. Both genes encode proteins homologous to the mammalian tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Inactivation of Smed-PTEN-1 and -2 by RNA interference (RNAi) in planarians disrupts regeneration, and leads to abnormal outgrowths in both cut and uncut animals followed soon after by death (lysis). The resulting phenotype is characterized by hyperproliferation of neoblasts (planarian stem cells), tissue disorganization and a significant accumulation of postmitotic cells with impaired differentiation capacity. Further analyses revealed that rapamycin selectively prevented such accumulation without affecting the normal neoblast proliferation associated with physiological turnover and regeneration. In animals in which PTEN function is abrogated, we also detected a significant increase in the number of cells expressing the planarian Akt gene homolog (Smed-Akt). However, functional abrogation of Smed-Akt in Smed-PTEN RNAi-treated animals does not prevent cell overproliferation and lethality, indicating that functional abrogation of Smed-PTEN is sufficient to induce abnormal outgrowths. Altogether, our data reveal roles for PTEN in the regulation of planarian stem cells that are strikingly conserved to mammalian models. In addition, our results implicate this protein in the control of stem cell maintenance during the regeneration of complex structures in planarians.

  2. Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome.

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    Chen, Hannah Jinlian; Romigh, Todd; Sesock, Kaitlin; Eng, Charis

    2017-10-01

    Germline mutations in the tumor-suppressor gene PTEN predispose to subsets of Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and autism. Evidence-based classification of PTEN variants as either deleterious or benign is urgently needed for accurate molecular diagnosis and gene-informed genetic counseling. We studied 34 different germline PTEN intronic variants from 61 CS patients, characterized their PTEN mRNA processing, and analyzed PTEN expression and downstream readouts of P-AKT and P-ERK1/2. While we found that many mutations near splice junctions result in exon skipping, we also identified the presence of cryptic splicing that resulted in premature termination or a shift in isoform usage. PTEN protein expression is significantly lower in the group with splicing changes while P-AKT, but not P-ERK1/2, is significantly increased. Our observations of these PTEN intronic variants should contribute to the determination of pathogenicity of PTEN intronic variants and aid in genetic counseling. © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc.

  3. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.

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    Kessler, Tobias; Sahm, Felix; Blaes, Jonas; Osswald, Matthias; Rübmann, Petra; Milford, David; Urban, Severino; Jestaedt, Leonie; Heiland, Sabine; Bendszus, Martin; Hertenstein, Anne; Pfenning, Philipp-Niclas; Ruiz de Almodóvar, Carmen; Wick, Antje; Winkler, Frank; von Deimling, Andreas; Platten, Michael; Wick, Wolfgang; Weiler, Markus

    2015-10-13

    Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

  4. A study of the dynamics of PTEN proteins in living cells using in vivo fluorescence correlation spectroscopy

    Science.gov (United States)

    Du, Zhixue; Dong, Chaoqing; Ren, Jicun

    2017-06-01

    PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most important tumor-suppressor proteins, which plays a key role in negative regulation of the PI3K/AKT pathway, and governs many cellular processes including growth, proliferation, survival and migration. The dynamics of PTEN proteins in single living cells is as yet unclear owing to a shortage of suitable in vivo approaches. Here, we report a single-molecule method for in vivo study of the dynamics of PTEN proteins in living cells using fluorescence correlation spectroscopy (FCS). First, we established a monoclonal H1299 stable cell line expressing enhanced green fluorescent protein (EGFP) and PTEN (EGFP-PTEN) fusion proteins; we then developed an in vivo FCS method to study the dynamics of EGFP-PTEN both in the nucleus and the cytoplasm. We investigated the diffusion behaviors of EGFP and EGFP-PTEN in solution, nucleus and cytosol, and observed that the motion of PTEN in living cells was restricted compared with EGFP. Finally, we investigated the protein dynamics in living cells under oxidative stress stimulation and a cellular ATP depletion treatment. Under oxidative stress stimulation, the EGFP-PTEN concentration increased in the nucleus, but slightly decreased in the cytoplasm. The diffusion coefficient and alpha value of EGFP-PTEN reduced significantly both in the nucleus and cytoplasm; the significantly decreased alpha parameter indicates a more restricted Brownian diffusion behavior. Under the cellular ATP depletion treatment, the concentration of EGFP-PTEN remained unchanged in the nucleus and decreased significantly in cytosol. The diffusion coefficient of EGFP-PTEN decreased significantly in cytosol, but showed no significant change in the nucleus; the alpha value decreased significantly in both the nucleus and cytoplasm. These results suggest that the concentration and mobility of PTEN in the nucleus and cytoplasm can be regulated by stimulation methods. Our approach provides a unique

  5. PTEN loss is associated with worse outcome in HER2-amplified breast cancer patients but is not associated with trastuzumab resistance

    Science.gov (United States)

    Stern, Howard M.; Gardner, Humphrey; Burzykowski, Tomasz; Elatre, Wafaa; O’Brien, Carol; Lackner, Mark R.; Pestano, Gary A.; Santiago, Angela; Villalobos, Ivonne; Eiermann, Wolfgang; Pienkowski, Tadeusz; Martin, Miguel; Robert, Nicholas; Crown, John; Nuciforo, Paolo; Bee, Valerie; Mackey, John; Slamon, Dennis J.; Press, Michael F.

    2015-01-01

    Purpose To investigate the clinical relevance of PTEN in HER2-amplified and HER2-non-amplified disease. Experimental Design We assessed PTEN status in two large adjuvant breast cancer trials (BCIRG-006 and BCIRG-005) using a PTEN IHC assay that was previously validated in a panel of 33 breast cancer cell lines and prostate cancer tissues with known PTEN gene deletion. Results In the HER2-positive patient population, absence of tumor cell PTEN staining occurred at a rate of 5.4% and was independent of ER/PR status. In contrast, 15.9% of HER2-negative patients exhibited absence of PTEN staining with the highest frequency seen in triple negative breast cancer (TNBC) subgroup versus ER/PR-positive patients (35.1% vs. 10.9%). Complete absence of PTEN staining in tumor cells was associated with poor clinical outcome in HER2-positive disease. Those patients whose cancers demonstrated absent PTEN staining had a significant decrease in disease-free survival (DFS) and overall survival (OS) compared to patients with tumors exhibiting any PTEN staining patterns (low, moderate or high). Trastuzumab appeared to provide clinical benefit even for patients lacking PTEN staining. In the HER2-negative population there were no statistically significant differences in clinical outcome based on PTEN status. Conclusions This study is the largest to date examining PTEN status in breast cancer and the data suggest that the rate and significance of PTEN status differ between HER2-positive and HER2-negative disease. Furthermore, the data clearly suggest that HER2-positive patients with PTEN loss still benefit from trastuzumab. PMID:25649019

  6. Hamartoma de músculo liso

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    Cassiano Tamura Vieira Gomes

    2016-10-01

    Full Text Available Introdução: O hamartoma de músculo liso (HML é uma malformação cutânea benigna e pouco frequente, caracterizada pela proliferação de fibras de músculo liso na derme, podendo ser congênito ou adquirido. Quanto a morfologia, descreve-se como placa de consistência firme ou elástica com elevações papulares, de coloração variada. A histopatologia se caracteriza por presença de múltiplas fibras musculares lisas, bem diferenciadas que seguem diferentes direções, dispostas aleatoriamente na derme superficial ou profunda. A intervenção terapêutica não é necessária, sendo indicada para melhora estética. Objetivo: Relatar um caso de hamartoma de músculo liso em paciente atendida no Ambulatório de Dermatologia do Conjunto Hospitalar de Sorocaba. Metodologia: Avaliação clínica da paciente em questão, revisão de prontuário e de literatura relacionada ao tema exposto. Relato de caso: L.S.P., 50 anos, sexo feminino, branca, apresenta múltiplas pápulas acastanhadas, pruriginosas, bem delimitadas em região abdominal e dorsal à direita, há aproximadamente 5 anos, que aumentaram em tamanho e número. Realizada biópsia de lesão, cujo exame histopatológico demonstrou presença de feixes de musculatura lisa na derme reticular distribuídas ao acaso e entremeadas por colágeno, sugestivo de hamartoma de músculo liso. Realizado tratamento com crioterapia nas lesões, com melhora na aparência das mesmas, sendo que a paciente permanece em acompanhamento no ambulatório de Dermatologia. Conclusão: O HML apresenta características clínicas e histopatológicas que permitem a diferenciação em relação a outras dermatoses. Como há boa evolução clínica, não se associar com manifestações sistêmicas e não ter potencial de malignização não é necessária intervenção terapêutica.

  7. Evolution of Brunner gland hamartoma associated with Helicobacter pylori infection.

    Science.gov (United States)

    Kurella, Ravi R; Ancha, Hanumantha R; Hussain, Sanam; Lightfoot, Stan A; Harty, Richard

    2008-06-01

    The pathogenesis of Brunner gland hamartoma of the duodenum is unknown. This case report describes the chronology of the development of Brunner gland hamartoma from Brunner gland hyperplasia over a 12-year interval. The study subject, a 64-year-old man with chronic iron deficiency anemia, underwent serial upper endoscopies during this period. Repeated endoscopies demonstrated the evolution of Brunner gland hyperplasia, as manifest endoscopically by a submucosal mass, to a pedunculated polyp with histologic features of Brunner gland hamartoma. The duodenal polypoid mass was removed by snare polypectomy. The patient also had a chronic Helicobacter pylori infection of the stomach. This report details the time-dependent evolution of Brunner gland hyperplasia to hamartoma in association with chronic gastric H. pylori infection.

  8. A Comparative Study of Oral Hamartoma and Choristoma

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    Ilana Kaplan

    2015-12-01

    Conclusion: Differentiating choristoma from hamartoma depends to a great extent on the recognition of the normal tissues expected at every individual location. [J Interdiscipl Histopathol 2015; 3(4.000: 129-134

  9. The soybean peptide lunasin promotes apoptosis of mammary epithelial cells via induction of tumor suppressor PTEN: similarities and distinct actions from soy isoflavone genistein

    Science.gov (United States)

    Breast cancer is the leading cause of cancer deaths in women. Diet and lifestyle are major contributing factors to increased breast cancer risk. While mechanisms underlying dietary protection of mammary tumor formation are increasingly elucidated, there remains a dearth of knowledge on the nature an...

  10. Relationsip between PTEN and VEGF Expression and Clinicopathological Characteristics in HCC

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    To investigate the expressions and significance of the tumor suppressor gene phosphatase and tensin homlog deleted on chromosome ten protein (PTEN) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC), and to analyze the relationship between their expressions and the tumor's invasion and their pericarcinomatous tissues, the correlation of their expressions with the tumor's clinicopathological characteristics and invasion potential were studied. Our study showed that the expression level of PTEN in HCC was remarkably lower than that in pericarcinomatous liver tissues, while the expressions of both VEGF and MVD were higher than that in pericarcinomatous liver tissues. Correlation analysis revealed that the expression of PTEN was negatively related to the progression of the pathological differentiation and invasion of tumor, whereas the expressions of VEGF and MVD were positively related. Moreover, there was a negative relationship between the expression of PTEN and the expressions of VEGF and MVD, and a positive one between VEGF and MVD. The expressions of PTEN and VEGF may reveal the degree of differentiation and the invasive potential of HCC tissues. The mechanism by which the lack of PTEN expression probably induces abnormal hyperexpression of VEGF may play an important role in the invasion and metastasis of HCC.

  11. An Undiagnosed Case of Hypothalamic Hamartoma with a Rare Presentation

    Science.gov (United States)

    Bahrani, Saeideh; Tabrizi, Nasim; Moein, Houshang; Zare, Mohammad; Barekatain, Majid; Basiratnia, Reza; Rahimian, Elham; Mehvari Habibabadi, Amirali; Moein, Payam

    2017-01-01

    Background. Hypothalamic hamartomas (HHs) are rare tumor-like malformations that may present with complex partial seizures refractory to anticonvulsants in adulthood. The condition may be misdiagnosed because of rarity. Case Presentation. We report a 25-year-old man with complaint of seizures presented by falling, tonic spasm of limbs, oral automatism, vocalization, and hypermotor activities. His seizures started at the age of one month and presented as eye deviation and upper limbs myoclonic jerk, followed by frequent seizures with variable frequency. The patient had delayed developmental milestones and was mentally retarded. He was hospitalized and underwent video-EEG monitoring and neuroimaging, and the diagnosis of HH was made. The patient became candidate for surgery after that. Conclusion. In this case, the underlying etiology of seizures was diagnosed after 25 years. HH is a rare condition and neurologists may encounter very small number of these cases during their practice. Therefore, they should consider it in patients who present with suspected signs and symptoms. PMID:28246530

  12. Biopsy-proven spontaneous regression of a rhabdomyomatous mesenchymal hamartoma.

    Science.gov (United States)

    Mazza, Joni M; Linnell, Erica; Votava, Henry J; Wisoff, Jeffrey H; Silverberg, Nanette B

    2015-01-01

    Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare, benign, congenital tumor of the dermis and subcutaneous tissue comprised of skeletal muscle and adipose and adnexal elements. Although the majority of cases are an incidental finding in otherwise healthy patients, some have been reported in association with other anomalies. We present a full-term boy evaluated on day 2 of life for two lesions located on the midline of the lower back and right buttock that each appeared clinically as an atrophic, pink plaque. Ultrasound of the midline lesion revealed an underlying lipomyelomeningocele with a tethered cord in the spinal canal. Histopathology of the right buttock cutaneous lesion was consistent with a diagnosis of RMH. Surgical excision was performed on the midline intradural lipoma and the lesion on the buttock was monitored clinically. Repeat biopsy of this site at 1 year of age revealed complete spontaneous regression. This case highlights three interesting features: the association with an occult spinal dysraphism lipomyelomeningocele and tethered cord, the clinical presentation of an atrophic plaque as opposed to the more commonly reported raised lesions, and the phenomenon of spontaneous regression of the lesion. Most importantly, this final feature of regression in our patient suggests that, in the absence of symptoms, clinical observation of RMH lesions is warranted for spontaneous regression for 1 to 2 years provided that no functional deficit is noted and that the cutaneous or deeper lesions are not causing a medical problem.

  13. An Undiagnosed Case of Hypothalamic Hamartoma with a Rare Presentation

    Directory of Open Access Journals (Sweden)

    Shervin Badihian

    2017-01-01

    Full Text Available Background. Hypothalamic hamartomas (HHs are rare tumor-like malformations that may present with complex partial seizures refractory to anticonvulsants in adulthood. The condition may be misdiagnosed because of rarity. Case Presentation. We report a 25-year-old man with complaint of seizures presented by falling, tonic spasm of limbs, oral automatism, vocalization, and hypermotor activities. His seizures started at the age of one month and presented as eye deviation and upper limbs myoclonic jerk, followed by frequent seizures with variable frequency. The patient had delayed developmental milestones and was mentally retarded. He was hospitalized and underwent video-EEG monitoring and neuroimaging, and the diagnosis of HH was made. The patient became candidate for surgery after that. Conclusion. In this case, the underlying etiology of seizures was diagnosed after 25 years. HH is a rare condition and neurologists may encounter very small number of these cases during their practice. Therefore, they should consider it in patients who present with suspected signs and symptoms.

  14. Cutaneous changes in fibrous hamartoma of infancy

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    Pilar F-Eire

    2013-01-01

    Full Text Available Only a few published case of fibrous hamartoma of infancy (FHI have commented on the changes in the overlying skin. There are descriptions of individual cases with cutaneous hyperpigmentation, hypertrichosis and hyperhidrosis. It is interesting to describe our case because, to our knowledge, the altered pigmentation of the overlying skin, with hairs on the surface, and eccrine gland hyperplasia combined with abortive hair follicles has not been reported together in association with the FHI. We recommend that all the biopsies must be excisional including overlying skin, thus the epidermal and dermal adnexal changes can be assessed in the microscopic evaluation which could have relevant implications from clinical and embryological point of view.

  15. The role of PTEN in chronic growth hormone-induced hepatic insulin resistance.

    Science.gov (United States)

    Gao, Yuan; Su, Peizhu; Wang, Chuqiong; Zhu, Kongqin; Chen, Xiaolan; Liu, Side; He, Jiman

    2013-01-01

    Chronic growth hormone (GH) therapy has been shown to cause insulin resistance, but the mechanism remains unknown. PTEN, a tumor suppressor gene, is a major negative regulator of insulin signaling. In this study, we explored the effect of chronic GH on insulin signaling in the context of PTEN function. Balb/c healthy mice were given recombinant human or bovine GH intraperitoneally for 3 weeks. We found that phosphorylation of Akt was significantly decreased in chronic GH group and the expression of PTEN was significantly increased. We further examined this effect in the streptozotocin-induced Type I diabetic mouse model, in which endogenous insulin secretion was disrupted. Insulin/PI3K/Akt signaling was impaired. However, different from the observation in healthy mice, the expression of PTEN did not increase. Similarly, PTEN expression did not significantly increase in chronic GH-treated mice with hypoinsulinemia induced by prolonged fasting. We conducted in-vitro experiments in HepG2 cells to validate our in-vivo findings. Long-term exposure to GH caused similar resistance of insulin/PI3K/Akt signaling in HepG2 cells; and over-expression of PTEN enhanced the impairment of insulin signaling. On the other hand, disabling the PTEN gene by transfecting the mutant PTEN construct C124S or siPTEN, disrupted the chronic GH induced insulin resistance. Our data demonstrate that PTEN plays an important role in chronic-GH-induced insulin resistance. These findings may have implication in other pathological insulin resistance.

  16. Molecular characterization and function of a PTEN gene from Litopenaeus vannamei after Vibrio alginolyticus challenge.

    Science.gov (United States)

    Xie, C-y; Kong, J-r; Zhao, C-s; Xiao, Y-c; Peng, T; Liu, Y; Wang, W-n

    2016-06-01

    PTEN, a tumor suppressor gene, suppresses cell survival, growth, apoptosis, cell migration and DNA damage repair by inhibiting the PI3K/AKT signaling pathway. In this study, the full-length Litopenaeus vannamei PTEN (LvPTEN) cDNA was obtained, containing a 5'UTR of 59bp, an ORF of 1269bp and a 3'UTR of 146bp besides the poly (A) tail. The PTEN gene encoded a protein of 422 amino acids with an estimated molecular mass of 48.3 KDa and a predicted isoelectric point (pI) of 7.6. Subcellular localization analysis revealed that LvPTEN was distributed in both cytoplasm and nucleus, and the tissue distribution patterns showed that LvPTEN was ubiquitously expressed in all the examined tissues. Vibrio alginolyticus challenge induced upregulation of LvPTEN expression. Moreover, RNAi knock-down of LvPTEN in vivo significantly increased the expression of LvAKT mRNA, while reducing that of the downstream apoptosis genes LvP53 and LvCaspase3. LvPTEN knock-down also caused a sharp increase in cumulative mortality, bacterial numbers, and DNA damage in the hemolymph of L. vannamei following V. alginolyticus challenge, together with a sharp decrease in the total hemocyte count (THC). These results suggested that LvPTEN may participate in apoptosis via the PI3K/AKT signaling pathway in L. vannamei, and play an important role in shrimp innate immunity.

  17. Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-γ

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    Chen, Chia-Ling [Translational Research Center, Taipei Medical University, Taipei 110, Taiwan (China); Chiang, Tzu-Hui; Tseng, Po-Chun [Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China); Wang, Yu-Chih [Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China); Lin, Chiou-Feng, E-mail: cflin2014@tmu.edu.tw [Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China); Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China)

    2015-10-23

    Src homology-2 domain-containing phosphatase (SHP) 2, an oncogenic phosphatase, inhibits type II immune interferon (IFN)-γ signaling by subverting signal transducers and activators of transcription 1 tyrosine phosphorylation and activation. For cancer immunoediting, this study aimed to investigate the decrease of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein, leading to cellular impairment of IFN-γ signaling. In comparison with human lung adenocarcinoma A549 cells, the natural PTEN loss in another human lung adenocarcinoma line, PC14PE6/AS2 cells, presents reduced responsiveness in IFN-γ-induced IFN regulatory factor 1 activation and CD54 expression. Artificially silencing PTEN expression in A549 cells also caused cells to be unresponsive to IFN-γ without affecting IFN-γ receptor expression. IFN-γ-induced inhibition of cell proliferation and cytotoxicity were demonstrated in A549 cells but were defective in PC14PE6/AS2 cells and in PTEN-deficient A549 cells. Aberrant activation of SHP2 by ROS was specifically shown in PC14PE6/AS2 cells and PTEN-deficient A549 cells. Inhibiting ROS and SHP2 rescued cellular responses to IFN-γ-induced cytotoxicity and inhibition of cell proliferation in PC14PE6/AS2 cells. These results demonstrate that a decrease in PTEN facilitates ROS/SHP2 signaling, causing lung cancer cells to become unresponsive to IFN-γ. - Highlights: • This study demonstrates that PTEN decrease causes cellular unresponsive to IFN-γ. • Lung cancer cells with PTEN deficiency show unresponsive to IFN-γ signaling. • PTEN decrease inhibits IFN-γ-induced CD54, cell proliferation inhibition, and cytotoxicity. • ROS-mediated SHP2 activation makes PTEN-deficient cells unresponsive to IFN-γ.

  18. Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing.

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    Travis A Burgers

    Full Text Available The failure of an osseous fracture to heal (development of a non-union is a common and debilitating clinical problem. Mice lacking the tumor suppressor Pten in osteoblasts have dramatic and progressive increases in bone volume and density throughout life. Since fracture healing is a recapitulation of bone development, we investigated the process of fracture healing in mice lacking Pten in osteoblasts (Ocn-cre(tg/+;Pten(flox/flox . Mid-diaphyseal femoral fractures induced in wild-type and Ocn-cre(tg/+;Pten(flox/flox mice were studied via micro-computed tomography (µCT scans, biomechanical testing, histological and histomorphometric analysis, and protein expression analysis. Ocn-cre(tg/+;Pten(flox/flox mice had significantly stiffer and stronger intact bones relative to controls in all cohorts. They also had significantly stiffer healing bones at day 28 post-fracture (PF and significantly stronger healing bones at days 14, 21, and 28 PF. At day 7 PF, the proximal and distal ends of the Pten mutant calluses were more ossified. By day 28 PF, Pten mutants had larger and more mineralized calluses. Pten mutants had improved intramembranous bone formation during healing originating from the periosteum. They also had improved endochondral bone formation later in the healing process, after mature osteoblasts are present in the callus. Our results indicate that the inhibition of Pten can improve fracture healing and that the local or short-term use of commercially available Pten-inhibiting agents may have clinical application for enhancing fracture healing.

  19. Posttranslational regulation of phosphatase and tensin homolog (PTEN and its functional impact on cancer behaviors

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    Xu WT

    2014-10-01

    Full Text Available Wenting Xu,1 Zhen Yang,1 Shu-Feng Zhou,2 Nonghua Lu1 1Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA Abstract: The incidence of cancer is increasing worldwide, but the biochemical mechanisms for the occurrence of cancer is not fully understood, and there is no cure for advanced tumors. Defects of posttranslational modifications of proteins are linked to a number of important diseases, such as cancer. This review will update our knowledge on the critical role of posttranscriptional regulation of phosphatase and tensin homolog (PTEN and its activities and the functional impact on cancer behaviors. PTEN is a tumor suppressor gene that occupies a key position in regulating cell growth, proliferation, apoptosis, mobility, signal transduction, and other crucial cellular processes. The activity and function of PTEN are regulated by coordinated epigenetic, transcriptional, posttranscriptional, and posttranslational modifications. In particular, PTEN is subject to phosphorylation, ubiquitylation, somoylation, acetylation, and active site oxidation. Posttranslational modifications of PTEN can dynamically change its activity and function. Deficiency in the posttranslational regulation of PTEN leads to abnormal cell proliferation, apoptosis, migration, and adhesion, which are associated with cancer initiation, progression, and metastasis. With increasing information on how PTEN is regulated by multiple mechanisms and networked proteins, its exact role in cancer initiation, growth, and metastasis will be revealed. PTEN and its functionally related proteins may represent useful targets for the discovery of new anticancer drugs, and gene therapy and the therapeutic potentials should be fully explored. Keywords: phosphorylation, ubiquitination, acetylation, oxidation

  20. Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss

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    Sendor AB

    2015-02-01

    Full Text Available Adam B Sendor,1 Kathryn E Hacker,1 Shufen Chen,1 Armando L Corona,1 Oishee Sen,1 Derek Y Chiang,1 Anna Snavely,1 Arlin B Rogers,2 Stephanie A Montgomery,1 W Kimryn Rathmell,1 Autumn J McRee11Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; 2Section of Pathology, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, Boston, MA, USABackground: PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC and cholangiocarcinoma (CC. The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model.Methods: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes.Results: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered.Conclusion: Pten deletion in Keratin 18 expressing cells leads to

  1. Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice.

    Science.gov (United States)

    Gutilla, Erin A; Buyukozturk, Melda M; Steward, Oswald

    2016-05-01

    Targeted deletion of the phosphatase and tensin homolog on chromosome ten (PTEN) gene in the sensorimotor cortex of neonatal mice enables robust regeneration of corticospinal tract (CST) axons following spinal cord injury as adults. Here, we assess the consequences of long-term conditional genetic PTEN deletion on cortical structure and neuronal morphology and screen for neuropathology. Mice with a LoxP-flanked exon 5 of the PTEN gene (PTENf/f mice) received AAV-Cre injections into the sensorimotor cortex at postnatal day 1 (P1) and were allowed to survive for up to 18months. As adults, mice were assessed for exploratory activity (open field), and motor coordination using the Rotarod®. Some mice received injections of Fluorogold into the spinal cord to retrogradely label the cells of origin of the CST. Brains were prepared for neurohistology and immunostained for PTEN and phospho-S6, which is a downstream marker of mammalian target of rapamycin (mTOR) activation. Immunostaining revealed a focal area of PTEN deletion affecting neurons in all cortical layers, although in some cases PTEN expression was maintained in many small-medium sized neurons in layers III-IV. Neurons lacking PTEN were robustly stained for pS6. Cortical thickness was significantly increased and cortical lamination was disrupted in the area of PTEN deletion. PTEN-negative layer V neurons that give rise to the CST, identified by retrograde labeling, were larger than neurons with maintained PTEN expression, and the relative area occupied by neuropil vs. cell bodies was increased. There was no evidence of tumor formation or other neuropathology. Mice with PTEN deletion exhibited open field activity comparable to controls and there was a trend for impaired Rotarod performance (not statistically significant). Our findings indicate that early postnatal genetic deletion of PTEN that is sufficient to enable axon regeneration by adult neurons causes neuronal hypertrophy but no other detectable

  2. Occult Breast Cancer due to Multiple Calcified Hamartomas in a Patient with Cowden Syndrome

    NARCIS (Netherlands)

    Gomez Garcia, E.B.; Lobbes, M.B.; van de Vijver, K.; Keymeulen, K.; van der Ent, F.; Yntema, H.G.; Tjan-Heijnen, V.C.; Boetes, C.

    2012-01-01

    Cowden syndrome (CS) is an autosomal dominant disorder characterized by presence of multiple hamartomas, and other benign and malignant abnormalities of the breasts, skin, thyroid, endometrium, gastrointestinal tract, and central nervous system. Hamartomas are benign, developmentally disorganized

  3. Hamartoma of the urinary bladder in a 15-year-old boy

    OpenAIRE

    Al Shahwani, Noora; Alnaimi, Abdulla Rashid; Ammar, Adham; Al-ahdal, Esra M.

    2016-01-01

    Hamartoma of the bladder is an unusual entity described in only eleven patients to date. It may present as painless hematuria, irritative urinary tract symptoms, or inability to void or it may be diagnosed incidentally. Hamartoma of the bladder may be isolated or occur as part of a syndrome. No isolated bladder hamartoma to date has shown malignant potential. We describe here a bladder hamartoma in a 15-year-old boy.

  4. Hamartoma of the urinary bladder in a 15-year-old boy

    Science.gov (United States)

    Al Shahwani, Noora; Alnaimi, Abdulla Rashid; Ammar, Adham; Al-ahdal, Esra M.

    2016-01-01

    Hamartoma of the bladder is an unusual entity described in only eleven patients to date. It may present as painless hematuria, irritative urinary tract symptoms, or inability to void or it may be diagnosed incidentally. Hamartoma of the bladder may be isolated or occur as part of a syndrome. No isolated bladder hamartoma to date has shown malignant potential. We describe here a bladder hamartoma in a 15-year-old boy. PMID:27274896

  5. Hamartoma fibrolipomatoso de nervo mediano: relato de caso Fibrolipomatous hamartoma of the median nerve: case report

    Directory of Open Access Journals (Sweden)

    Paulo José Lorenzoni

    2005-09-01

    Full Text Available O hamartoma fibrolipomatoso é neoplasia benigna rara que em alguns casos esta associada com macrodactilia. Descrevemos o caso de homem de 31 anos que apresentava desde o nascimento aumento de volume em região de punho, segundo e terceiro quirodáctilos da mão esquerda. Aos 23 anos iniciou dor contínua, de forte intensidade, predominante no período noturno e de evolução progressiva em mão esquerda. Associada à dor havia hipoestesia e parestesias de predomínio nos segundo e terceiro quirodáctilos esquerdos. A investigação complementar com radiografia, ultrassonografia, estudo eletrofisiológico e ressonância magnética de mão e punho esquerdos confirmaram a suspeita de síndrome do túnel do carpo secundária a macrodactilia com hamartoma fibrolipomatoso do nervo mediano. O paciente foi submetido à descompressão cirúrgica do túnel do carpo esquerdo devido a ausência de resposta ao tratamento clínico e evoluiu com melhora dos sintomas em avaliação após três meses do procedimento.Fibrolipomatous hamartoma is a rare benign neoplasm that in some cases is associated with macrodactylia. We describe a 31-years-old man who had a tissue enlargement in the wrist, second and third fingers of the left hand since infancy. At 23-years-old he began with continuous, progressive and high intensity pain that occurred more frequently at night, localized in the left hand. It was associated with paraesthesias and hypostesias predominantly at the fingers described above. Investigation with X-ray, ultrasonography, electrodiagnosis, magnetic resonance image of the left wrist and hand showed carpal tunnel syndrome with macrodactylia by fibrolipomatous hamartoma of the median nerve. The patient did not a have good response to clinical therapy, so he was submitted to a surgical decompression of the left carpal tunnel, and after three months of follow up is asymptomatic.

  6. PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation.

    Science.gov (United States)

    Rahal, Omar M; Simmen, Rosalia C M

    2010-08-01

    The tumor suppressors phosphatase and tensin homologue deleted on chromosome ten (PTEN) and p53 are closely related to the pathogenesis of breast cancer, yet pathway-specific mechanisms underlying their participation in mediating the protective actions of dietary bioactive components on breast cancer risk are poorly understood. We recently showed that dietary exposure to the soy isoflavone genistein (GEN) induced PTEN expression in mammary epithelial cells in vivo and in vitro, consistent with the breast cancer preventive effects of soy food consumption. Here, we evaluated PTEN and p53 functional interactions in the nuclear compartment of mammary epithelial cells as a mechanism for mammary tumor protection by GEN. Using the non-tumorigenic human mammary epithelial cells MCF10-A, we demonstrate that GEN increased PTEN expression and nuclear localization. We show that increased nuclear PTEN levels initiated an autoregulatory loop involving PTEN-dependent increases in p53 nuclear localization, PTEN-p53 physical association, PTEN-p53 co-recruitment to the PTEN promoter region and p53 transactivation of PTEN promoter activity. The PTEN-p53 cross talk induced by GEN resulted in increased cell cycle arrest; decreased pro-proliferative cyclin D1 and pleiotrophin gene expression and the early formation of mammary acini, indicative of GEN promotion of lobuloalveolar differentiation. Our findings provide support to GEN-induced PTEN as both a target and regulator of p53 action and offer a mechanistic basis for PTEN pathway activation to underlie the antitumor properties of dietary factors, with important implications for reducing breast cancer risk.

  7. 肺错构瘤的临床病理学分析%Clinical and pathological analysis of pulmonary hamartoma

    Institute of Scientific and Technical Information of China (English)

    李伟华; 陈健; 夏康; 阮荣和; 高源统

    2013-01-01

    Objective:To explore the clinical and pathological features of pulmonary hamartoma,in order to help clinical diagnosis and treatment correctly.Methods:Twenty-one cases of pulmonary hamartoma were analyzed retrospectively based on clinical manifestations,imaging features,histological features,immunohis-tochemical phenotype,and summarized key points of pulmonary hamartoma diagnosis.Results:There were several types of pulmonary hamartoma,including intrapulmonary type,bronchial type and mixed type (intrapulmonary with endobronchial).The intrapulmonary type located in the peripheral lung had no obvious clinical symptoms,and normally had clear boundary; the bronchial type located in bronchus with shape of polypus.microscopically consisted of different proportions of mesenchymal tissue and respiratory epithelium,and someone mixed cartilage with little fat even with no fat.Conclusion:Pulmonary hamartoma is the most common benign lung tumor,there are a variety of clinical types and histological types,no fat or cartilage density image cannot rule out the diagnosis of hamartoma,its clear diagnosis must be combined with clinical manifestations,imaging data and pathological examination.%目的:探讨肺错构瘤的临床病理学特征,以助于临床正确诊断与治疗.方法:回顾性分析21例肺错构瘤的临床表现、影像学特征、组织学特点、免疫组化表型,总结肺错构瘤的诊断要点.结果:肺错构瘤包括肺内型、支气管内型及混合型(肺内合并支气管内型错构瘤).肺内型位于肺外周,大多数没有明显临床症状,肿瘤通常境界清楚;支气管内型位于支气管内,呈息肉状.镜下由不同比例的间叶组织和呼吸型上皮混杂组成,有者软骨和脂肪成分很少甚至缺乏.结论:肺错构瘤是最常见的良性肺肿瘤,有多种临床类型和组织学类型,影像上未见脂肪或软骨密度亦不能排除错构瘤的诊断,需结合临床表现、影像学资料及病理检查以确诊.

  8. Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.

    Science.gov (United States)

    Liu, Jeff C; Voisin, Veronique; Wang, Sharon; Wang, Dong-Yu; Jones, Robert A; Datti, Alessandro; Uehling, David; Al-awar, Rima; Egan, Sean E; Bader, Gary D; Tsao, Ming; Mak, Tak W; Zacksenhaus, Eldad

    2014-12-01

    The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited hyper-activated AKT signaling and more mesenchymal features relative to Pten or p53 single-mutant tumors. Twenty-four genes that were significantly and differentially expressed between WAP-Cre:Pten/p53 and MMTV-Cre:Pten/p53 tumors predicted poor survival for claudin-low patients. Kinome screens identified eukaryotic elongation factor-2 kinase (eEF2K) inhibitors as more potent than PI3K/AKT/mTOR inhibitors on both mouse and human Pten/p53-deficient TNBC cells. Sensitivity to eEF2K inhibition correlated with AKT pathway activity. eEF2K monotherapy suppressed growth of Pten/p53-deficient TNBC xenografts in vivo and cooperated with doxorubicin to efficiently kill tumor cells in vitro. Our results identify a prognostic signature for claudin-low patients and provide a rationale for using eEF2K inhibitors for treatment of TNBC with elevated AKT signaling.

  9. Mesenchymal hamartoma of the chest wall in an infant.

    Science.gov (United States)

    Ayadi-Kaddour, A; Mlika, M; Chaabouni, S; Kilani, T; El Mezni, F

    2007-12-01

    Mesenchymal hamartoma of the chest wall is a very rare, benign tumour with distinct clinical, radiological and histopathologic characteristics. The lesion develops during foetal life, and is present at or shortly after birth with an extrapleural mass arising from the rib cage with or without respiratory distress and marked rib deformity. Several imaging techniques have been used for diagnosis, but a definitive diagnosis is established only by histopathological examination. Such lesions are composed of a varying admixture of hyaline cartilage that has features resembling growth plate cartilage, along with fascicles of spindle cells, woven bone and hemorrhagic cysts. Accurate diagnosis of mesenchymal hamartoma is important since many chest wall masses in children are malignant. We report a case of mesenchymal hamartoma of the left posterior chest wall surgically resected in an infant who was found to have a palpable mass at birth. Two years after surgery, the patient is alive and well, with no evidence of recurrence.

  10. The Significance of PTEN Expression and DNA Ploidy Analysis in Malignant Peripheral Nerve Sheath Tumors%恶性外周神经鞘瘤中PTEN表达及DNA倍体分析的意义

    Institute of Scientific and Technical Information of China (English)

    郝风云; 杨凤霞; 张彩新; 张景芳; 纪祥瑞

    2008-01-01

    目的:通过检测第10号染色体上磷酸酶和张力蛋白同源缺失基因(PTEN)在恶性外周神经鞘瘤(malignant peripheral nerve sheath tumors,MPNST)中的表达,佐以流式细胞术对MPNST进行DNA倍体分析,研究两者与其临床生物学行为之问的关系.方法:对65例良、恶性外周神经肿瘤石蜡包埋组织应用免疫组化进行PTEN的检测,兼以流式细胞术行DNA倍体分析.结果:PTEN在良、恶性外周神经肿瘤中阳性表达有显著差异(x2=17.628,P<0.001);PTEN阳性表达强度与MPNST的分化程度无相关性(rs=0.067,P:0.699).MPNST发生异倍体4例,均为低异倍体(DI值<0.90);SPF、PI值在良、恶性外周神经肿瘤中有显著差剔(x2=28.674,P<0.001;x2=23.730,P<0.001),且与MPNST病理组织学分级呈正相关(rs=0.418,P<0.01;rs=0.347,P<0.05);PTEN的阳性表达以及阳性表达强度与DNA倍体分析3项指标均无关联.结论:PTEN可以作为鉴别良、恶性外周神经肿瘤以及判断外周神经鞘瘤恶性程度高低的一个有价值的指标;异倍体的出现以及SPF、PI值的增高是判断MPNST恶性程度(演进与异质化)的重要标志.

  11. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities.

    Science.gov (United States)

    Filbin, Mariella Gruber; Dabral, Sukriti K; Pazyra-Murphy, Maria F; Ramkissoon, Shakti; Kung, Andrew L; Pak, Ekaterina; Chung, Jarom; Theisen, Matthew A; Sun, Yanping; Franchetti, Yoko; Sun, Yu; Shulman, David S; Redjal, Navid; Tabak, Barbara; Beroukhim, Rameen; Wang, Qi; Zhao, Jean; Dorsch, Marion; Buonamici, Silvia; Ligon, Keith L; Kelleher, Joseph F; Segal, Rosalind A

    2013-11-01

    In glioblastoma, phosphatidylinositol 3-kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. We interrogated large databases and found that sonic hedgehog (SHH) signaling is activated in PTEN-deficient glioblastoma. We demonstrate that the SHH and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and SHH signaling inhibitors not only suppressed the activation of both pathways but also abrogated S6 kinase (S6K) signaling. Accordingly, targeting both pathways simultaneously resulted in mitotic catastrophe and tumor apoptosis and markedly reduced the growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear to be safe in humans; therefore, this combination may provide a new targeted treatment for glioblastoma.

  12. Large mammary hamartoma with focal invasive ductal carcinoma

    Directory of Open Access Journals (Sweden)

    Pervatikar Suneet

    2009-04-01

    Full Text Available Mammary hamartomas are uncommon benign lesions rarely associated with malignancy. We report a case of a 25-year-old female patient presenting with a lump in the left breast. Fine needle aspiration cytology showed features of invasive ductal carcinoma along with normal benign glands that were mistaken for normal breast tissue. However, the mastectomy specimen revealed the malignant mass within a larger hamartomatous mass. Mammary hamartomas are benign lesions but, on exceedingly rare occasions, they may be involved by incidental, coexisting carcinoma, as illustrated in this case report.

  13. Mesenchymal hamartoma of the chest wall: prenatal sonographic manifestations.

    Science.gov (United States)

    Wie, Jeong ha; Kim, Ju Yeon; Kwon, Ji Young; Ko, Hyun Sun; Shin, Jong Chul; Park, In Yang

    2013-06-01

    Mesenchymal hamartoma of the chest wall is a rare, benign lesion that arises from one or more ribs, almost exclusively found in infants. Some cases that developed in the fetal period have been reported, but accurate diagnosis was usually possible only after birth, except in a few cases in which fetal magnetic resonance imaging or computed tomography were performed. We present a case of a congenital mesenchymal hamartoma of the chest wall. Although the diagnosis was not confirmed until birth, the prenatal sonographic examination showed strongly suggestive findings. We review the published reports on this condition, and suggest the prenatal sonographic features. Prenatal sonography is valuable in the differential diagnosis of chest mass.

  14. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

  15. Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Fournier, Marcia V.; Fata, Jimmie E.; Martin, Katherine J.; Yaswen, Paul; Bissell, Mina J.

    2009-06-03

    PTEN is a dual function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two non-malignant human mammary epithelial cell lines (HMECs) that form polarized, growth-arrested structures (acini) when cultured in 3-dimensional laminin-rich extracellular matrix gels (3D lrECM). As acini begin to form, PTEN accumulates in both the cytoplasm, and at cell-cell contacts where it colocalizes with E-cadherin/{beta}-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in SKBR3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in 3D lrECM indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus appears to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.

  16. Occult Breast Cancer due to Multiple Calcified Hamartomas in a Patient with Cowden Syndrome

    Directory of Open Access Journals (Sweden)

    E. B. Gómez García

    2012-01-01

    Full Text Available Cowden syndrome (CS is an autosomal dominant disorder characterized by presence of multiple hamartomas, and other benign and malignant abnormalities of the breasts, skin, thyroid, endometrium, gastrointestinal tract, and central nervous system. Hamartomas are benign, developmentally disorganized tumors that can develop in any of the above mentioned organs. The presence of massive calcifications in the breasts in very young women is an indication to perform a breast MRI to exclude a neoplasm since, like in the current case report, presence of breast calcifications may obscure a neoplasm. Although fibrocystic disease and cooccurrence of fibrocystic disease and breast cancer are much more common than CS, the presence of massive calcifications in the breasts of very young women should elicit the possibility of an underlying genetic disease. Furthermore, breast cancer and macrocephaly are considered major criteria for the diagnosis of CS and the combination of both is enough to establish the clinical diagnosis of this entity. Fibrocystic disease of the breasts and multinodular goiter are minor criteria. Family history is also important for the diagnosis of (any hereditary disease.

  17. Computational Analysis of PTEN Gene Mutation

    Directory of Open Access Journals (Sweden)

    Siew-Kien Mah

    2012-01-01

    Full Text Available Post-genomic data can be efficiently analyzed using computational tools. It has the advantage over the biochemical and biophysical methods in term of higher coverage. In this research, we adopted a computational analysis on PTEN gene mutation.  Mutation in PTEN is responsible for many human diseases. The results of this research provide insights into the protein domains of PTEN and the distribution of mutation.

  18. PTEN and p16 genes as epigenetic biomarkers in oral squamous cell carcinoma (OSCC): a study on south Indian population.

    Science.gov (United States)

    Sushma, P S; Jamil, Kaiser; Kumar, P Uday; Satyanarayana, U; Ramakrishna, M; Triveni, B

    2016-06-01

    Phosphatase and tensin homolog (PTEN) and p16INK4a (p16) genes are tumor suppressor genes, associated with epigenetic alterations. PTEN and p16 promoter hypermethylation is a major epigenetic silencing mechanism leading to cancer. The cooperation between PTEN and p16 in pathogenesis of cancers suggest that their combination might be considered as potential molecular marker for specific subgroups of patients. Hence, the present study aimed to investigate whether PTEN and p16 promoter methylations were involved in oral squamous cell carcinoma (OSCC) in south Indian subjects. DNA methylation quantitative analyses of the two candidate tumor suppressor genes PTEN and p16 were performed by methylation-specific polymerase chain reaction (MSP). Fifty OSCC biopsy samples and their corresponding non-malignant portions as controls were studied comparatively. The methylation status was correlated with the clinical manifestations. Twelve out of 50 patients (24 %) were found to be methylated for PTEN gene, whereas methylation of the p16 gene occurred in 19 out of 50 cases (38 %). A statistically significant result was obtained (P = p16 genes. PTEN and p16 promoter methylation may be the main mechanism leading to the low expression of PTEN and p16 genes indicating the progress of tumor development. Our data suggest that a low PTEN and p16 expression due to methylation may contribute to the cancer progression and could be useful for prognosis of OSCC. Therefore, analysis of promoter methylation in such genes may provide a biomarker valuable for early detection of oral cancer.

  19. Role of PTEN in the Tumor Microenvironment

    Science.gov (United States)

    2010-06-01

    Bronisz‐Kowalczyk,Agnieszka M  Research Scientist  Cantemir‐Stone, Carmen  Zenaida  Research Scientist  Chen,Hui‐Zi  Graduate Research Associate  Gurcan,Metin...Trimboli1,2*, Carmen Z. Cantemir-Stone3*, Fu Li1,3*, Julie A. Wallace3, Anand Merchant3, Nicholas Creasap1,2, John C. Thompson1,2, Enrico Caserta1,2, Hui...separation length ‘, one needs to create auto- and cross-histograms at every point in the discrete image plane. There- fore, Monte Carlo methods were used to

  20. Role of PTEN in the Tumor Microenvironment

    Science.gov (United States)

    2009-06-01

    associated with aggressive periodontitis and severe chronic periodontitis in Japanese. Biochem Biophys Res Commun. 317, 887-892. 56. Eckfeld K, Hesson L...Endocrinol Diabetes 114, 371-376. 123. Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF. (2007

  1. Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.

    Directory of Open Access Journals (Sweden)

    Hasan Korkaya

    2009-06-01

    Full Text Available Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells.

  2. Bilateral hamartoma of tonsils bearing ectopic teeth: a case report

    OpenAIRE

    Barman, Debasis; Majumdar, Pallab Kumar; Majumdar, Swapan Kumar

    2003-01-01

    Ectopic teeth presenting in bath the tonsils with hatnartomatous lesion has not been reported earlier. We present here a case of benign hamartoma of both the tonsils bearing 7 teeth in a 13 year old girl and also discuss about unusual Ectopic sites of tooth eruption as well as benign lesions of tonsil.

  3. Loss of PTEN is not associated with poor survival in newly diagnosed glioblastoma patients of the temozolomide era.

    Directory of Open Access Journals (Sweden)

    Christine Carico

    Full Text Available INTRODUCTION: Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. METHODS: Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age, extent of resection, Karnofsky performance scale (KPS, and treatment on overall survival. RESULTS: Sixty-five percent of patients were men with median age of 63 years, and 70% had KPS≥80. Most patients (81% received standard treatment (temozolomide with concurrent radiation. A total of 72 (47% patients had retained PTEN expression. Median overall survival (OS was 19.1 months (95% CI: 15.0-22.5. Median survival of 20.0 months (95% CI: 15.0-25.5 and 18.2 months (95% CI: 13.0-25.7 was observed in PTEN retained and PTEN loss patients, respectively (p = .71. PTEN loss patients were also found to have amplifications of EGFR gene more frequently than patients with retained PTEN (70.8% vs. 47.8%, p = .01. Multivariate analysis showed that older age (HR 1.64, CI: 1.02-2.63, p = .04, low KPS (HR 3.57, CI: 2.20-5.79, p<.0001, and lack of standard treatment (HR 3.98, CI: 2.38-6.65, p<.0001 yielded worse survival. PTEN loss was not prognostic of overall survival (HR 1.31, CI: 0.85-2.03, p = .22. CONCLUSIONS: Loss of expression of PTEN does not confer poor overall survival in the temozolomide era. These findings imply a complex and non-linear molecular relationship between PTEN, its regulators and effectors in the tumorigenesis of glioblastoma. Additionally, there is evidence that temozolomide may be more effective in eradicating GBM cancer cells with PTEN loss and hence, level the outcomes between the PTEN

  4. PTEN enhances G2/M arrest in etoposide-treated MCF‑7 cells through activation of the ATM pathway.

    Science.gov (United States)

    Zhang, Ruopeng; Zhu, Li; Zhang, Lirong; Xu, Anli; Li, Zhengwei; Xu, Yijuan; He, Pei; Wu, Maoqing; Wei, Fengxiang; Wang, Chenhong

    2016-05-01

    As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the contribution of PTEN to the etoposide-induced G2/M cell cycle arrest. PTEN was knocked down in MCF-7 cells by specific shRNA, and the effects of PTEN on the ATM-Chk2 pathway were investigated through various approaches. The results showed that knockdown of PTEN strongly antagonized ATM activation in response to etoposide treatment, and thereby reduced the phosphorylation level of ATM substrates, including H2AX, P53 and Chk2. Furthermore, depletion of PTEN reduced the etoposide-induced phosphorylation of CDC25C and strikingly compromised etoposide-induced G2/M arrest in the MCF-7 cells. Altogether, we demonstrated that PTEN plays a unique role in etoposide-induced G2/M arrest by facilitating the activation of the ATM pathway, and PTEN was required for the proper activation of checkpoints in response to DNA damage in MCF-7 cells.

  5. Tnactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Ye-Jiang Zhou; Yu-Xia Xiong; Xiao-Ting Wu; De Shi; Wei Fan; Tong Zhou; Yue-Chun Li; Xiong Huang

    2004-01-01

    -negative gastric cancer was significantly stronger than that in PTEN-positive gastric cancer (t = 2.61,P<0.05), and there was a significantly negative correlation between the expression of VEGF and PTEN (γ = -0.403,P<0.05).CONCLUSION: Our results imply that inactivation of PTEN gene and over-expression of VEGF contribute to the neovascularization and progression of gastric cancer. PTENrelated angiogenesis might be attributed to its up-regulation of VEGF expression. PTEN and VEGF could be used as the markers reflecting the biologic behaviors of tumor and viable targets in therapeutic approaches to inhibit angiogenesis of gastric cancers.

  6. Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx

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    Karagoz Filiz

    2010-06-01

    Full Text Available Abstract Background The aim of this study was to assess the relationship between expression of vascular endothelial growth factor (VEGF and phosphatase and tensin homolog deleted in chromosome ten (PTEN, angiogenesis and clinicopathological parameters of squamous cell carcinoma of the larynx. Methods We examined immunohistochemical expression of VEGF and PTEN and CD34 for microvessel density (MVD in sections of formalin-fixed, paraffin embedded tissue blocks of 140 patients with squamous cell carcinoma of the larynx. The intensity of VEGF and PTEN staining and the proportion of cells staining were scored. Results The tumor grade was not significantly related to PTEN expression, but it was to VEGF expression (p = 0.400; p = 0.015, respectively. While there was no significant relationship between PTEN expression and tumor size and cartilage invasion (p = 0.311, p = 0.128, there was a significant relationship between the severity of VEGF expression and tumor size (p = 0.006 and lymph node metastasis (p = 0.048 but not cartilage invasion (p = 0.129. MVD was significantly higher in high-grade tumors (p = 0.003 but had no significant relationship between MVD, lymph node metastasis, and cartilage invasion (p = 0.815, p = 0.204. There was also no significant relationship between PTEN and VEGF expression (p = 0.161 and between PTEN and VEGF expression and the MVD (p = 0.120 and p = 0.175, respectively. Conclusions Increased VEGF expression may play an important role in the outcome of squamous cell carcinoma of the larynx. PTEN expression was not related to VEGF expression and clinicopathological features of squamous cell carcinoma of the larynx.

  7. Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer.

    Science.gov (United States)

    Nip, Hannah; Dar, Altaf A; Saini, Sharanjot; Colden, Melissa; Varahram, Shahryari; Chowdhary, Harshika; Yamamura, Soichiro; Mitsui, Yozo; Tanaka, Yuichiro; Kato, Taku; Hashimoto, Yutaka; Shiina, Marisa; Kulkarni, Priyanka; Dasgupta, Pritha; Imai-Sumida, Mitsuho; Tabatabai, Z Laura; Greene, Kirsten; Deng, Guoren; Dahiya, Rajvir; Majid, Shahana

    2016-10-18

    Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Statistical analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy.

  8. Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung-Young; Hong, Chansik; Wie, Jinhong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Kim, Euiyong [Department of Physiology, College of Medicine, Inje University, Busan 614-735 (Korea, Republic of); Kim, Byung Joo [Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870 (Korea, Republic of); Ha, Kotdaji [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Cho, Nam-Hyuk; Kim, In-Gyu [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Jeon, Ju-Hong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); So, Insuk, E-mail: insuk@snu.ac.kr [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)

    2014-04-25

    Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

  9. Conditional Inactivation of Pten with EGFR Overexpression in Schwann Cells Models Sporadic MPNST

    Directory of Open Access Journals (Sweden)

    Vincent W. Keng

    2012-01-01

    Full Text Available The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs remain unclear. It is hypothesized that many genetic changes are involved in transformation. Recently, it has been shown that both phosphatase and tensin homolog (PTEN and epidermal growth factor receptor (EGFR play important roles in the initiation of peripheral nerve sheath tumors (PNSTs. In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, and EGFR was expressed under the control of the 2′,3′-cyclic nucleotide 3′phosphodiesterase (Cnp promoter and a desert hedgehog (Dhh regulatory element driving Cre recombinase transgenic mice (Dhh-Cre. Complete loss of Pten and EGFR overexpression in Schwann cells led to the development of high-grade PNSTs. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. This mouse model can rapidly recapitulate PNST onset and progression to high-grade PNSTs, as seen in sporadic MPNST patients.

  10. Quantitative and dynamic analysis of PTEN phosphorylation by NMR.

    Science.gov (United States)

    Cordier, Florence; Chaffotte, Alain; Wolff, Nicolas

    2015-05-01

    The dual lipid and protein phosphatase PTEN is a tumor suppressor controlling key biological processes, such as cell growth, proliferation and neuro-survival. Its activity and intracellular trafficking is finely regulated notably by multi-site phosphorylation of its C-terminal tail. The reversible and highly dynamic character of these regulatory events confers a temporal dimension to the cell for triggering crucial decisions. In this review, we describe how a recently developed time-resolved NMR spectroscopy approach unveils the dynamic establishment of the phosphorylation events of PTEN C-terminal tail controlled by CK2 and GSK3β kinases. Two cascades of reactions have been identified, in vitro and in extracts of human neuroblastoma cells. They are triggered independently on two nearby clusters of sites (S380-S385 and S361-S370) and occur on different timescales. In each cascade, the reactions follow an ordered model with a distributive kinetic mechanism. The vision of these cascades as two delay timers activating distinct or time-delayed regulatory responses gives a temporal dimension on PTEN regulation and is discussed in relation to the known functional roles of each cluster. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Supratentorial tumors; Supratentorielle Tumoren

    Energy Technology Data Exchange (ETDEWEB)

    Grunwald, I.; Dillmann, K.; Roth, C.; Backens, M.; Reith, W. [Universitaetsklinikum Saarland, Homburg (Germany). Klinik fuer Diagnostische und Interventionelle Neuroradiologie

    2007-06-15

    Magnetic resonance imaging is a routine diagnostic measure for a suspected intracerebral mass. Computed tomography is usually also indicated. Further diagnostic procedures as well as the interpretation of the findings vary depending on the tumor location. This contribution discusses the symptoms and diagnostics for supratentorial tumors separated in relation to their intra- or extracranial location. Supratentorial tumors include astrocytoma, differentiated by their circumscribed and diffuse growth, ganglioglioma, ependyoma, neurocytoma, primitive neuroectodermal tumors (PNET), oligodendroglioma, dysembryoplastic neuroepithelial tumors (DNET), meningoangiomatosis, pineal tumors, hamartoma, lymphoma, craniopharyngeoma and metastases. The supratentorial extracranial tumors include the choroid plexus, colloid cysts, meningeoma, infantile myofibromatosis and lipoma. The most common subforms, especially of astrocytoma, will also be presented. (orig.)

  12. Hypothalamic dysfunction without hamartomas causing gelastic seizures in optic nerve hypoplasia.

    Science.gov (United States)

    Fink, Cassandra; Borchert, Mark; Simon, Carrie Zaslow; Saper, Clifford

    2015-02-01

    This report describes gelastic seizures in patients with optic nerve hypoplasia and hypothalamic dysfunction without hypothalamic hamartoma. All participants (n = 4) from the optic nerve hypoplasia registry study at Children's Hospital Los Angeles presenting with gelastic seizures were included. The clinical and pathology characteristics include hypothalamic dysgenesis and dysfunction, but no hamartomas. Optic nerve hypoplasia is the only reported condition with gelastic seizures without hypothalamic hamartomas, suggesting that hypothalamic disorganization alone can cause gelastic seizures.

  13. Welcoming Treat: Astrocyte-Derived Exosomes Induce PTEN Suppression to Foster Brain Metastasis.

    Science.gov (United States)

    Alečković, Maša; Kang, Yibin

    2015-11-09

    Metastasis to distant organs depends on pathological crosstalk between tumor cells and various tissue-specific stromal components. Zhang and colleagues recently demonstrated that astrocyte-derived exosomal miR-19a reversibly downregulated PTEN expression in cancer cells, thereby increasing their CCL2 secretion and recruitment of myeloid cell to promote brain metastasis.

  14. Small Bowel Hamartoma: A Huge Diverticulum of Small Bowel

    Directory of Open Access Journals (Sweden)

    Hamdi Ebdewi

    2013-01-01

    Full Text Available A-20-year old male, with no significant medical history, presented with clinical features mimicking a perforated acute appendicitis. Because of features of peritonitis, a laparotomy was performed which showed a segment of small bowel with multiple large diverticula and mesenteric cysts. A segmental small bowel resection was performed. The patient made an uneventful recovery from surgery. Histology revealed features of a small bowel hamartoma.

  15. Pulmonary chondroid hamartoma with nontuberculous mycobacterial infection: two case reports.

    Science.gov (United States)

    Lee, Yong Chul; Moon, Jin Chang; Gang, Su Jin; Park, Seung Yong; Kim, So Ri

    2015-04-01

    Solitary pulmonary nodules (SPNs) can be manifested in a variety of disorders including neoplasms, infection, inflammation, and vascular or congenital abnormalities. In addition, they are often accompanied with other pulmonary pathologic lesions such as consolidations and several pulmonary disorders present as similar pulmonary nodular lesions simultaneously. Diagnostic workup is important for these SPNs; however, many physicians often miss the second diagnosis for multiple pulmonary lesions with SPNs due to lack of clinical suspicion that each pulmonary nodule or pathologic lesion can have each other's diagnosis. Herein, we report 2 cases of coexistence of pulmonary chondroid hamartoma with nontuberculous mycobacterial (NTM) infection presenting as pulmonary nodules and multiple consolidative lesions. A 60-year-old man was admitted for the evaluation of multifocal pulmonary lesions including SPN with chronic exertional dyspnea. Multiple lung tissues were obtained from each lesion through percutaneous transthoracic needle biopsy (PTNB). At the same time, bacteriologic examination was performed using respiratory samples obtained by bronchoscopy. Based on pathologic and microbiologic results, the patient diagnosed as pulmonary chondroid hamartoma with pulmonary NTM infectious disease. In addition, a 56-year-old woman visited for the evaluation of a small SPN. The SPN was resected surgically for the pathologic examination and turned out to be pulmonary chondroid hamartoma. Interestingly, the diagnostic workup revealed that the patient had Lady Windermere syndrome which is one of features for Mycobacterium avium complex (MAC) pulmonary disease. Both patients were treated with the standard antibiotics against MAC as recommended by the ATS/IDSA guideline. This is the first report of 2 patients, as far as we know, that chondroid hamartoma and NTM disease develop simultaneously in the lung. This report emphasizes that physicians should endeavor to confirm the individual

  16. Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes.

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    Brian F Niemeyer

    Full Text Available Ewing Sarcoma is an aggressive malignancy of bone and soft tissue affecting children and young adults. Ewing Sarcoma is driven by EWS/Ets fusion oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent tumor suppressor, is lost in a subset of Ewing Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of Ewing Sarcoma cells to the microtubule inhibitor vincristine, a relevant chemotherapeutic agent in this cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in Ewing Sarcoma, with potential clinical implications.

  17. Cancer Prognosis Defined by the Combined Analysis of 8q, PTEN and ERG

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    Maria P. Silva

    2016-12-01

    Full Text Available Overtreatment is a major concern in men diagnosed with prostate cancer. The aim of this study was to evaluate the combined prognostic role of three frequent molecular alterations in prostate cancer, namely relative 8q gain, ERG overexpression, and loss of PTEN expression, in a series of 136 patients with prostate cancer treated with prostatectomy and with a long follow-up. Fluorescent in situ hybridization was used to detect the relative copy number of 8q and immunohistochemistry was used for quantitative assessment of ERG and PTEN expression. During a median follow-up period of 117.8 months, 66 (49% patients had disease recurrence. Relative 8q gain, ERG overexpression, and loss of PTEN expression were observed in 18%, 56%, and 33% of the cases, respectively. No association with patient recurrence-free survival was found for relative 8q gain or ERG overexpression on their own, whereas loss of PTEN expression was associated with worse recurrence-free survival (P = .006. Interestingly, in the subgroup of patients with normal PTEN expression, we found that the combined relative 8q gain/ERG overexpression is associated with high risk of recurrence (P = .008, suggesting that alternative mechanisms exist for progression into clinically aggressive disease. Additionally, in intermediate-risk patients with normal PTEN expression in their tumors, the combination of 8q gain/ERG overexpression was associated with a poor recurrence-free survival (P < .001, thus indicating independent prognostic value. This study shows that the combined analysis of 8q, ERG and PTEN contributes to an improved clinical outcome stratification of prostate cancer patients treated with radical prostatectomy.

  18. Congenital smooth muscle hamartoma of the palpebral conjunctiva.

    Science.gov (United States)

    Mora, L Evelyn; Rodríguez-Reyes, Abelardo A; Vera, Ana M; Rubio, Rosa Isela; Mayorquín-Ruiz, Mariana; Salcedo, Guillermo

    2012-01-01

    Smooth muscle hamartoma is defined as a disorganized focus or an overgrowth of mature smooth muscle, generally with low capacity of autonomous growth and benign behavior. The implicated tissues are mature and proliferate in a disorganized fashion. A healthy 5-day-old Mexican boy was referred to the authors' hospital in México city for evaluation of a "cystic" lesion of the right eye that had been noted since birth. The pregnancy and delivery were unremarkable. On physical examination, there was a reddish-pink soft lesion with a tender "cystic" appearance, which was probably emerging from the upper eyelid conjunctiva, which measured 2.7 cm in its widest diameter and transilluminated. Ultrasound imaging revealed an anterior "cystic" lesion with normally formed phakic eye. An excisional biopsy was performed, and the lesion was dissected from the upper tarsal subconjunctival space. Subsequent histologic and immunohistochemical findings were consistent with the diagnosis of congenital smooth muscle hamartoma (CSMH) of the tarsal conjunctiva. The authors' research revealed that only one case of CSMH localized in the conjunctiva (Roper GJ, Smith MS, Lueder GT. Congenital smooth muscle hamartoma of the conjunctival fornix. Am J Ophthalmol. 1999;128:643-4) has been reported to date in the literature. To the best of the authors' knowledge, this current case would be the second case reported of CSMH in this anatomic location. Therefore, the authors' recommendation is to include CSMH in the differential diagnosis of a cystic mass that presents in the fornix and palpebral conjunctiva.

  19. PTEN in liver diseases and cancer

    Institute of Scientific and Technical Information of China (English)

    Marion; Peyrou; Lucie; Bourgoin; Michelangelo; Foti

    2010-01-01

    The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt axis is a key signal transduction node that regulates crucial cellular functions, including insulin and other growth factors signaling, lipid and glucose metabolism, as well as cell survival and apoptosis. In this pathway, PTEN acts as a phosphoinositide phosphatase, which terminates PI3Kpropagated signaling by dephosphorylating PtdIns(3,4)P2 and PtdIns(3,4,5)P3. However, the role of PTEN does not appear to be restricted only to ...

  20. Preclinical Remodeling of Human Prostate Cancer through the PTEN/AKT Pathway

    Directory of Open Access Journals (Sweden)

    Marco A. De Velasco

    2012-01-01

    Full Text Available Knowledge gained from the identification of genetic and epigenetic alterations that contribute to the progression of prostate cancer in humans is now being implemented in the development of functionally relevant translational models. GEM (genetically modified mouse models are being developed to incorporate the same molecular defects associated with human prostate cancer. Haploinsufficiency is common in prostate cancer and homozygous loss of PTEN is strongly correlated with advanced disease. In this paper, we discuss the evolution of the PTEN knockout mouse and the cooperation between PTEN and other genetic alterations in tumor development and progression. Additionally, we will outline key points that make these models key players in the development of personalized medicine, as potential tools for target and biomarker development and validation as well as models for drug discovery.

  1. Parenchimatous lung hamartoma in 42-year-old woman Hamartoma pulmonar parenquimatoso en mujer de 42 años

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    Caridad Socorro Castro

    Full Text Available The pulmonary hamartoma, described in 1904, is presented as a mass of 3 cm of diameter and endobronchial or parenchymatous location. The lesion is registered in men two or three times more than in women, and is diagnosed generally over 60 years of age, always casually or appears in necropsies. A non frequent case of this disease is reported in a 42 year old woman. The macro-microscopic frame of the studied biopsic specimen is described, as well as its clinical conditions.

    El hamartoma pulmonar, descrito en 1904, se presenta como masa de hasta 3 cm de diámetro con ubicación endobronquial o parenquimatosa. La lesión se registra en hombres 2 a 4 veces más que en mujeres y se diagnostica por lo general sobre los 60 años de edad, siempre de forma casual o aparece como hallazgo en las necropsias. Se reporta un caso poco frecuente de hamartoma pulmonar parenquimatoso en una mujer de 42 años de edad. Se describe el cuadro macro-microscópico del espécimen biópsico estudiado, así como sus condicionales clínicas.

  2. PTEN sequence analysis in endometrial hyperplasia and endometrial carcinoma in Slovak women.

    Science.gov (United States)

    Gbelcová, H; Bakeš, P; Priščáková, P; Šišovský, V; Hojsíková, I; Straka, Ľ; Konečný, M; Markus, J; D'Acunto, C W; Ruml, T; Böhmer, D; Danihel, Ľ; Repiská, V

    2015-01-01

    Phosphatase and tensin homolog (PTEN) is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa). ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3), complex hyperplasia (5), atypical complex hyperplasia (7), endometrioid carcinomas G1 (20) and G3 (5), and serous carcinoma (5) were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

  3. PTEN Gene and Prostate Cancer%PTEN基因与前列腺癌

    Institute of Scientific and Technical Information of China (English)

    孙健玮(综述); 王剑松(审校)

    2013-01-01

    The deletion of tumor suppressor gene PTEN's expression was familiar in many tumors, including prostate cancer. The guide would be given in the diagnosis, therapy and prognosis of prostate cancer by studying about PTEN's tumor suppression mechanism and relation with expression deletion. This review makes an overview focusing on the recent progress of PTEN's structure, function, expression deletion, and the correlation between PTEN and prostate cancer.%抑癌基因PTEN的表达缺失多见于包括前列腺癌在内的多种散发性肿瘤,对其抑癌机制以及表达缺失所导致的肿瘤发生发展机理的研究,将为前列腺癌的诊断、治疗以及预后判断提供指导。就PTEN基因的结构、作用机制、表达缺失及其与前列腺癌发病相关的研究进展作一综述。

  4. PTEN Sequence Analysis in Endometrial Hyperplasia and Endometrial Carcinoma in Slovak Women

    Directory of Open Access Journals (Sweden)

    H. Gbelcová

    2015-01-01

    Full Text Available Phosphatase and tensin homolog (PTEN is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa. ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3, complex hyperplasia (5, atypical complex hyperplasia (7, endometrioid carcinomas G1 (20 and G3 (5, and serous carcinoma (5 were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

  5. Pten Regulates Epithelial Cytodifferentiation during Prostate Development

    DEFF Research Database (Denmark)

    Lokody, Isabel B; Francis, Jeffrey C; Gardiner, Jennifer R;

    2015-01-01

    Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic...... deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses...... that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study...

  6. Gene expression analysis of PTEN positive glioblastoma stem cells identifies DUB3 and Wee1 modulation in a cell differentiation model.

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    Stefano Forte

    Full Text Available The term astrocytoma defines a quite heterogeneous group of neoplastic diseases that collectively represent the most frequent brain tumors in humans. Among them, glioblastoma multiforme represents the most malignant form and its associated prognosis is one of the poorest among tumors of the central nervous system. It has been demonstrated that a small population of tumor cells, isolated from the brain neoplastic tissue, can reproduce the parental tumor when transplanted in immunodeficient mouse. These tumor initiating cells are supposed to be involved in cancer development and progression and possess stem cell-like features; like their normal counterpart, these cells remain quiescent until they are committed to differentiation. Many studies have shown that the role of the tumor suppressor protein PTEN in cell cycle progression is fundamental for tumor dynamics: in low grade gliomas, PTEN contributes to maintain cells in G1 while the loss of its activity is frequently observed in high grade gliomas. The mechanisms underlying the above described PTEN activity have been studied in many tumors, but those involved in the maintenance of tumor initiating cells quiescence remain to be investigated in more detail. The aim of the present study is to shed light on the role of PTEN pathway on cell cycle regulation in Glioblastoma stem cells, through a cell differentiation model. Our results suggest the existence of a molecular mechanism, that involves DUB3 and WEE1 gene products in the regulation of Cdc25a, as functional effector of the PTEN/Akt pathway.

  7. Pten Regulates Epithelial Cytodifferentiation during Prostate Development.

    Directory of Open Access Journals (Sweden)

    Isabel B Lokody

    Full Text Available Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses, abnormal luminal cells fill the ductal lumens together with augmented epithelial proliferation. This phenotype resembles the hyperplasia seen in postnatal Pten deletion models that develop neoplasia at later stages. Consistent with this, gene expression analysis showed a number of genes affected that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study provides novel insight into the role of Pten in prostate development as part of the process of coordinating the differentiation and proliferation of cell types in time and space to form a functional organ.

  8. Pten Regulates Epithelial Cytodifferentiation during Prostate Development

    Science.gov (United States)

    Lokody, Isabel B.; Francis, Jeffrey C.; Gardiner, Jennifer R.; Erler, Janine T.; Swain, Amanda

    2015-01-01

    Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses, abnormal luminal cells fill the ductal lumens together with augmented epithelial proliferation. This phenotype resembles the hyperplasia seen in postnatal Pten deletion models that develop neoplasia at later stages. Consistent with this, gene expression analysis showed a number of genes affected that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study provides novel insight into the role of Pten in prostate development as part of the process of coordinating the differentiation and proliferation of cell types in time and space to form a functional organ. PMID:26076167

  9. An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

    2008-05-06

    Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

  10. PTEN insufficiency modulates ER+ breast cancer cell cycle progression and increases cell growth in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Chiang KC

    2015-08-01

    Full Text Available Kun-Chun Chiang,1,4 Huang-Yang Chen,1 Shu-Yuan Hsu,2 Jong-Hwei S Pang,3 Shang-Yu Wang,4 Jun-Te Hsu,4 Ta-Sen Yeh,4 Li-Wei Chen,5 Sheng-Fong Kuo,6 Chi-Chin Sun,7 Jim-Ming Lee,1 Chun-Nan Yeh,4 Horng-Heng Juang21Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, Keelung, 2Department of Anatomy, 3Graduate Institute of Clinical Medical Sciences, 4Department of General Surgery, 5Department of Gastroenterology, 6Department of Endocrinology and Metabolism, 7Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, Republic of China Abstract: Phosphatase and tensin homolog (PTEN, a well-known tumor suppressor gene and frequently mutated or lost in breast cancer, possesses the negative regulation function over the PI3K/Akt/mTOR pathway. PTEN insufficiency has been associated with advanced breast cancer and poor prognosis of breast cancer patients. Recently, target therapies aimed at PI3K/Akt/mTOR pathway to treat breast cancer have got popularity. However, the exact effect of PTEN on breast cancer cells is still not well understood. This study demonstrated that PTEN knockdown in MCF-7 cells strengthened the downstream gene expressions, including p-Akt, p-ERK1/2, p-mTOR, p-p70s6k, and p-GSK3ß. PTEN knockdown MCF-7 cells had increased cell growth and Ki-67 expression. Further Western blot demonstrated that p27 was repressed obviously with p21 slightly inhibited and CDK1, 2, 4, 6, cyclin A, and Cdc25C were upregulated in MCF-7 PTEN knockdown cells, leading to the higher growth rate. More importantly, PTEN knockdown MCF-7 cells had higher tumorigenesis and tumor growth in vivo. From our current work, we provided more detailed PTEN-mediated mechanisms to stimulate ER+ breast cancer cell growth. Our result may pave the way for further target therapy development used alone or in combination with other drugs for ER+ breast cancer with PTEN insufficiency.Keywords: PTEN, breast cancer, MCF-7

  11. Plumbagin Inhibits Prostate Carcinogenesis in Intact and Castrated PTEN Knockout Mice via Targeting PKCε, Stat3, and Epithelial-to-Mesenchymal Transition Markers.

    Science.gov (United States)

    Hafeez, Bilal Bin; Fischer, Joseph W; Singh, Ashok; Zhong, Weixiong; Mustafa, Ala; Meske, Louise; Sheikhani, Mohammad Ozair; Verma, Ajit Kumar

    2015-05-01

    Prostate cancer continues to remain the most common cancer and the second leading cause of cancer-related deaths in American males. The Pten deletions and/or mutations are frequently observed in both primary prostate cancers and metastatic prostate tissue samples. Pten deletion in prostate epithelium in mice results in prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma. The Pten conditional knockout mice [(Pten-loxp/loxp:PB-Cre4(+)) (Pten-KO)] provide a unique preclinical model to evaluate agents for efficacy for both the prevention and treatment of prostate cancer. We present here for the first time that dietary plumbagin, a medicinal plant-derived naphthoquinone (200 or 500 ppm) inhibits tumor development in intact as well as castrated Pten-KO mice. Plumbagin has shown no signs of toxicity at either of these doses. Plumbagin treatment resulted in a decrease expression of PKCε, AKT, Stat3, and COX2 compared with the control mice. Plumbagin treatment also inhibited the expression of vimentin and slug, the markers of epithelial-to-mesenchymal transition (EMT) in prostate tumors. In summary, the results indicate that dietary plumbagin inhibits growth of both primary and castration-resistant prostate cancer (CRPC) in Pten-KO mice, possibly via inhibition of PKCε, Stat3, AKT, and EMT markers (vimentin and slug), which are linked to the induction and progression of prostate cancer.

  12. mRNA EXPRESSION OF PTEN AND VEGF GENES IN EPITHELIAL OVARIAN CANCER

    Institute of Scientific and Technical Information of China (English)

    陈颖; 赵雨杰; 郑华川; 杨雪飞; 汪桂兰; 辛彦

    2003-01-01

    Objective: To investigate the mRNA expression of PTEN and vascular endothelial growth factor (VEGF) genes in ovarian cancer. Methods:We examined mRNA expression of PTEN and VEGF165 in normal ovary (n=5), ovarian cyst (n=5), ovarian borderline tumor (n=9), epithelial ovarian cancer (n=60) and ovarian cancer cell line (CAOV-3) by RT-PCR. Their expressions were compared with clinicopathological features of ovarian cancer. The relationship between their expressions was concerned in all ovarian samples as well. Results:mRNA expression level of PTEN gene was significantly lower in ovarian borderline tumor or ovarian cancer than that in normal ovary or ovarian cyst(P<0.05). It was negatively correlated with clinicopathological staging(P<0.05),whereas positively with histological differentiation (P<0.05). mRNA expression level of PTEN gene was significantly lower in ovarian endometrioid cancer than ovarian serous or mucinous cancer(P<0.05). mRNA expression level of VEGF165 gene was significantly higher in ovarian cancer than that in normal ovary or ovarian cyst(P<0.05). It was positively correlated with clinicopathological staging(P<0.05), whereas negatively with histological differentiation (P<0.05). mRNA expression level of VEGF165 gene was significantly higher in ovarian serous cancer than in other ovarian epithelial cancers (P<0.05). mRNA expression of VEGF165 gene was inversely correlated with mRNA expression level of PTEN gene. Conclusion:Down-regulated expression of PTEN and up-regulated expression of VEGF were considered as two important events in tumorigenesis of ovarian cancer and could be used as molecular markers to indicate the pathobiological behaviors of ovarian cancer. Decreased PTEN expression and increased VEGF expression were closely associated with tumorigenesis and pathobiological behaviors of ovarian endometrioid and serous cancer respectively. Reduced expression of PTEN gene might be involved in carcinogenesis and progression of ovarian cancer by

  13. Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN.

    Directory of Open Access Journals (Sweden)

    Patricia Kreis

    Full Text Available Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN. However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus--serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.

  14. Role of PTEN in TNFα induced insulin resistance

    Energy Technology Data Exchange (ETDEWEB)

    Bulger, David A. [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Wellcome Trust Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ (United Kingdom); National Institute of Diabetes & Digestive & Kidney Disease, National Institutes of Health, Bethesda, MD 20892 (United States); Conley, Jermaine [Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Conner, Spencer H.; Majumdar, Gipsy [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Solomon, Solomon S., E-mail: ssolomon@uthsc.edu [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States)

    2015-06-05

    Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2.

  15. Congenital systematized basaloid follicular hamartoma with microphthalmia and hemimegalencephaly.

    Science.gov (United States)

    Boccaletti, Valeria; Accorsi, Patrizia; Pinelli, Lorenzo; Ungari, Marco; Giordano, Lucio; Neri, Iria; De Panfilis, Giuseppe

    2011-01-01

    The lines of Blaschko are a cutaneous pattern of mosaicism present in a variety of skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are sometimes associated. Here, we describe a 5-year-old boy with basaloid follicular hamartoma affecting the left side of the body in linear multiple bands, following Blaschko lines. Lesions were predominantly hypopigmented macules and streaks, but among these, we could observe brownish atrophic patches and brown papules. Furthermore, ipsilateral hemimegaloencephaly and microphthalmia were present. These findings suggest a neurocutaneous condition recently described by Happle and Tinschert. Its nosologic classification will be discussed. © 2010 Wiley Periodicals, Inc.

  16. A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

    Science.gov (United States)

    Fernández, S; Genis, L; Torres-Alemán, I

    2014-08-07

    Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

  17. Relationship between the expression of tumor suppressor gene PTEN and the metastasis of colorectal cancer%抑癌基因PTEN与人大肠癌转移的相关性研究

    Institute of Scientific and Technical Information of China (English)

    郑国宝; 王元和; 高春芳; 王红阳; 万兴旺

    2003-01-01

    目的探讨抑癌基因PTEN的表达在大肠癌转移侵袭过程中的作用.方法 (1)应用Nothern blot和免疫组织化学的方法检测47例大肠癌组织中PTEN mRNA和蛋白的表达,分析其与大肠癌转移的关系.(2)利用Western blot法检测不同转移潜能的大肠癌细胞系内PTEN蛋白的表达水平,说明PTEN蛋白的表达对大肠癌细胞转移潜能的影响.(3)用阳离子脂质体作载体,将PTEN基因转染大肠癌细胞株LOVO后,采用计数细胞悬液加到粘附底物后20和120min的细胞贴壁数用以测定细胞粘附能力,采用Costar的浸润小室检测PTEN基因转染前后细胞的浸润能力.结果 (1)在有淋巴结及远处转移的大肠癌组织中,PTEN mRNA和蛋白的表达显著低于无转移者;(2)转移潜能高的LOVO细胞PTEN的表达量通过显著低于转移潜能较低的HT-29、LS-174T;(3)LOVO、转染pcDNA3.0-PTEN的细胞(LOVO/pcDNA3.0-PTEN)在特异性粘附底物(Laminin)上20min时贴壁率分别为(18.6±1.4)%和(13.9±0.5)%(P<0.05),120min时贴壁率分别为(71.2±2.5)%和(56.0±1.6)%(P<0.05);(4)采用Costar的浸润小室对LOVO、LOVO/pcDNA3.0-PTEN细胞的浸润能力分析结果显示:细胞悬液静置培养6h后,对照细胞LOVO浸润穿透多聚碳膜的细胞数为(11.7±1.7)个,LOVO/pcDNA3.0-PTEN细胞穿透多聚碳膜的细胞数为(7.5±1.6)个(P<0.05).结论在肿瘤组织内抑癌基因PTEN的表达与大肠癌的转移侵袭行为密切相关.

  18. Loss of PTEN Is Associated with Aggressive Behavior in ERG-Positive Prostate Cancer

    Science.gov (United States)

    Leinonen, Katri A.; Saramäki, Outi R.; Furusato, Bungo; Kimura, Takahiro; Takahashi, Hiroyuki; Egawa, Shin; Suzuki, Hiroyoshi; Keiger, Kerri; Hahm, Sung Ho; Isaacs, William B.; Tolonen, Teemu T.; Stenman, Ulf-Håkan; Tammela, Teuvo L.J.; Nykter, Matti; Bova, G. Steven; Visakorpi, Tapio

    2014-01-01

    Background The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. Methods The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. Results ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. Conclusions A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. Impact Interaction of PTEN and ERG pathways warrants further studies. PMID:24083995

  19. Broccoli, PTEN deletion and prostate cancer: where is the link?

    Directory of Open Access Journals (Sweden)

    Bardelli Alberto

    2010-12-01

    Full Text Available Abstract The concept that vegetables and fruits are relevant sources of cancer-preventive substances is strongly supported by population studies. Among others, cruciferous vegetables like broccoli, cabbage, cauliflower and Brussels sprouts are thought to affect the development of various types of cancers and especially prostate tumors. Yet, the identification of the molecular mechanisms by which the 'active' compounds contained in these vegetables mediate their anticancer activity has historically lagged behind. Accordingly, direct laboratory evidence of how individual nutrients affect cancer genes and the pathways they control remains the major obstacle to progress in this research field. Here we review a recent report investigating the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, and expression of the PTEN tumor suppressor gene in pre malignant prostate tissue.

  20. Inhibition of transfected PTEN on human colon cancer

    Institute of Scientific and Technical Information of China (English)

    Shou-Shui Xu; Wen-Lu Shen; Song-Ying Ouyang

    2004-01-01

    AIM: To study the inhibitory effect of transfected PTEN on LoVo cells.METHODS: Human PTEN cDNA was transferred into LoVo cells via lipofectin and PTEN mRNA levels and its expression were analyzed by Western blot and flow cytometry. Before or after transfection, the effects of 5-Fu on inhibiting cell proliferation and inducing apoptosis were measured by flow cytometry, DNA bands and MTT.RESULTS: PTEN transfection significantly up-regulated PTEN expression in LoVo cells. 5-Fu inhibited cell proliferation and induced apoptosis in transfected LoVo cells.CONCLUSION: Transfected PTEN can remark ably up-regulate PTEN expression in LoVo cells and promote the apoptosis.PTEN transfection is associated with 5-Fu treatment effect and has a cooperatively cytotoxic effect.

  1. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  2. Disease: H00539 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available C566636 C567337 OMIM: 158350 153480 176920 PMID:19668082 (description, gene) Hobert JA, Eng C PTEN hamartoma tumor syndrome: an overv...iew. Genet Med 11:687-94 (2009) PMID:12938083 (descripti

  3. Adult Mesenchymal Hamartoma of the Liver: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Zachary Klaassen

    2010-03-01

    Full Text Available Mesenchymal hamartoma of the liver (MHL is a rare benign lesion occurring primarily in the pediatric population. While the precise pathogenesis of the tumor is not certain, the most common theory relates to aberrant mesenchyme development in the portal tract likely related to the bile ducts. A 53-year-old female was evaluated for an incidental liver mass. Initial CT scan showed a cystic lesion in the right lobe of the liver and follow-up imaging revealed an increase in size and the percent solid component within the mass. In view of these changes, a nondiagnostic biopsy was obtained followed by extirpation of the lesion. Gross pathological review of the lesion identified a 9 × 9 × 7.5 cm, pink-yellow-tan, gelatinous mass, with a >1 cm clear surgical margin. Histologically, the mass consisted of benign dilated bile ducts, as well as myxoid stroma with spindle cells showing smooth muscle differentiation. The patient was discharged home on postoperative day five. A review of the literature for MHL in adults reports 30 previous cases, predominantly published as individual case reports describing the size, lobe(s of the liver affected, and the cystic/solid nature of the tumor. MHL in adults may represent a potentially premalignant lesion, as the emerging literature supports a potential relationship between MHL and malignant undifferentiated embryonal sarcoma in regards to cytogenetic analysis. Aggressive surgical management of MHL in adults is mandated when feasible.

  4. Can we accurately report PTEN status in advanced colorectal cancer?

    OpenAIRE

    Hocking, Christopher; Hardingham, Jennifer E.; Broadbridge, Vy; Wrin, Joe; Townsend, Amanda R; Tebbutt, Niall; Cooper, John; Ruszkiewicz, Andrew; Lee, Chee; Price, Timothy J.

    2014-01-01

    Background Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results. Methods We assessed loss of PTEN function in 51 colorectal cancer ...

  5. EXPRESSION AND SIGNIFICANCE OF PTEN IN ENDOMETRIAL CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    GE Xiu-jun; LIU Zhi-hui; LI Ying-yong; Gao Rui-ping

    2005-01-01

    Objective: To investigate the expression of PTEN in endometrial carcinoma and its clinical significance. Methods: Reverse transcriptase-polymerase chain reaction and Western-blot methods were used to detect PTEN expression in 28 cases of endometrial carcinoma. Results: mRNA and protein expression levels of PTEN in endometrial carcinomas were significantly lower than those in normal endometrium (P<0.01). Conclusion: PTEN may play an important role in the tumorigenesis of endometrial carcinoma.

  6. PTEN regulates colorectal epithelial apoptosis through Cdc42 signalling

    OpenAIRE

    Deevi, R; A. Fatehullah; Jagan, I; Nagaraju, M; Bingham, V; Campbell, F C

    2011-01-01

    Background: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulation of the Rho-like GTPase Cdc42 has a central role in epithelial polarised growth, but effects of this molecular network on apoptosis remain unclear. Methods: To investigate the role of Cdc42 in PTEN-dependent cell death, we used flow cytometry, in vitro pull-down assays, poly(ADP ribose) polymerase (PARP) cleavage and other immunoblots in isogenic PTEN-expressing and -deficient colorectal cells (HCT116PTEN+/...

  7. PTEN mosaicism with features of Cowden syndrome.

    Science.gov (United States)

    Gammon, A; Jasperson, K; Pilarski, R; Prior, Tw; Kuwada, S

    2013-12-01

    We present the first known case of somatic PTEN mosaicism causing features of Cowden syndrome (CS) and inheritance in the subsequent generation. A 20-year-old woman presented for genetics evaluation with multiple ganglioneuromas of the colon. On examination, she was found to have a thyroid goiter, macrocephaly, and tongue papules, all suggestive of CS. However, her reported family history was not suspicious for CS. A deleterious PTEN mutation was identified in blood lymphocytes, 966A>G, 967delA. Genetic testing was recommended for her parents. Her 48-year-old father was referred for evaluation and was found to have macrocephaly and a history of Hashimoto's thyroiditis, but no other features of CS. Site-specific genetic testing carried out on blood lymphocytes showed mosaicism for the same PTEN mutation identified in his daughter. Identifying PTEN mosaicism in the proband's father had significant implications for the risk assessment/genetic testing plan for the rest of his family. His result also provides impetus for somatic mosaicism in a parent to be considered when a de novo PTEN mutation is suspected.

  8. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer.

    Science.gov (United States)

    Chaux, Alcides; Peskoe, Sarah B; Gonzalez-Roibon, Nilda; Schultz, Luciana; Albadine, Roula; Hicks, Jessica; De Marzo, Angelo M; Platz, Elizabeth A; Netto, George J

    2012-11-01

    PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most frequently lost tumor suppressor genes in human cancers and it has been described in more than two-thirds of patients with advanced/aggressive prostate cancer. Previous studies suggest that, in prostate cancer, genomic PTEN loss is associated with tumor progression and poor prognosis. Thus, we evaluated whether immunohistochemical PTEN expression in prostate cancer glands was associated with higher risk of recurrence, using a nested case-control study that included 451 men who recurred and 451 men who did not recur with clinically localized prostate cancer treated by radical prostatectomy. Recurrence was defined as biochemical recurrence (serum prostate-specific antigen >0.2 ng/ml) or clinical recurrence (local recurrence, systemic metastases, or prostate cancer-related death). Cases and controls were matched on pathological T stage, Gleason score, race/ethnicity, and age at surgery. Odds ratios of recurrence and 95% confidence intervals were estimated using conditional logistic regression to account for the matching factors and to adjust for year of surgery, preoperative prostate-specific antigen concentrations, and status of surgical margins. Men who recurred had a higher proportion of PTEN negative expression (16 vs 11%, P=0.05) and PTEN loss (40 vs 31%, P=0.02) than controls. Men with markedly decreased PTEN staining had a higher risk of recurrence (odds ratio=1.67; 95% confidence intervals 1.09, 2.57; P=0.02) when compared with all other men. In summary, in patients with clinically localized prostate cancer treated by prostatectomy, decreased PTEN expression was associated with an increased risk of recurrence, independent of known clinicopathological factors.

  9. PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation

    OpenAIRE

    2010-01-01

    The tumor suppressors phosphatase and tensin homologue deleted on chromosome ten (PTEN) and p53 are closely related to the pathogenesis of breast cancer, yet pathway-specific mechanisms underlying their participation in mediating the protective actions of dietary bioactive components on breast cancer risk are poorly understood. We recently showed that dietary exposure to the soy isoflavone genistein (GEN) induced PTEN expression in mammary epithelial cells in vivo and in vitro, consistent wit...

  10. Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene

    Science.gov (United States)

    Lyu, Xiaoming; Jiang, Qiang; Wang, Jianguo; Lu, Juan; Yao, Kaitai; Liu, Kunping; Li, Jinbang; Li, Xin

    2016-01-01

    Phosphatase and tensin homolog (PTEN) is a major tumor suppressor and usually silenced via the deletion, insertion and mutation. We previously discovered its inactivation via aberrant CpG island methylation. Here, we provide further evidence that EBV latent membrane protein 1(LMP1) can induce a higher intensity of DNA methylation at PTEN CpG islands, inactivating PTEN at the cellular and molecular level. Initially, increased methylation intensity of PTEN CpG islands was observed in EBV-infected nasopharyngeal carcinoma (NPC) cells, accompanied by decreased PTEN expression. In NPC tissue samples showing the methylation at PTEN promoter, LMP1 was highly expressed in higher methylation intensity group relative to lower intensity group, and DNA methyltransferase 3b (DNMT3b) expression was positively correlated with LMP1 expression. Moreover, transfection of LMP1 gene into EBV-negative NPC cells demonstrated that LMP1 up-regulated DNMT3b expression, leading to a higher intensity of PTEN CpG island methylation. Mechanistically, computational prediction and luciferase reporter assay identified a functional NF-κB binding site on DNMT3b promoter and the mutated NF-κB binding site abolished LMP1-mediated DNMT3b activation. Chromatin immunoprecipitation displayed that NF-κB p65 subunit constitutively bound to DNMT3b promoter, supporting the activation of DNMT3b by EBV LMP1 via NF-κB signaling. Furthermore, the expression level of DNMT3b was observed to be increased in the nuclei of LMP1-expressing NPC cells, and a NF-κB inhibitor, PDTC, counteracted LMP1-mediated DNMT3b overexpression. Thus, this study first reports that LMP1-mediated NF-κB can up-regulate DNMT3b transcription, thereby leading to relatively higher methylation intensity at PTEN CpG islands, and ultimately silencing major tumor suppressor PTEN. PMID:27223069

  11. Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene.

    Science.gov (United States)

    Peng, Hong; Chen, Yuxiang; Gong, Pinggui; Cai, Longmei; Lyu, Xiaoming; Jiang, Qiang; Wang, Jianguo; Lu, Juan; Yao, Kaitai; Liu, Kunping; Li, Jinbang; Li, Xin

    2016-06-28

    Phosphatase and tensin homolog (PTEN) is a major tumor suppressor and usually silenced via the deletion, insertion and mutation. We previously discovered its inactivation via aberrant CpG island methylation. Here, we provide further evidence that EBV latent membrane protein 1(LMP1) can induce a higher intensity of DNA methylation at PTEN CpG islands, inactivating PTEN at the cellular and molecular level. Initially, increased methylation intensity of PTEN CpG islands was observed in EBV-infected nasopharyngeal carcinoma (NPC) cells, accompanied by decreased PTEN expression. In NPC tissue samples showing the methylation at PTEN promoter, LMP1 was highly expressed in higher methylation intensity group relative to lower intensity group, and DNA methyltransferase 3b (DNMT3b) expression was positively correlated with LMP1 expression. Moreover, transfection of LMP1 gene into EBV-negative NPC cells demonstrated that LMP1 up-regulated DNMT3b expression, leading to a higher intensity of PTEN CpG island methylation. Mechanistically, computational prediction and luciferase reporter assay identified a functional NF-κB binding site on DNMT3b promoter and the mutated NF-κB binding site abolished LMP1-mediated DNMT3b activation. Chromatin immunoprecipitation displayed that NF-κB p65 subunit constitutively bound to DNMT3b promoter, supporting the activation of DNMT3b by EBV LMP1 via NF-κB signaling. Furthermore, the expression level of DNMT3b was observed to be increased in the nuclei of LMP1-expressing NPC cells, and a NF-κB inhibitor, PDTC, counteracted LMP1-mediated DNMT3b overexpression. Thus, this study first reports that LMP1-mediated NF-κB can up-regulate DNMT3b transcription, thereby leading to relatively higher methylation intensity at PTEN CpG islands, and ultimately silencing major tumor suppressor PTEN.

  12. 骨肉中PTEN蛋白表达及临床意义的研究%Expression and clinical significance of PTEN protein in osteosarcoma

    Institute of Scientific and Technical Information of China (English)

    Yubin Wang; Anmin Chen; Fengjin Guo; Yujun Xia

    2008-01-01

    Objective:To investigate the expression and significance of cancer inhibitory gene PTEN protein in osteosarcoma.To analyze the level of its expression in different histological classification of osteosarcoma.To determine the possibility of taking PTEN protein as a marker gene for diagnosing osteosarcoma.To observe the clinical value of PTEN expression levels as a reference index for osteosarcoma classification.Methods:43 specimens collected from osteosarcoma excision were studied.30 specimens collected during the same period from benign lesion of bone (osteochondroma) operation were taken as the control group.Immunohistochemistry staining (ElivisonTM two steps method) was used to detect the expression of PTEN protein in 43 cases of osteosarcoma.SPSS 10.0 was used in statistical analysis.Results:Immunohistochemistry staining showed that the positive reaction of PTEN protein was all oriented to cytoplasm,which were brown or yellowishbrown granules.By way of X2 test,the significant difference of the positive expressions of PTEN protein between bone benign lesion and osteosarcoma (X2=7.976,P<0.01) was observed.Osteosarcoma with different degrees of histodifferentiation showed different level expression of PTEN protein.There was significant difference between well-differentiated osteosarcoma (grades Ⅰ-Ⅱ) and poorly-differentiated osteosarcoma (grade Ⅲ) statistically (P<0.01).The level of expression of PTEN was negatively correlated to the histological grade of osteosarcoma.There was great significance statistically (rs=-0.4922,P<0.01).Conclusion:PTEN protein may be used as candidate gene of cancer inhibitory gene:PTEN protein is a cancer suppressor gene protein which has expression in bone tumors.It might not only be used in the study of pulmonary carcinoma and neurogliocytoma,but also in the study of bone tumor; the expression of PTEN is related to benignancy or malignancy of bone tumor and their degree of differentiation.The expression of PTEN is

  13. Inflammatory myofibroblastic tumor

    Directory of Open Access Journals (Sweden)

    Sangeeta Palaskar

    2011-01-01

    Full Text Available Inflammatory myofibroblastic tumor is an uncommon lesion of unknown cause. It encompasses a spectrum of myofibroblastic proliferation along with varying amount of inflammatory infiltrate. A number of terms have been applied to the lesion, namely, inflammatory pseudotumor, fibrous xanthoma, plasma cell granuloma, pseudosarcoma, lymphoid hamartoma, myxoid hamartoma, inflammatory myofibrohistiocytic proliferation, benign myofibroblatoma, and most recently, inflammatory myofibroblastic tumor. The diverse nomenclature is mostly descriptive and reflects the uncertainty regarding true biologic nature of these lesions. Recently, the concept of this lesion being reactive has been challenged based on the clinical demonstration of recurrences and metastasis and cytogenetic evidence of acquired clonal chromosomal abnormalities. We hereby report a case of inflammatory pseudotumor and review its inflammatory versus neoplastic behavior.

  14. PTEN Mediates the Antioxidant Effect of Resveratrol at Nutritionally Relevant Concentrations

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    Marta Inglés

    2014-01-01

    Full Text Available Introduction. Antioxidant properties of resveratrol have been intensively studied for the last years, both in vivo and in vitro. Its bioavailability after an oral dose is very low and therefore it is very important to make sure that plasma concentrations of free resveratrol are sufficient enough to be active as antioxidant. Aims. In the present study, using nutritionally relevant concentrations of resveratrol, we aim to confirm its antioxidant capacity on reducing peroxide levels and look for the molecular pathway involved in this antioxidant effect. Methods. We used mammary gland tumor cells (MCF-7, which were pretreated with different concentrations of resveratrol for 48 h, and/or a PTEN inhibitor (bpV: bipy. Hydrogen peroxide levels were determined by fluorimetry, PTEN levels and Akt phosphorylation by Western Blotting, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR. Results. Resveratrol treatment for 48 h lowered peroxide levels in MCF-7, even at low nutritional concentrations (1 nM. This effect was mediated by the activation of PTEN/Akt pathway, which resulted in an upregulation of catalase and MnSOD mRNA levels. Conclusion. Resveratrol acts as an antioxidant at nutritionally relevant concentrations by inducing the expression of antioxidant enzymes, through a mechanism involving PTEN/Akt signaling pathway.

  15. Methodological aspects of the molecular and histological study of prostate cancer: focus on PTEN.

    Science.gov (United States)

    Ugalde-Olano, Aitziber; Egia, Ainara; Fernández-Ruiz, Sonia; Loizaga-Iriarte, Ana; Zuñiga-García, Patricia; Garcia, Stephane; Royo, Félix; Lacasa-Viscasillas, Isabel; Castro, Erika; Cortazar, Ana R; Zabala-Letona, Amaia; Martín-Martín, Natalia; Arruabarrena-Aristorena, Amaia; Torrano-Moya, Verónica; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Caro-Maldonado, Alfredo; González-Tampan, Jorge; Cachi-Fuentes, Guido; Bilbao, Elena; Montero, Rocío; Fernández, Sara; Arrieta, Edurne; Zorroza, Kerman; Castillo-Martín, Mireia; Serra, Violeta; Salazar, Eider; Macías-Cámara, Nuria; Tabernero, Jose; Baselga, Jose; Cordón-Cardo, Carlos; Aransay, Ana M; Villar, Amaia Del; Iovanna, Juan L; Falcón-Pérez, Juan M; Unda, Miguel; Bilbao, Roberto; Carracedo, Arkaitz

    2015-05-01

    Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer. Copyright © 2015. Published by Elsevier Inc.

  16. Bile duct hamartomas (von Mayenburg complexes) mimicking liver metastases from bile duct cancer: MRC findings

    Institute of Scientific and Technical Information of China (English)

    Yasuhiko Nagano; Kenichi Matsuo; Katsuya Gorai; Kazuya Sugimori; Chikara Kunisaki; Hideyuki Ike; Katsuaki Tanaka; Toshio Imada; Hiroshi Shimada

    2006-01-01

    We present a case of a 72-year-old man with a common bile duct cancer, who was initially believed to have multiple liver metastases based on computed tomography findings, and in whom magnetic resonance cholangiography (MRC) revealed a diagnosis of bile duct hamartomas. At exploration for pancreaticoduodenectomy, liver palpation revealed disseminated nodules at the surface of the liver. These nodules showed gray-white nodular lesions of about 0.5cm in diameter scattered on the surface of both liver lobes, which were looked like multiple liver metastases from bile duct cancer. Frozen section of the liver biopsy disclosed multiple bile ducts with slightly dilated lumens embedded in the collagenous stroma characteristics of multiple bile duct hamartomas (BDHs). Only two reports have described the MRC features of bile duct hamartomas. Of all imaging procedures, MRC provides the most relevant features for the imaging diagnosis of bile duct hamartomas.

  17. Bifid scrotum, perineal hamartoma and high imperforate anus: a case report.

    Science.gov (United States)

    Villarreal, D H; Ortiz, V N; Iturregui, J R; Suarez, G; Duran, N

    1998-01-01

    This is a case report of a newborn patient with imperforate anus, urethro-colonic fistula, perianal hamartoma, and bifid scrotum. Successful staged repair of these anomalies is described together with review of the embriology related to the case.

  18. Loss of SOX9 Expression Is Associated with PSA Recurrence in ERG-Positive and PTEN Deleted Prostate Cancers.

    Directory of Open Access Journals (Sweden)

    Christoph Burdelski

    Full Text Available The transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in luminal cells of normal prostate glands (50% SOX9 positive and 3,671 cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive, but was markedly increased in 3,116 ERG-fusion positive cancers (81% SOX9 positive, p<0.0001. While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG-positive cancers (p<0.0001 each. SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive tumors harboring PTEN deletions (p=0.001, but had no significant effect in ERG-negative cancers or in tumors with normal PTEN copy numbers. In summary, the results of our study argue against a tumor-promoting role of SOX9 in prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive cancers harboring PTEN deletions.

  19. A novel PTEN gene promoter mutation and untypical Cowden syndrome

    Institute of Scientific and Technical Information of China (English)

    Chen Liu; Guangbing Li; Rongrong Chen; Xiaobo Yang; Xue Zhao; Haitao Zhao

    2013-01-01

    Cowden syndrome (CS),an autosomal dominant disorder,is one of a spectrum of clinical disorders that have been linked to germline mutations in the phosphatase and tensin homolog (PTEN) gene.Although 70-80% of patients with CS have an identifiable germline PTEN mutation,the clinical diagnosis presents many challenges because of the phenotypic and genotypic variations.In the present study,we sequenced the exons and the promoter of PTEN gene,mutations and variations in the promoter and exons were identified,and a PTEN protein expression negative region was determined by immunohistochemistry (IHC).In conclusion,a novel promoter mutation we found in PTEN gene may turn off PTEN protein expression occasionally,leading to the disorder of PTEN and untypical CS manifestations.

  20. [Ursolic acid as antitumor agent and inductor of PTEN and brown fat].

    Science.gov (United States)

    Bershteĭn, L M

    2012-01-01

    In this mini-review the basic evidence about anticancer properties of ursolic acid (UA), the compound belonging to the class of triterpenoids, is given. Beside inhibiting tumor cell growth in vitro and in vivo and activating of apoptosis, UA (as well as some other related and not related compounds) is capable to induce PTEN (a tumor suppressor mutation of which is rather often discovered in human tumors including endometrial cancer type I) and amount/activity of brown fat. The latter action may explain obesity-preventing capacity of UA that also may lead to an additional antiblastomogenic effect.

  1. Great saphenous vein dilatation with reflux at the saphenofemoral junction: A rare underlying association of eccrine angiomatous hamartoma

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    Sanjiv Choudhary

    2016-01-01

    Full Text Available Eccrine angiomatous hamartoma (EAH is an exceedingly rare benign tumor-like lesion prevalent in childhood, which can produce pain and marked sweating. Histological features include proliferation of eccrine sweat glands and angiomatous capillary channels. It may be rarely associated with underlying pathological conditions. A 15-year-old female patient presented with multiple tender reddish papules and nodules coalescing to form plaques of 10 × 8 cm over the anterior aspect of the right lower thigh since birth. It was associated with hypertrichosis, hyperhidrosis, pain, and occasional bleeding on trauma. Histopathological examination of the lesion showed increased proliferation of both eccrine and angiomatous channels. Ultrasonography and Color Doppler of the right thigh showed dilatation of the great saphenous vein (GSV above the right knee, with evidence of grade 3 reflux at saphenofemoral junction. Magnetic resonance imaging revealed large dilated GSV with slow flow and venous malformation in the anterior part of the right knee

  2. Hamartomas, teratomas and teratocarcinosarcomas of the head and neck: Report of 3 new cases with clinico-pathologic correlation, cytogenetic analysis, and review of the literature

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    Lydiatt William M

    2008-11-01

    Full Text Available Abstract Background Germ-cell tumors (GCT are a histologically and biologically diverse group of neoplasms which primarily occur in the gonads but also develop at different extragonadal sites in the midline of the body. The head and neck region including the upper respiratory tract is a very rare location for such tumors in both children and adults, which can cause diagnostic and therapeutic difficulties. Methods We describe here two new cases of multilineage tumors including sinonasal teratocarcinosarcoma [SNTCS], and congenital oronasopharyngeal teratoma (epignathus and compare their features with those of a new case of a rare salivary gland anlage tumor [SGAT], an entity for which the pathogenesis is unclear (i.e. hamartoma versus neoplasm. We correlate their presenting clinico-pathological features and compare histologic and cytogenetic features in an attempt to elucidate their pathogenesis and biologic potentials. Results and discussion Cytogenetic analysis revealed chromosomal abnormalities only in the case of SNTCS that showed trisomy 12 and 1p deletion. Both cytogenetic abnormalities are characteristically present in malignant germ cell tumors providing for the first time evidence that this rare tumor type indeed might represent a variant of a germ cell neoplasm. The SGAT and epignathus carried no such cytogenetic abnormalities, in keeping with their limited and benign biologic potential. Conclusion The comparison of these three cases should serve to emphasize the diversity of multilineage tumors (hamartomas and GCT of the upper respiratory tract in regards to their biology, age of presentation and clinical outcomes. Malignant tumors of germ cell origins are more likely to affect adults with insidious symptom development, while benign tumors can nevertheless cause dramatic clinical symptoms which, under certain circumstances, can be fatal.

  3. Multiple Hamartoma Syndrome with Characteristic Oral and Cutaneous Manifestations

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    Prashanthi Chippagiri

    2013-01-01

    Full Text Available Aim. To present a case of Cowden's syndrome and emphasize the importance of continued cancer surveillance in these patients. Cowden syndrome is an inherited autosomal dominant trait with incomplete penetrance and a range of expressivity. It is characterized by multiple hamartomas and neoplasms. Mucocutaneous features include trichilemmomas, oral mucosal papillomatosis, acral keratosis, and palmoplantar keratosis. Here, we report a case of Cowdens syndrome of a 30-year-old female patient who came with a complaint of multiple growths in the oral cavity of a three-month duration. On examination, multiple skin-colored, flat-topped papules over her forehead and right malar bone and multiple papillomatous papules involving all the mucosal surfaces intraorally were observed. This syndrome is associated with the development of several types of malignancies, especially breast carcinoma and thyroid carcinoma, which is why early recognition and regular and vigilant surveillance of individuals with the syndrome are important.

  4. Multiple congenital familial smooth muscle hamartoma in two siblings.

    Science.gov (United States)

    García-Gavín, Juan; Pérez-Pérez, Lidia; Allegue, Francisco; Pérez-Pedrosa, Alberto; Ortíz-Rey, Jose Antonio; Zulaica, Ander

    2012-05-15

    Smooth muscle hamartoma (SMH) is a cutaneous malformation mainly composed of a disorganized proliferation of normal muscle fibers that arise from arrector pili. It usually presents as a single congenital lesion that frequently involves the back and the lower limbs. Unusual clinical presentations, such as atypical localizations, multiple disseminated lesions, and generalized forms have been rarely described. In 2001, Gualandri et al. reported the presence of multiple SMH in three members of the same family, namely two brothers and their mother. This is, as far as we know, the only familial case reported in the English literature. We herein describe a similar case affecting two siblings who presented with identical congenital lesions in the same location.

  5. Rhabdomyomatous mesenchymal hamartoma of the face causing trigeminal neuralgia.

    Science.gov (United States)

    White, Leon R; Agrawal, Vaidehi; Sutton, Lisa; Balbosa, Aiysha C

    2015-06-03

    Rhabdomyomatous mesenchymal hamartoma (RMH) is a benign, potentially pigmented lesion that occurs in the head and neck region. It generally consists of haphazardly arranged skeletal muscle with adipose tissue, blood vessels, collagen and nerve fibers and is largely asymptomatic. Trigeminal neuralgia is pain due to compression of the trigeminal nerve. TN may be idiopathic or associated with lesion-mediated compression. We describe the case of a 14-year-old female presenting with trigeminal neuralgia (TN) associated with RMH. On initial consultation, the patient presented with a history of right-sided lower facial swelling, numbness, and pain. Evaluation by various specialists confirmed TN. Surgical resection of the lesion resolved the condition and pathology confirmed RMH. This is the first case report demonstrating RMH-mediated TN. Surgical resection of the RMH is a safe management approach for this diagnosis.

  6. Gelastic seizures associated with hypothalamic hamartomas. An update in the clinical presentation, diagnosis and treatment

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    José F. Tellez-Zenteno

    2008-10-01

    Full Text Available José F. Tellez-Zenteno1, Cesar Serrano-Almeida2, Farzad Moien-Afshari11Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 2Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, CanadaAbstract: Gelastic seizures are epileptic events characterized by bouts of laughter. Laughter-like vocalization is usually combined with facial contraction in the form of a smile. Autonomic features such as flushing, tachycardia, and altered respiration are widely recognized. Conscious state may not be impaired, although this is often difficult to asses particularly in young children. Gelastic seizures have been associated classically to hypothalamic hamartomas, although different extrahypothalamic localizations have been described. Hypothalamic hamartomas are rare congenital lesions presenting with the classic triad of gelastic epilepsy, precocious puberty and developmental delay. The clinical course of patients with gelastic seizures associated with hypothalamic hamartomas is progressive, commencing with gelastic seizures in infancy, deteriorating into more complex seizure disorder resulting in intractable epilepsy. Electrophysiological, radiological, and pathophysiological studies have confirmed the intrinsic epileptogenicity of the hypothalamic hamartoma. Currently the most effective surgical approach is the trancallosal anterior interforniceal approach, however newer approaches including the endoscopic and other treatment such as radiosurgery and gamma knife have been used with success. This review focuses on the syndrome of gelastic seizures associated with hypothalamic hamartomas, but it also reviews other concepts such as status gelasticus and some aspects of gelastic seizures in other locations.Keywords: epilepsy, gelastic seizures, epilepsy surgery, hypothalamic hamartoma, intractable epilepsy

  7. Image Features of Retinal Astrocytic Hamartoma in a Patient with Tuberous Sclerosis Complex

    Institute of Scientific and Technical Information of China (English)

    Peng Zhang; Dongjie Sun; Jinting Zhu; Juan Li; Yusheng Wang

    2014-01-01

    Purpose:.To describe the image features of retinal astrocytic hamartoma in a 35-year-old male patient with tuberous sclero-sis complex (TSC). Methods:. Fundus photography , . fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), and spectral domain optical coherence tomography. (SD-OCT).were per-formed for this retinal astrocytic hamartoma. Results:Fundus photography showed that the retinal astrocyt-ic hamartoma presented as a well-circumscribed,.mulberry-like lesion consisting of glistening yellowish spherules of calcifica-tion..FAF demonstrated dense hyper-autofluorescence spots corresponding to retinal astrocytic hamartoma..FFA revealed leakage from dilated retinal capillaries over the hamartoma. SD-OCT indicated moth-eaten optically empty spaces and hy-perreflective dots within the lesion..The lesion surface was fluctuate. Conclusion: FAF is a useful imaging modality for obtaining greater contrast between a retinal astrocytic hamartoma and the surrounding retina due to hyper-autofluorescence of calcifica-tion in the lesion. FFA is beneficial for monitoring the abnor-mal blood vessels in these lesions. SD-OCT is capable of visu-alization the structural details, such as the uneven surface and inner hyperreflective dots.

  8. The mitochondrial localization of tumor suppressor PTEN promotes apoptosis in A431 cells%抑癌基因PTEN在线粒体上的定位促进A431细胞的凋亡

    Institute of Scientific and Technical Information of China (English)

    岳晓婧; 宋卫东; 姜学军

    2007-01-01

    为研究抑癌基因PTEN在线粒体上的定位对细胞凋亡的影响,构建N端融合有细胞色素C氧化酶亚基七(CoxⅦ)的PTEN腺病毒重组体(Mito-PTEN).将CoxⅦ-PTEN片段克隆至腺病毒穿梭载体pAdTrack-CMV中,PmeⅠ线性化穿梭质粒,并与腺病毒基因组载体pAdeasy-1共转化大肠杆菌菌株BJ5183,鉴定重组体,并将阳性重组体转化至大肠杆菌菌株DH5α中进行扩增;经PacⅠ酶切后的重组体通过脂质体方法转染用于腺病毒包装的细胞HEK-293A,包装重组腺病毒,收集病毒液,反复扩增,进行病毒滴度的测定;通过绿色荧光蛋白(GFP)标签检测转染及感染效率;用Mito-PTEN腺病毒感染人表皮鳞状癌细胞A431,以流式细胞分析仪检测细胞凋亡情况.成功构建了Mito-PTEN的腺病毒重组体,并进行了该重组体的病毒包装,滴度为107pfu/mL,通过免疫印迹检测目的蛋白,并发现Mito-PTEN可以促进A431细胞的凋亡.Mito-PTEN的成功构建以及它对A431细胞凋亡的促进作用为研究PTEN在线粒体上的功能以及可能的在肿瘤治疗方面的应用提供了理论依据.

  9. The Parvalbumin/Somatostatin Ratio Is Increased in Pten Mutant Mice and by Human PTEN ASD Alleles

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    Daniel Vogt

    2015-05-01

    Full Text Available Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD. Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST+ interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST interneurons, ectopic PV+ projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG power. Using medial ganglionic eminence (MGE transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.

  10. Mesenchymal hamartoma of liver: Magnetic resonance imaging and histopathologic correlation

    Institute of Scientific and Technical Information of China (English)

    Bin-Bin Ye; Bing Hu; Li-Jun Wang; Hong-Sheng Liu; Yan Zou; Yu-Bin Zhou; Zhuang Kang

    2005-01-01

    AIM: To describe the imaging features of hepatic mesenchymal hamartoma with emphasis on magnetic resonance imaging (MRI) compared to histopathologic results.METHODS: Spin-echo sequence(SE),fast spin-echo sequence(FSE) were detected in 12 children (7 males, 5 females) with mesenchymal hamartoma of the liver (MHL), aged 1.2 months to 12 years,( mean age, 6.3 years) by axial, saggital, coronary plain imaging with an Elscint 2.0T MR equipment. Their main symptoms were abdominal mass (5 cases), enlarged liver (8 cases), abdominal pain (1 case) and anemia (2 cases),and negative alpha-fetoprotein. Dynamic enhancement examination was added in 2 cases.RESULTS: Six cases had single mass type of MHL, in which 3 cases had solid masses showing slight low-signal-intensity in T1WI, and irregular high-signal-intensity in T2WI, 1 case had a cystic-solid mixed mass showing several border-clear cysts in a solid mass, 2 cases had cystic masses with multi-septa. Five cases had diffuse and multifocal lesions type of MHL with its signal intensity being similar to that of the solid mass. One case had a combined diffuse and single cystic mass. In the early dynamic enhancement examination, the lesions were slightly circum-enhanced, and the center was enhanced in the later scan images. Inner hepatic vessels were compressed in 5 cases, vena cava and abdominal aortae were compressed in 3 cases. Pathological findings included fiber hyperplasia, hyaline degeneration, biliary duct hyperplasia, lobule-like array.CONCLUSION: MR imaging is a better way to differentiate and diagnose MHL. MHL may be recognized by its characteristic occurrence in infancy and MR imaging features.

  11. Progression of Epididymal Maldevelopment Into Hamartoma-like Neoplasia in VHL Disease

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    Gautam U. Mehta

    2008-10-01

    Full Text Available Inactivation of the von Hippel-Lindau (VHL gene and activation of the hypoxia-inducible factor (HIF in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation.

  12. Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma

    Science.gov (United States)

    Fernandez-Marcos, Pablo J.; Abu-Baker, Shadi; Joshi, Jayashree; Galvez, Anita; Castilla, Elias A.; Cañamero, Marta; Collado, Manuel; Saez, Carmen; Moreno-Bueno, Gema; Palacios, Jose; Leitges, Michael; Serrano, Manuel; Moscat, Jorge; Diaz-Meco, Maria T.

    2009-01-01

    Prostate cancer is one of the most common neoplasias in men. The tumor suppressor Par-4 is an important negative regulator of the canonical NF-κB pathway and is highly expressed in prostate. Here we show that Par-4 expression is lost in a high percentage of human prostate carcinomas, and this occurs in association with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss. Par-4 null mice, similar to PTEN-heterozygous mice, only develop benign prostate lesions, but, importantly, concomitant Par-4 ablation and PTEN-heterozygosity lead to invasive prostate carcinoma in mice. This strong tumorigenic cooperation is anticipated in the preneoplastic prostate epithelium by an additive increase in Akt activation and a synergistic stimulation of NF-κB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-κB pathway as a critical event in prostate tumorigenesis. PMID:19470463

  13. Feedback regulation on PTEN/AKT pathway by the ER stress kinase PERK mediated by interaction with the Vault complex

    DEFF Research Database (Denmark)

    Zhang, Wei; Neo, Suat Peng; Gunaratne, Jayantha

    2015-01-01

    The high proliferation rate of cancer cells, together with environmental factors such as hypoxia and nutrient deprivation can cause Endoplasmic Reticulum (ER) stress. The protein kinase PERK is an essential mediator in one of the three ER stress response pathways. Genetic and pharmacological...... inhibition of PERK has been reported to limit tumor growth in xenograft models. Here we provide evidence that inactive PERK interacts with the nuclear pore-associated Vault complex protein and that this compromises Vault-mediated nuclear transport of PTEN. Pharmacological inhibition of PERK under ER stress...... results is abnormal sequestration of the Vault complex, leading to increased cytoplasmic PTEN activity and lower AKT activation. As the PI3K/PTEN/AKT pathway is crucial for many aspects of cell growth and survival, this unexpected effect of PERK inhibitors on AKT activity may have implications...

  14. The genetic basis of Cowden's syndrome: three novel mutations in PTEN/MMAC1/TEP1.

    Science.gov (United States)

    Tsou, H C; Ping, X L; Xie, X X; Gruener, A C; Zhang, H; Nini, R; Swisshelm, K; Sybert, V; Diamond, T M; Sutphen, R; Peacocke, M

    1998-04-01

    Cowden's syndrome (CS) is an autosomal dominant disorder associated with an increased risk of developing benign and malignant tumors in a variety of tissues, including the skin, thyroid, breast and brain. Women with CS are felt to have an increased risk of developing breast cancer, and virtually all women with CS develop bilateral fibrocystic disease of the breast. Recently, a series of germline mutations have been identified from CS families in a gene known as PTEN/MMAC1/TEP1. In this study, we used heteroduplex analysis and direct sequencing analysis and identified three novel germline mutations in the PTEN/MMAC1/TEP1 coding sequence from unrelated individuals with CS. We report a de novo transition (T-->C) at nucleotide 335 in exon 5. This missense mutation resulted in a leucine to proline (CTA to CCA) change at codon 112. We also describe a novel splice site mutation (801+2T-->G) in intron 7 that caused exon skipping in PTEN/MMAC1/TEP1 mRNA. The third mutation we report is a missense mutation, consisting of a transition (T-->C) at nucleotide 202 in exon 3, resulting in a tyrosine to histidine (TAC to CAC) change at codon 68. Finally, we also detected a rare polymorphism in exon 7 of the PTEN/MMAC1/TEP1 coding sequence. These data confirm the observation that mutations of the PTEN/MMAC1/TEP1 coding sequence are responsible for at least some cases of CS, and further define the spectrum of mutations in this autosomal dominant disorder.

  15. Impaired Pten expression in human malignant peripheral nerve sheath tumours.

    Directory of Open Access Journals (Sweden)

    Maren Bradtmöller

    Full Text Available Malignant peripheral nerve sheath tumours (MPNST are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1. Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n=16 than in neurofibromas (n=16 and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n=31 and PIK3CA (n=38. However, we found frequent PTEN promotor methylation in primary MPNST (11/26 and MPNST cell lines (7/8 but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1-/- and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.

  16. Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression

    Science.gov (United States)

    Xu, Chunxiao; Fillmore, Christine M.; Koyama, Shohei; Wu, Hongbo; Zhao, Yanqiu; Chen, Zhao; Herter-Sprie, Grit S.; Akbay, Esra A.; Tchaicha, Jeremy H.; Altabef, Abigail; Reibel, Jacob B.; Walton, Zandra; Ji, Hongbin; Watanabe, Hideo; Jänne, Pasi A.; Castrillon, Diego H.; Rustgi, Anil K.; Bass, Adam J.; Freeman, Gordon J.; Padera, Robert F.; Dranoff, Glenn; Hammerman, Peter S.; Kim, Carla F.; Wong, Kwok-Kin

    2014-01-01

    SUMMARY Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1+NGFR+ fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR+ cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs. PMID:24794706

  17. PTEN status in advanced colorectal cancer treated with cetuximab

    Science.gov (United States)

    Negri, F V; Bozzetti, C; Lagrasta, C A; Crafa, P; Bonasoni, M P; Camisa, R; Pedrazzi, G; Ardizzoni, A

    2009-01-01

    Background: Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway. Methods: PTEN expression tested by indirect immunofluorescence was evaluated both on primary (n=43) and on metastatic (n=24) sites in CRC patients treated with cetuximab. Results: The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases vs 30% PD in PTEN-positive cases; P<0.05), PFS (0.8 vs 8.2 months; P<0.001) and OS (2.9 vs 14.2 months; P<0.001). Conclusion: A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised. PMID:19953097

  18. Depletion of DNMT3A Suppressed Cell Proliferation and Restored PTEN in Hepatocellular Carcinoma Cell

    Directory of Open Access Journals (Sweden)

    Zhujiang Zhao

    2010-01-01

    Full Text Available Promoter hypermethylation mediated by DNA methyltransferases (DNMTs is the main reason for epigenetic inactivation of tumor suppressor genes (TSGs. Previous studies showed that DNMT1 and DNMT3B play an important role in CpG island methylation in tumorigenesis. Little is known about the role of DNMT3A in this process, especially in hepatocellular carcinoma (HCC. In the present study, increased DNMT3A expression in 3 out of 6 HCC cell lines and 16/25 (64% HCC tissues implied that DNMT3A is involved in hepatocellular carcinogenesis. Depletion of DNMT3A in HCC cell line SMMC-7721 inhibited cell proliferation and decreased the colony formation (about 65%. Microarray data revealed that 153 genes were upregulated in DNMT3A knockdown cells and that almost 71% (109/153 of them contain CpG islands in their 5′ region. 13 of them including PTEN, a crucial tumor suppressor gene in HCC, are genes involved in cell cycle and cell proliferation. Demethylation of PTEN promoter was observed in DNMT3A-depleted cells implying that DNMT3A silenced PTEN via DNA methylation. These results provide insights into the mechanisms of DNMT3A to regulate TSGs by an epigenetic approach in HCC.

  19. PTEN基因与皮肤肿瘤%PTEN gene and skin cancer

    Institute of Scientific and Technical Information of China (English)

    郭泽; 周炳荣; 李巍; 骆丹

    2011-01-01

    皮肤肿瘤是一类最常见的肿瘤,在引起皮肤肿瘤发生的诸多原因中,紫外线照射是主要影响因素之一。PTEN是近年来研究较多的一个肿瘤抑制基因,位于染色体10q23,3。目前研究证实,PTEN在多种皮肤肿瘤,如基底细胞癌、鳞状细胞癌、恶性黑素瘤中都起着抑制基因的作用,发现在皮肤肿瘤形成过程中,紫外线照射可引起PTEN失活,对肿瘤的形成可能起着促进的作用。%Skin cancer is one of the most common cancers. Ultraviolet irradiation is the predominant environmental factor causing skin cancer. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene located on chromosome 10 q23,3, which has been frequently studied in recent years. There is evidence that PTEN acts as a tumor suppressor in many skin cancers, such as basal cell carcinoma, squamous cell carcinoma, and melanoma. Ultraviolet irradiation can result in the inactivation of PTEN and in turn promote the development of cancer.

  20. The effectiveness of power Doppler vocal fremitus imaging in the diagnosis of breast hamartoma.

    Science.gov (United States)

    Yildiz, Seyma; Bakan, Ayse Ahsen; Aydın, Sinem; Kadıoglu, Huseiyn; Serter, Asli; Bilgin, Sennur; Alkan, Alpay

    2014-09-01

    To evaluate the usefulness of power Doppler vocal fremitus (PDVF) breast sonography for differentiation of hamartomas from other breast (malign or benign) masses. Two hundred and six breast masses in 180 women were evaluated. The breast lesions were scanned first by mammography (MG), then by ultrasonography (US) with PDVF imaging. Finally, biopsy was performed on lesions suspicious for malignancy (n=172). We used PDVF imaging to evaluate whether the Power acoustic Doppler artifact existed in all breast lesions. Pathology results of 172 biopsied lesions showed that 83 were malign and 89 masses were benign. Totally 39 breast hamartomas were diagnosed radiologically (n=25) or histopathologically (n=14). All hamartomas (n=39) produced the power acoustic Doppler artifact as the surrounding tissue at the same depth in PDVF imaging. On the other hand, none of the malign or benign lesions, apart from hamartomas, evidenced a similar vibrational artifact as the surrounding tissue at the same depth in the PDVF imaging. PDVF imaging during breast sonography is an invaluable technique in the identification of breast hamartomas from other benign or malign breast masses.

  1. [Clinical and electroencephalogram study of 5 children with hypothalamic hamartoma].

    Science.gov (United States)

    Otsuka, Eiko; Oguni, Hirokazu; Funatsuka, Makoto; Usugi, Tomoko; Nakayama, Tomohiro; Hayashi, Kitami; Nagaki, Shigeru; Osawa, Makiko; Ono, Yuko; Yamane, Fumitaka; Hori, Tomokatsu

    2005-09-01

    We retrospectively studied 5 children with hypothalamic hamartoma (HH) to elucidate the clinical, neuroimaging and electroencephalogram (EEG) characteristics of this disorder. In all cases, high resolution MRI scans demonstrated an intrahypothalamic mass protruding into the 3rd ventricle. An initial symptom was epileptic attack in 4 cases and precocious puberty in the remaining one. Gelastic seizures developed in 4 of 5 patients at ranging from 2 days to 11 years of age. The ictal EEGs during the gelastic seizures showed diffuse attenuation of background activity, followed by rhythmic slow discharges either diffusely or in the central area. Gamma-knife radiosurgery was performed on 2 cases whose seizures were resistant to available antiepileptic drugs. One of the 2 patients was responded significantly to this treatment, showing the disappearance of combined attacks and a marked reduction of the generalized spike-waves discharges. A more aggressive therapy, including gamma-knife radiosurgery and surgical treatment, should be considered for patients whose seizures are resistant to the medical treatment and causing deterioration of intelligence and behavioral problem.

  2. Giant hypothalamic hamartoma associated with an intracranial cyst in a newborn

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo Yeon; Khang, Shin Kwang [University of Ulsan College of Medicine, Seoul (Korea, Republic of); Yoon, Hye Kyung [Dept. of Radiology, Kangwon National University Hospital, Chuncheon (Korea, Republic of)

    2016-08-15

    We report the case of a giant hypothalamic hamartoma with a large intracranial cyst in a neonate. On ultrasonography, the lesion presented as a lobulated, mass-like lesion with similar echogenicity to the adjacent brain parenchyma, located anterior to the underdeveloped and compressed left temporal lobe, and presenting as an intracranial cyst in the left cerebral convexity without definite internal echogenicity or septa. The presence of a hypothalamic hamartoma and intracranial neurenteric cyst were confirmed by surgical biopsy. The association of a giant hypothalamic hamartoma and a neurenteric cyst is rare. Due to the rarity of this association, the large size of the intracranial cyst, and the resulting distortion in the regional anatomy, the diagnosis of the solid mass was not made correctly on prenatal high-resolution ultrasonography.

  3. Reconstruction Approach to a Rare Case of Acquired Scrotal Giant Muscular Hamartoma

    Science.gov (United States)

    Bogetti, Paolo; Rolle, Luigi; Baglioni, Elisabetta Adelaide; Parisi, Andrea; Spaziante, Luca; Rivarossa, Filippo; Ceruti, Carlo; Preto, Mirko; Bocchiotti, Maria Alessandra

    2016-01-01

    Summary: Acquired scrotal giant muscular hamartoma is an uncommon benign lesion with fewer than 10 documented cases all over the world. It is characterized by a proliferation of dermal smooth muscle bundles of scrotum dartos fascia. The authors report a rare case of acquired scrotal giant muscular hamartoma, which occurred in a 70-year-old severely obese and diabetic man presenting with a progressive scrotal enlargement and swelling in the last year, causing marked reduction in quality of life and cosmetic problems. The patient underwent a wide excision of the hamartomatous lesion, and then, a reductive scrotoplasty and autologous skin grafting of penis were performed. Anatomopathological examination showed an acquired scrotal giant muscular hamartoma arising from muscular fascia of dartos. This surgical technique is a valid, safe, effective, and minimally invasive option to treat this pathology, achieving both excellent functional and aesthetic results, with a marked improvement of the patient’s quality of life.

  4. Sellar tumors; Tumoren der Sellaregion

    Energy Technology Data Exchange (ETDEWEB)

    Weber, M.A.; Essig, M. [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Abt. Radiologie; Zoubaa, S. [GSF - Forschungszentrum fuer Gesundheit und Umwelt, Neuherberg, Muenchen (Germany). Abt. Neuropathologie; Politi, M.; Grunwald, I. [Universitaetsklinikum Saarland, Homburg (Germany). Klinik fuer Diagnostische und Interventionelle Neuroradiologie

    2007-06-15

    Because of the complex anatomy, examination of the sella turcica and hypophysis needs a dedicated MR sequence protocol. Not every sellar lesion is a pituitary adenoma. Thus, this review article summarizes the most frequently encountered intra-, supra-, and parasellar tumors and lesions. Differential diagnoses comprise besides adenoma among others craniopharyngioma, meningioma, glioma, germinoma, hamartoma, aneurysm, trigeminal schwannoma, pituitary carcinoma, chordoma, metastasis, infection, and empty sella. Characteristic imaging findings are presented and correlated to micro- and macro-pathology. (orig.)

  5. Firing behavior and network activity of single neurons in human epileptic hypothalamic hamartoma

    Directory of Open Access Journals (Sweden)

    Peter N. Steinmetz

    2013-12-01

    Full Text Available Objective: Human hypothalamic hamartomas (HH are intrinsically epileptogenic and are associated with treatment-resistant gelastic seizures. The basic cellular mechanisms responsible for seizure onset within HH are unknown. We used intra-operative microwire recordings of single neuron activity to measure the spontaneous firing rate of neurons and the degree of functional connection between neurons within the tumor.Technique: Fourteen patients underwent transventricular endoscopic resection of HH for treatment-resistant epilepsy. Prior to surgical resection, single neuron recordings from bundled microwires (total of 9 contacts were obtained from HH tissue. Spontaneous activity was recorded for two or three 5-minute epochs under steady-state general anesthesia. Off-line analysis included cluster analysis of single unit activity and probability analysis of firing relationships between pairs of neurons.Results: Altogether, 222 neurons were identified (mean 6 neurons per recording epoch. Cluster analysis of single neuron firing utilizing a mixture of Gaussians model identified two distinct populations on the basis of firing rate (median firing frequency 0.6 versus 15.0 spikes per second; p<10-5. Cluster analysis identified three populations determined by levels of burst-firing (median burst indices of 0.015, 0.18, and 0.39; p<10-15. Unbiased analysis of spontaneous single unit behavior showed that 51% of all possible neuron pairs within each recording epoch had a significant level of firing synchrony (p<10-15. The subgroup of neurons with higher median firing frequencies was more likely to demonstrate synchronous firing (p<10-7. Conclusions: HH tissue in-vivo contains neurons which fire spontaneously. The activity of single neurons is diverse but distributes into at least two electrophysiological phenoytpes. Functional linkage between single neurons suggests that HH neurons exist within local networks that may contribute to ictogenesis.

  6. Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

    Directory of Open Access Journals (Sweden)

    Vo Kevin

    2011-11-01

    Full Text Available Abstract Background Pancreas cancer is one of most aggressive human cancers with the survival rate for patients with metastatic pancreas cancer at 5-6 months. The poor survival demonstrates a clear need for better target identification, drug development and new therapeutic strategies. Recent discoveries have shown that the role for Notch pathway is important in both development and cancer. Its contribution to oncogenesis also involves crosstalks with other growth factor pathways, such as Akt and its modulator, PTEN. The mounting evidence supporting a role for Notch in cancer promotion and survival suggests that targeting this pathway alone or in combination with other therapeutics represents a promising therapeutic strategy. Results Using a pancreas cancer tissue microarray, we noted that Jagged1, Notch3 and Notch4 are overexpressed in pancreas tumors (26%, 84% and 31% respectively, whereas Notch1 is expressed in blood vessels. While there was no correlation between Notch receptor expression and survival, stage or tumor grade, Notch3 was associated with Jagged1 and EGFR expression, suggesting a unique relationship between Notch3 and Jagged1. Inhibition of the Notch pathway genetically and with gamma-secretase inhibitor (GSI resulted in tumor suppression and enhanced cell death. The observed anti-tumor activity appeared to be through Akt and modulation of PTEN phosphorylation. We discovered that transcriptional regulation of RhoA by Notch is important for PTEN phosphorylation. Finally, the mTOR inhibitor Rapamycin enhanced the effect of GSI on RhoA expression, resulting in down regulation of phospho-Akt and increased in vitro tumor cytotoxity. Conclusions Notch pathway plays an important role in maintaining pancreas tumor phenotype. Targeting this pathway represents a reasonable strategy for the treatment of pancreas cancers. Notch modulates the Akt pathway through regulation of PTEN phosphorylation, an observation that has not been made

  7. MyosinV controls PTEN function and neuronal cell size.

    Science.gov (United States)

    van Diepen, Michiel T; Parsons, Maddy; Downes, C Peter; Leslie, Nicholas R; Hindges, Robert; Eickholt, Britta J

    2009-10-01

    The tumour suppressor PTEN can inhibit cell proliferation and migration as well as control cell growth, in different cell types. PTEN functions predominately as a lipid phosphatase, converting PtdIns(3,4,5)P(3) to PtdIns(4,5)P(2), thereby antagonizing PI(3)K (phosphoinositide 3-kinase) and its established downstream effector pathways. However, much is unclear concerning the mechanisms that regulate PTEN movement to the cell membrane, which is necessary for its activity towards PtdIns(3,4,5)P(3) (Refs 3, 4, 5). Here we show a requirement for functional motor proteins in the control of PI3K signalling, involving a previously unknown association between PTEN and myosinV. FRET (Förster resonance energy transfer) measurements revealed that PTEN interacts directly with myosinV, which is dependent on PTEN phosphorylation mediated by CK2 and/or GSK3. Inactivation of myosinV-transport function in neurons increased cell size, which, in line with known attributes of PTEN-loss, required PI(3)K and mTor. Our data demonstrate a myosin-based transport mechanism that regulates PTEN function, providing new insights into the signalling networks regulating cell growth.

  8. A large infiltrating fibrous hamartoma of infancy in the abdominal wall with rare associated tuberous sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Han, Hye-Jeong; Lim, Gye-Yeon [The Catholic University of Korea, Department of Radiology, St. Mary' s Hospital, Seoul (Korea); You, Chang-Young [The Catholic University of Korea, Department of Pathology, St. Mary' s Hospital, Seoul (Korea)

    2009-07-15

    Tuberous sclerosis is a complex autosomal-dominant neurocutaneous syndrome characterized by hamartomatous malformations of fibrous and connective tissues in various organs. Although various histologic types of soft-tissue masses can occur with tuberous sclerosis, we present a unique case of fibrous hamartoma of infancy presenting as large infiltrating cutaneous and subcutaneous masses in the abdominal wall in a 4-year-old boy with tuberous sclerosis. Although the co-occurrence of tuberous sclerosis and fibrous hamartoma of infancy is very rare, it should be considered in the differential diagnosis of subcutaneous soft-tissue masses found in children with tuberous sclerosis. (orig.)

  9. Surgical treatment in combined hamartoma of the retina and retinal pigment epithelium.

    Science.gov (United States)

    Sánchez-Vicente, J L; Rueda-Rueda, T; Llerena-Manzorro, L; Molina-Socola, F E; Contreras-Díaz, M; Szewc, M; Vital-Berral, C; Alfaro-Juárez, A; Medina-Tapia, A; López-Herrero, F; González-García, L; Muñoz-Morales, A

    2017-03-01

    The case is presented of a 39 year-old man with a combined hamartoma of the retina and retinal pigment epithelium, who experienced progressive visual loss and worsening of metamorphopsia. The patient underwent vitrectomy and epiretinal component peeling, with improvement in visual acuity, metamorphopsia, and retinal architecture, assessed by optical coherence tomography. Selected patients with combined hamartomas of the retina and retinal pigment epithelium may benefit from surgical management. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  10. SIGNIFICANCE OF Skp2 EXPRESSION IN HUMAN GASTRIC CARCINOMA AND THE RELATIONSHIP BETWEEN Skp2,p27 AND PTEN EXPRESSION

    Institute of Scientific and Technical Information of China (English)

    MA Xiu-mei; ZUO Lian-fu

    2005-01-01

    Objective: S-phase kinase-associated protein 2 (Skp2) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis. In this study, we investigated significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression. Methods: Immunohistochemical analysis was performed on 138 surgical resected primary gastric carcinoma specimens, 102 paired metastasis carcinoma tissue specimens in lymph node from the same set of 138 surgical resected primary gastric carcinoma specimens, 30 dysplasia specimens, 30 intestinal metaplasia specimens, and 20 normal gastric mucosa specimens for Skp2 and performed on the same set of 138 surgical resected primary gastric carcinoma specimens for p27 and PTEN. Results: Skp2 labeling frequency % was increased dramatically in intestinal metaplasia, dysplasia, and primary gastric carcinoma compared with normal gastric mucosa (P=0.000, all the same). Skp2 labeling frequency % in metastasis gastric carcinoma in lymph node was significantly higher than primary gastric carcinoma (P=0.037). Skp2 labeling frequency % was positively associated with differentiated degree (rho=0.315, P=0.000), vessel invasion (rho=0.303, P=0.000) and lymph node metastasis (rho=0.254, P=0.000) respectively.An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in gastric carcinoma (rho=-0.451, P=0.000) and with its putative negative regulator, the PTEN tumor suppressor protein (rho=-0.480, P=0.000).p27 expression had positive relationship with PTEN expression in gastric carcinoma (rho=0.642, P=0.000). Conclusion:Skp2 overexpression is correlated with carcinogenesis and progression of gastric carcinoma: elevated Skp2 expression is correlated with decreased p27 and PTEN in gastric carcinoma, and p27 expression is parallel with PTEN expression

  11. Lingual leiomyomatous hamartoma with bifid tip and ankyloglossia in a patient without oral-facial-digital syndrome: a case report and literature review.

    Science.gov (United States)

    Wang, Hsing-Liang; Chiang, Feng-Yu; Tai, Chih-Feng; Tsai, Kun-Bow; Wang, Ling-Feng

    2013-09-16

    Here is a rare case of lingual leiomyomatous hamartoma (LLH) with bifid tongue tip and tongue-tie in a patient with non-oral-facial-digital syndrome (OFDS). A 29-year-old male consulted for a painless tumor over the midline of the tongue dorsum measuring 2 × 1.5 cm. The tumor was excised and the tongue-tie was corrected. Diagnosis of LLH was based on histo-pathologic and immuno-histochemical studies. The epidemiologic data and differential diagnosis of LLH, as well as related literature, are discussed. To date, only 14 cases of LLH have been reported in English literature. This may be the first reported case of LLH with bifid tip and ankyloglossia in a non-OFDS patient.

  12. Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Arafa, El-Shaimaa A.; Zhu Qianzheng [Department of Radiology, Ohio State University, Columbus, OH 43210 (United States); Shah, Zubair I. [James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus, OH 43210 (United States); Wani, Gulzar; Barakat, Bassant M.; Racoma, Ira [Department of Radiology, Ohio State University, Columbus, OH 43210 (United States); El-Mahdy, Mohamed A., E-mail: Mohamed.el-mahdy@osumc.edu [Department of Radiology, Ohio State University, Columbus, OH 43210 (United States); Wani, Altaf A., E-mail: wani.2@osu.edu [Department of Radiology, Ohio State University, Columbus, OH 43210 (United States); Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210 (United States); James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus, OH 43210 (United States); DNA Research Chair, King Saud University, Riyadh (Saudi Arabia)

    2011-01-10

    The use of innocuous naturally occurring compounds to overcome drug resistance and cancer recalcitrance is now in the forefront of cancer research. Thymoquinone (TQ) is a bioactive constituent of the volatile oil derived from seeds of Nigella sativa Linn. TQ has shown promising anti-carcinogenic and anti-tumor activities through different mechanisms. However, the effect of TQ on cell signaling and survival pathways in resistant cancer cells has not been fully delineated. Here, we report that TQ greatly inhibits doxorubicin-resistant human breast cancer MCF-7/DOX cell proliferation. TQ treatment increased cellular levels of PTEN proteins, resulting in a substantial decrease of phosphorylated Akt, a known regulator of cell survival. The PTEN expression was accompanied with elevation of PTEN mRNA. TQ arrested MCF-7/DOX cells at G2/M phase and increased cellular levels of p53 and p21 proteins. Flow cytometric analysis and agarose gel electrophoresis revealed a significant increase in Sub-G1 cell population and appearance of DNA ladders following TQ treatment, indicating cellular apoptosis. TQ-induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of caspases and PARP cleavage in MCF-7/DOX cells. Moreover, TQ treatment increased Bax/Bcl2 ratio via up-regulating Bax and down-regulating Bcl2 proteins. More importantly, PTEN silencing by target specific siRNA enabled the suppression of TQ-induced apoptosis resulting in increased cell survival. Our results reveal that up-regulation of the key upstream signaling factor, PTEN, in MCF-7/DOX cells inhibited Akt phosphorylation, which ultimately causes increase in their regulatory p53 levels affecting the induction of G2/M cell cycle arrest and apoptosis. Overall results provide mechanistic insights for understanding the molecular basis and utility of the anti-tumor activity of TQ.

  13. MicroRNA-22 promotes cell survival upon UV radiation by repressing PTEN

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Guangyun [Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN (United States); Center for Adult Cancer Research, University of Tennessee Health Science Center, Memphis, TN (United States); Jilin Province Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun (China); Shi, Yuling [Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN (United States); Center for Adult Cancer Research, University of Tennessee Health Science Center, Memphis, TN (United States); Wu, Zhao-Hui, E-mail: zwu6@uthsc.edu [Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN (United States); Center for Adult Cancer Research, University of Tennessee Health Science Center, Memphis, TN (United States)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer miR-22 is induced in cells treated with UV radiation. Black-Right-Pointing-Pointer ATM is required for miR-22 induction in response to UV. Black-Right-Pointing-Pointer miR-22 targets 3 Prime -UTR of PTEN to repress its expression in UV-treated cells. Black-Right-Pointing-Pointer Upregulated miR-22 inhibits apoptosis in cells exposed to UV. -- Abstract: DNA damage response upon UV radiation involves a complex network of cellular events required for maintaining the homeostasis and restoring genomic stability of the cells. As a new class of players involved in DNA damage response, the regulation and function of microRNAs in response to UV remain poorly understood. Here we show that UV radiation induces a significant increase of miR-22 expression, which appears to be dependent on the activation of DNA damage responding kinase ATM (ataxia telangiectasia mutated). Increased miR-22 expression may result from enhanced miR-22 maturation in cells exposed to UV. We further found that tumor suppressor gene phosphatase and tensin homolog (PTEN) expression was inversely correlated with miR-22 induction and UV-induced PTEN repression was attenuated by overexpression of a miR-22 inhibitor. Moreover, increased miR-22 expression significantly inhibited the activation of caspase signaling cascade, leading to enhanced cell survival upon UV radiation. Collectively, these results indicate that miR-22 is an important player in the cellular stress response upon UV radiation, which may promote cell survival via the repression of PTEN expression.

  14. miRNA-21 promotes proliferation and invasion of triple-negative breast cancer cells through targeting PTEN

    Science.gov (United States)

    Fang, Hong; Xie, Jiping; Zhang, Min; Zhao, Ziwei; Wan, Yi; Yao, Yongqiang

    2017-01-01

    MicroRNAs (miRNAs) are small single-stranded RNAs that bind to the 3’UTR of the mRNAs of target genes. They can target multiple genes and regulate translation or degradation of the mRNA. miRNAs target genes in a tissue-specific manner, and the role of a particular miRNA varies according to tumor origin or even subtype within the same cancer. This study evaluated the effect of miR-21 expression in triple-negative breast cancer (TNBC) tissues and MDA-MB-468, a cell line derived from TNBC tissues. miR-21 was consistently upregulated in TNBC and MDA-MB-468 cells compared to normal tissues. Inhibition of miR-21 by miR-21 antisense oligonucleotides decreased the proliferation, viability, and invasiveness of MDA-MB-468 cells and enhanced apoptosis. Furthermore, we confirmed that PTEN was downregulated by miR-21 in MDA-MB-468 cells. The results indicated that PTEN may mediate the oncogenic properties of miR-21 in TNBC. In summary, miR-21 was upregulated in TNBC tissues and cells, and promoted the proliferation and invasion of MDA-MB-468 cells, but negatively regulated the expression of PTEN protein. Inhibition of miR-21 or overexpression of PTEN protein could be promising strategies for the treatment of patients with TNBC.

  15. PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation

    Science.gov (United States)

    The tumor suppressors PTEN and p53 are closely related to the pathogenesis of breast cancer, yet pathway-specific mechanisms underlying their participation in mediating the protective actions of dietary bioactive components on breast cancer risk are poorly understood. We recently showed that dietary...

  16. Right adrenal gland neuroblastoma infiltrating the liver and mimicking mesenchymal hamartoma: A case report

    Directory of Open Access Journals (Sweden)

    Ahmed Abo-Elenain

    2015-01-01

    Conclusion: We represent a rare case of neuroblastoma which arose from the right adrenal gland and infiltrated the adjacent liver substance mimicking mesenchymal hamartoma of the liver. Neuroblastoma is rarely presented with pyrexia of unknown origin. Neuroblastoma should be considered in differential diagnosis of abdominal mass in all infants and children.

  17. Urgent resection of bleeding congenital mesenchymal chest wall hamartoma in an infant

    Directory of Open Access Journals (Sweden)

    Bieda, Jan-Christoph

    2013-10-01

    Full Text Available We report a case with prenatally diagnosed large cystic-solid mesenchymal chest wall hamartoma. An attempt of conservative management was made however repeated intralesional hemorrhage led to enlargement and severe anemia which required urgent resection at the age of 8 weeks. The infant had an unimpaired development over a follow-up of 4 years.

  18. Respiratory epithelial adenomatoid hamartoma of the maxillary sinus presenting as an antrochoanal polyp

    Directory of Open Access Journals (Sweden)

    Selcuk Mulazimoglu

    2015-07-01

    Full Text Available Respiratory epithelial adenomatoid hamartoma (REAH is a rare benign upper airway lesion that is characterized by abnormal glandular proliferation. Maxillary sinus localization is extremely rare. Maxillary sinus involvement along with the extension beyond the sinus could be a challenge in differential diagnosis. In this article, a case of an isolated maxillary sinus REAH extending to the choana is presented.

  19. Urgent resection of bleeding congenital mesenchymal chest wall hamartoma in an infant.

    Science.gov (United States)

    Bieda, Jan-Christoph; Tröbs, Ralf-Bodo; Roll, Claudia; Wunsch, Rainer; Neid, Matthias

    2013-01-01

    We report a case with prenatally diagnosed large cystic-solid mesenchymal chest wall hamartoma. An attempt of conservative management was made however repeated intralesional hemorrhage led to enlargement and severe anemia which required urgent resection at the age of 8 weeks. The infant had an unimpaired development over a follow-up of 4 years.

  20. PTEN expression in patients with carcinoma of the cervix and its association with p53, Ki-67 and CD31

    OpenAIRE

    2014-01-01

    PURPOSE: To investigate protein expression and mutations in phosphatase and tensin homolog (PTEN) in patients with stage IB cervical squamous cell carcinoma (CSCC) and the association with clinical-pathologic features, tumor p53 expression, cell proliferation and angiogenesis.METHODS:Women with stage IB CSCC (n=20 - Study Group) and uterine myoma (n=20 - Control Group), aged 49.1±1.7 years (mean±standard deviation, range 27-78 years), were prospectively evaluated. Patients with cervical cance...

  1. Mesodermal Pten inactivation leads to alveolar capillary dysplasia- like phenotype.

    Science.gov (United States)

    Tiozzo, Caterina; Carraro, Gianni; Al Alam, Denise; Baptista, Sheryl; Danopoulos, Soula; Li, Aimin; Lavarreda-Pearce, Maria; Li, Changgong; De Langhe, Stijn; Chan, Belinda; Borok, Zea; Bellusci, Saverio; Minoo, Parviz

    2012-11-01

    Alveolar capillary dysplasia (ACD) is a congenital, lethal disorder of the pulmonary vasculature. Phosphatase and tensin homologue deleted from chromosome 10 (Pten) encodes a lipid phosphatase controlling key cellular functions, including stem/progenitor cell proliferation and differentiation; however, the role of PTEN in mesodermal lung cell lineage formation remains unexamined. To determine the role of mesodermal PTEN in the ontogeny of various mesenchymal cell lineages during lung development, we specifically deleted Pten in early embryonic lung mesenchyme in mice. Pups lacking Pten died at birth, with evidence of failure in blood oxygenation. Analysis at the cellular level showed defects in angioblast differentiation to endothelial cells and an accompanying accumulation of the angioblast cell population that was associated with disorganized capillary beds. We also found decreased expression of Forkhead box protein F1 (Foxf1), a gene associated with the ACD human phenotype. Analysis of human samples for ACD revealed a significant decrease in PTEN and increased activated protein kinase B (AKT). These studies demonstrate that mesodermal PTEN has a key role in controlling the amplification of angioblasts as well as their differentiation into endothelial cells, thereby directing the establishment of a functional gas exchange interface. Additionally, these mice could serve as a murine model of ACD.

  2. Tumor

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008479 Preliminary study of MR elastography in brain tumors. XU Lei(徐磊), et al.Neurosci Imaging Center, Beijing Tiantan Hosp, Capital Med Univ, Beijing 100050.Chin J Radiol 2008;42(6):605-608. Objective To investigate the potential values of magnetic resonance elastography (MRE) for evaluating the brain tumor consistency in vivo. Methods Fourteen patients with known solid brain tumor (5 male, 9 female; age range: 16-63 years)

  3. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice.

    Science.gov (United States)

    Kinross, Kathryn M; Montgomery, Karen G; Kleinschmidt, Margarete; Waring, Paul; Ivetac, Ivan; Tikoo, Anjali; Saad, Mirette; Hare, Lauren; Roh, Vincent; Mantamadiotis, Theo; Sheppard, Karen E; Ryland, Georgina L; Campbell, Ian G; Gorringe, Kylie L; Christensen, James G; Cullinane, Carleen; Hicks, Rodney J; Pearson, Richard B; Johnstone, Ricky W; McArthur, Grant A; Phillips, Wayne A

    2012-02-01

    Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.

  4. Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells.

    Science.gov (United States)

    Pires, Maira M; Hopkins, Benjamin D; Saal, Lao H; Parsons, Ramon E

    2013-03-01

    Breast cancer can be classified into different molecular subtypes with varying clinical and pathological characteristics. The basal-like breast cancer subtype represents one of the most aggressive and lethal types of breast cancer, and due to poor mechanistic understanding, it lacks targeted therapy. Many basal-like breast cancer patient samples display alterations of established drivers of cancer development, including elevated expression of EGFR, p53 inactivating mutations and loss of expression of the tumor suppressor PTEN; however, their contribution to human basal-like breast cancer pathogenesis remains ill-defined. Using non-transformed human mammary epithelial cells, we set out to determine whether altering EGFR, p53 and PTEN in different combinations could contribute to basal-like breast cancer progression through transformation of cells. Altering PTEN in combination with either p53 or EGFR in contrast to any of the single alterations caused increased growth of transformed colonies in soft agar. Concomitantly modifying all three genes led to the highest rate of cellular proliferation and the greatest degree of anchorage-independent colony formation. Results from our effort to engineer a model of BBC expressing alterations of EGFR, p53 and PTEN suggest that these changes are cooperative and likely play a causal role in basal-like breast cancer pathogenesis. Consideration should be given to targeting EGFR and restoring p53 and PTEN signaling simultaneously as a strategy for treatment of this subtype of breast cancer.

  5. Inhibitory Effect of Isoflavones on Prostate Cancer Cells and PTEN Gene

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To explore the mechanisms by which genistein and daidzein inhibit the growth of prostate cancer cells. Methods LNCaP and PC-3 cells were exposed to genistein and daidzein and cell viability was determined by MTT assay and cytotoxicity of the drugs by LDH test. Flow cytometry (FCM) was used to assess the cell cycle in LNCaP and PC-3 cells.Reverse transcription-polymerase chain reaction (RT-PCR) was applied to examine the expression of PTEN gene (a tumor suppressor gene), estrogen receptor alpha gene (Erα), estrogen receptor beta gene (Erβ), androgen receptor gene (AR) and vascular endothelial growth factor gene (VEGF). Results The viability of PC-3 and LNCaP cells decreased with increasing concentrations and exposure time of genistein and daidzein. Genistein increased G2/M phase cells in PC-3 cells while decreased S phase cells in LNCaP cells in a dose-dependent manner. Daidzein exerted no influence on the cell cycle of LNCaP and PC-3 cells, but the apoptosis percentage of LNCaP cells was elevated significantly by daidzein. Genistein induced the expression of PTEN gene in PC-3 and LNCaP cells. Daidzein induced the expression of PTEN gene in LNCaP but not in PC-3 cells. The expression of VEGF, Erα and Erβ genes decreased and AR gene was not expressed after incubation with genistein and daidzein in PC-3 cells. In LNCaP cells, the expression of VEGF and AR gene decreased but there was no change in the expression of Erα and Erβ gene after incubation with genistein and daidzein. Conclusion Genistein and daidzein exert a time- and dose-dependent inhibitory effect on PC-3 and LNCaP cells. The down-regulation of ER gene by daidzein influences the growth of PC-3 cells directly. The inhibition of PC-3 cells by genistein and that of LNCaP cells by genistein and daidzein may be via Akt pathway that is repressed by PTEN gene, which subsequently down-regulates the expression of AR and VEGF genes. Our results suggest that the expression of PTEN gene plays a key

  6. Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer

    Science.gov (United States)

    Su, Qingtai; Zhang, Boyu; Zhang, Li; Dang, Truong; Rowley, David; Ittmann, Michael; Xin, Li

    2016-01-01

    The role of Notch signaling in prostate cancer has not been defined definitively. Several large scale tissue microarray studies revealed that the expression of some Notch signaling components including the Jagged1 ligand are upregulated in advanced human prostate cancer specimens. Jagged1 expressed by tumor cells may activate Notch signaling in both adjacent tumor cells and cells in tumor microenvironment. However, it remains undetermined whether increased Jagged1 expression reflects a cause for or a consequence of tumor progression in vivo. To address this question, we generated a novel R26-LSL-JAG1 mouse model that enables spatiotemporal Jagged1 expression. Prostate specific upregulation of Jagged1 neither interferes with prostate epithelial homeostasis nor significantly accelerates tumor initiation or progression in the prostate-specific Pten deletion mouse model for prostate cancer. However, Jagged1 upregulation results in increased inflammatory foci in tumors and incidence of intracystic adenocarcinoma. In addition, Jagged1 overexpression upregulates Tgfβ signaling in prostate stromal cells and promotes progression of a reactive stromal microenvironment in the Pten null prostate cancer model. Collectively, Jagged1 overexpression does not significantly accelerate prostate cancer initiation and progression in the context of loss-of-function of Pten, but alters tumor histopathology and microenvironment. Our study also highlights an understudied role of Notch signaling in regulating prostatic stromal homeostasis. PMID:27345403

  7. PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma

    Directory of Open Access Journals (Sweden)

    Mirjam C. Boelens

    2016-08-01

    Full Text Available Invasive lobular carcinoma (ILC is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC, the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K signaling as a potential therapeutic strategy for targeting CLC.

  8. HMGB1-Induced Cross Talk between PTEN and miRs 221/222 in Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    S. Mardente

    2015-01-01

    Full Text Available High mobility group box 1 (HMGB1 is an ubiquitous protein that plays different roles in the nucleus, cytoplasm, and extracellular space. It is an important DAMP molecule that allows communication between damaged or tumor cells and the immune system. Tumor cells exploit HMGB1’s ability to activate intracellular pathways that lead to cell growth and migration. Papillary thyroid cancer is a well-differentiated tumor and is often used to study relationships between cells and the inflammatory microenvironment as the latter is characterized by high levels of inflammatory cells and cytokines. Anaplastic thyroid cancer is one of the most lethal human cancers in which many microRNAs and tumor suppressor genes are deregulated. Upregulation of microRNAs 221 and 222 has been shown to induce the malignant phenotype in many human cancers via inhibition of PTEN expression. In this study we suggest that extracellular HMGB1 interaction with RAGE enhances expression of oncogenic cluster miR221/222 that in turn inhibits tumor suppressor gene PTEN in two cell lines derived from human thyroid anaplastic and papillary cancers. The newly identified pathway HMGB1/RAGE/miR221/222 may represent an effective way of tumor escape from immune surveillance that could be used to develop new therapeutic strategies against anaplastic tumors.

  9. DNA methylation of PTEN gene promoter region is not correlated ...

    African Journals Online (AJOL)

    Yomi

    2012-02-23

    Feb 23, 2012 ... Key words: PTEN, promoter methylation, bladder cancer. INTRODUCTION ... al., 2005), pancreatic cancer (Asano et al., 2004), thyroid cancer (Frisk et al., ..... papillary mucinous neoplasms of the pancreas. J. Hepatobiliary.

  10. Late onset eccrine angiomatous hamartoma treated with intralesional sclerosant: A case report and brief review of literature

    Directory of Open Access Journals (Sweden)

    Kaliyadan Feroze

    2007-01-01

    Full Text Available A 29-year-old male patient presented to us with multiple swellings on his left leg associated with localized sweating and occasional throbbing pain. Based on the clinical features and histopathology, a diagnosis of Eccrine angiomatous hamartoma was made. The patient showed good response with regression of lesions after four intralesional injections of ethoxysclerol (polidocanol. We present this as a case of late onset eccrine angiomatous hamartoma with multiple lesions, responding to treatment with intralesional ethoxysclerol.

  11. Translocation t(12;17)(q24.1;q21) as the sole anomaly in a nasal chondromesenchymal hamartoma arising in a patient with pleuropulmonary blastoma.

    Science.gov (United States)

    Behery, Radwa El; Bedrnicek, Jiri; Lazenby, Audrey; Nelson, Marilu; Grove, Jennifer; Huang, Dali; Smith, Russell; Bridge, Julia A

    2012-01-01

    The identification of recurrent chromosomal abnormalities in benign and malignant mesenchymal neoplasms has provided important pathogenetic insight as well as powerful diagnostic adjuncts. Nasal chondromesenchymal hamartoma (NCMH), an extremely rare benign tumor arising in the sinonasal tract of infants and children, has not been previously subjected to cytogenetic analysis. Histopathologically composed of mixed mesenchymal elements, NCMH exhibits a relatively wide differential diagnosis to include chondromyxoid fibroma, chondroblastoma, aneurysmal bone cyst, fibrous dysplasia, and osteochondromyxoma. An interesting association with pleuropulmonary blastoma has been reported in a small subset of NCMH patients. In the current study, cytogenetic analysis of a NCMH arising in an 11-year-old boy with a past medical history of pleuropulmonary blastoma revealed a novel 12;17 translocation, t(12;17)(q24.1;q21), as the sole anomaly.

  12. Clinicopatholgical features of Brunner's gland hamartoma%Brunner腺错构瘤7例临床病理分析

    Institute of Scientific and Technical Information of China (English)

    杨敏; 刘爱军; 张继平; 王巍峰; 祝庆孚

    2011-01-01

    Purpose To investigate the clinicopatholgical features and pathogenesis of Brunner' s gland hamartoma( BGH ). Methods The clinico-pathological features were analyzed in 7 cases of BGH. and the literature was reviewed. Reasults The mean age of the patients of BGH was 53. 6 years ( ranger from 25 to 80 years ). The common clinical manifestations were abdominal pain, ahdominal distention , gastrointestinal hemorrhage, duodenal obstruction, constipation and so on. The more common location is the posterior wall of the duodenum of the hulbar zone and descending part with the appearance of polypoid, solid, cystic. Microscopically, the hyperplastic Brunner' s gland were separated by bundles of smooth muscle cells. with the duct dilated, cyst, adipose cell in it. Focal lymphocytes infiltration were found frequently in the tumor. Conclusions BGH is a rare kind of benign lesion of duodenal. Pathological morphological features are the key point of diagnosis and differential diagnosis of this disease.%目的 探讨Brunner腺错构瘤(Burnner's gland hamartoma, BGH)的临床病理特征及发病机制.方法 收集7例BGH临床及病理资料,进行病理形态学观察,并复习相关文献.结果 BGH发病年龄平均53.6岁(25~80岁),临床表现腹痛、腹胀、黑便、肠梗阻、便秘等症状;常发生在十二指肠球部、降部,外观呈息肉状,实性或囊性;光镜下表现为Brunner腺结节状增生,被平滑肌束分隔呈小叶状,伴有导管扩张、囊肿、脂肪细胞,常见灶性淋巴细胞浸润等.结论 BGH是十二指肠罕见的良性疾病,诊断和鉴别诊断主要依据病理形态学特征.

  13. Molecular Analysis of AFP and HSA Interactions with PTEN Protein.

    Science.gov (United States)

    Zhu, Mingyue; Lin, Bo; Zhou, Peng; Li, Mengsen

    2015-01-01

    Human cytoplasmic alpha-fetoprotein (AFP) has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA), but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP), and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog), demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN. In silicon substitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

  14. Methods to Study PTEN in Mitochondria and Endoplasmic Reticulum.

    Science.gov (United States)

    Missiroli, Sonia; Morganti, Claudia; Giorgi, Carlotta; Pinton, Paolo

    2016-01-01

    Although PTEN has been widely described as a nuclear and cytosolic protein, in the last 2 years, alternative organelles, such as the endoplasmic reticulum (ER), pure mitochondria, and mitochondria-associated membranes (MAMs), have been recognized as pivotal targets of PTEN activity.Here, we describe different methods that have been used to highlight PTEN subcellular localization.First, a protocol to extract nuclear and cytosolic fractions has been described to assess the "canonical" PTEN localization. Moreover, we describe a protocol for mitochondria isolation with proteinase K (PK) to further discriminate whether PTEN associates with the outer mitochondrial membrane (OMM) or resides within the mitochondria. Finally, we focus our attention on a subcellular fractionation protocol of cells that permits the isolation of MAMs containing unique regions of ER membranes attached to the outer mitochondrial membrane (OMM) and mitochondria without contamination from other organelles. In addition to biochemical fractionations, immunostaining can be used to determine the subcellular localization of proteins; thus, a detailed protocol to obtain good immunofluorescence (IF) is described. The employment of these methodological approaches could facilitate the identification of different PTEN localizations in several physiopathological contexts.

  15. Osthole Induces Cell Cycle Arrest and Inhibits Migration and Invasion via PTEN/Akt Pathways in Osteosarcoma

    Directory of Open Access Journals (Sweden)

    Lu Wang

    2016-05-01

    Full Text Available Background/Aims: Osteosarcoma is the second highest cause of cancer-related death in children and adolescents. Majority of osteosarcoma patients (90% show metastasis. Previous reports revealed that osthole showed antitumor activities via induction of apoptosis and inhibition of proliferation. However, the potential effects and detailed molecular mechanisms involved remained unclear. Methods: Cell viability was analyzed by MTT assay in osteosarcoma cell lines MG-63 and SAOS-2. Cell cycle was detected by flow cytometry. The effects of migration and invasion were evaluated by wound healing assay and transwell assays. Moreover, the level of proteins expression was determined by Western blot. Results: The cell viability of MG63 and SAOS-2 were markedly inhibited by osthole in a dose- and time-dependent manner. Cell cycle was arrested and the ability of migration and invasion was obviously reduced when cells were exposed to osthole. Moreover, enzymes involved in PTEN/Akt pathway were regulated such as PTEN and p-Akt proteins. Furthermore, osthole inhibited the tumor growth in vivo. Conclusion: Our study unraveled, for the first time, the ability of osthole to suppress osteosarcoma and elucidated the regulation of PTEN/Akt pathway as a signaling mechanism for the anti-tumor action of osthole. These findings indicate that osthole may represent a novel therapeutic strategy in the treatment of osteosarcoma.

  16. MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4.

    Science.gov (United States)

    Wei, Xueju; Wang, Weibin; Wang, Lanlan; Zhang, Yuanyuan; Zhang, Xian; Chen, Mingtai; Wang, Fang; Yu, Jia; Ma, Yanni; Sun, Guotao

    2016-04-01

    Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21.

  17. Fish oil suppresses cell growth and metastatic potential by regulating PTEN and NF-κB signaling in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Shevali Kansal

    Full Text Available Homeostasis in eukaryotic tissues is tightly regulated by an intricate balance of the prosurvival and antisurvival signals. The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10, a dual-specificity phosphatase, plays a functional role in cell cycle arrest and apoptosis. NF-κB and its downstream regulators (such as VEGF play a central role in prevention of apoptosis, promotion of inflammation and tumor growth. Therefore, we thought to estimate the expression of PTEN, Poly-ADP-ribose polymerase (PARP, NF-κBp50, NF-κBp65 and VEGF to evaluate the effect of supplementation of fish oil on apoptotic and inflammatory signaling in colon carcinoma. Male wistar rats in Group I received purified diet while Group II and III received modified diet supplemented with FO∶CO(1∶1&FO∶CO(2.5∶1 respectively. These were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and that sacrificed after 16 weeks constituted post-initiation phase. We have analysed expression of PTEN, NF-κBp50, NF-κBp65 by flowcytometer and nuclear localization of NF-κB by immunofluorescence. PARP and VEGF were assessed by immunohistochemistry. In the initiation phase, animals receiving DMH have shown increased % of apoptotic cells, PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF however in post-initiation phase no significant alteration in apoptosis with decreased PTEN and increased PARP, NF-κBp50, NF-κBp65 and VEGF were observed as compared to control animals. On treatment with both ratios of fish oil in both the phases, augmentation in % of apoptotic cells, decreased PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF were documented with respect to DMH treated animals with effect being more exerted with higher ration in post-initiation phase. Hence, fish oil activates

  18. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

    Directory of Open Access Journals (Sweden)

    Tim F Cloughesy

    2008-01-01

    Full Text Available BACKGROUND: There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. METHODS AND FINDINGS: Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR, we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation varied substantially. Tumor cell proliferation (measured by Ki-67 staining was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin

  19. A role for Pten in paediatric intestinal dysmotility disorders.

    LENUS (Irish Health Repository)

    O'Donnell, Anne-Marie

    2012-02-01

    PURPOSE: The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities. Hirschsprung\\'s disease (HD) is a congenital defect of the ENS, characterised by an absence of ganglia in the distal colon. Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterised by hyperganglionosis, giant and ectopic ganglia, resulting in intestinal dysmotility. Intestinal ganglioneuromatosis is characterised by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudo-obstruction (CIPO). Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a phosphatase that is critical for controlling cell growth, proliferation and cell death. A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS suggesting a role for this protein in ENS development. Ganglioneuromatosis patients have also been shown to have a decreased level of Pten expression in the colon. The aim of our study was to investigate Pten expression in the ENS of HD and IND patients compared to normal controls. METHODS: Resected tissue from 10 HD and 10 IND type B patients was fixed and embedded in paraffin wax. Normal control colon tissue was obtained from ten patients who underwent a colostomy closure for imperforate anus. Sections were cut and immunohistochemistry was carried out using a Pten antibody. Results were analysed by light microscopy. RESULTS: Staining showed that Pten was strongly expressed in ganglia of both the submucosal and myenteric plexus of normal and HD specimens from the ganglionic colon. Pten expression was significantly reduced in the giant ganglia in IND patients in both the myenteric and submucosal plexuses compared to the normal controls. Specimens from the aganglionic region of HD did not show Pten expression. CONCLUSION: To the best of our knowledge, this is the first study

  20. Successful surgical excision of a massive symptomatic partially obstructing Brunner's gland hamartoma: a case report

    Science.gov (United States)

    Delvecchio, Khortnal; Seman, Susan

    2016-01-01

    Brunner gland function within the duodenal epithelium is secretion of alkaline mucin to counteract acidic chyme. These glands may grow beyond the duodenal wall to become hamartomas. Rarely, they become large enough to cause obstructive symptoms in the upper gastrointestinal tract. We report a case of one of the largest lesions identified in the literature causing obstruction symptoms. A previously asymptomatic 65-year-old gentleman presented to the emergency department with a single-day history of colicky abdominal pain, cramping and vomiting. After initial imaging with computed tomography was inconclusive, a subsequent esophagogastroduodenoscopy with biopsy and small bowel series was performed indicating a pedunculated polypoid mass. Our patient underwent an uncomplicated exploratory laparotomy with duodenotomy and Heineke-Mikulicz pyloroplasty for resection of a massive Brunner's gland hamartoma. For similar presentations, we recommend this technique. PMID:27994010

  1. Chondro-osseous respiratory epithelial adenomatoid hamartoma of the nasal cavity

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    Fedda, Faysal

    2013-04-01

    Full Text Available Introduction: Chondro-osseous respiratory epithelial adenomatoid hamartoma (COREAH is a benign lesion of the nose and sinuses that is extremely rare, with only 2 cases reported in the literature to date. Case report: We present herein the third reported case of COREAH, in a 38-year-old woman who presented with left nasal obstruction and a mass in her left nasal cavity. The mass was completely resected endoscopically. Microscopic examination showed hamartomatous proliferation of respiratory-type glands with mucinous metaplasia admixed with numerous spicules of mature bone, characteristic of COREAH. Conclusion: COREAH is a benign hamartomatous proliferation of respiratory epithelium, submucosal glands, and chondro-osseous mesenchyme. The clinical differential diagnoses for such lesions include glandular hamartoma, inflammatory polyp, inverted papilloma, and low-grade sinonasal adenocarcinoma. Recognition of this lesion as benign despite its potentially worrisome radiographic appearance is important to avoid an unnecessarily radical surgical procedure.

  2. A new pathway of glucocorticoid action for asthma treatment through the regulation of PTEN expression

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    Chen Qingge

    2011-04-01

    Full Text Available Abstract Background "Phosphatase and tensin homolog deleted on chromosome 10" (PTEN is mostly considered to be a cancer-related gene, and has been suggested to be a new pathway of pathogenesis of asthma. The purpose of this study was to investigate the effects of the glucocorticoid, dexamethasone, on PTEN regulation. Methods OVA-challenged mice were used as an asthma model to investigate the effect of dexamethasone on PTEN regulation. Immunohistochemistry was used to detect expression levels of PTEN protein in lung tissues. The human A549 cell line was used to explore the possible mechanism of action of dexamethasone on human PTEN regulation in vitro. A luciferase reporter construct under the control of PTEN promoter was used to confirm transcriptional regulation in response to dexamethasone. Results PTEN protein was found to be expressed at low levels in lung tissues in asthmatic mice; but the expression was restored after treatment with dexamethasone. In A549 cells, human PTEN was up-regulated by dexamethasone treatment. The promoter-reporter construct confirmed that dexamethasone could regulate human PTEN transcription. Treatment with the histone deacetylase inhibitor, TSA, could increase PTEN expression in A549 cells, while inhibition of histone acetylase (HAT by anacardic acid attenuated dexamethasone-induced PTEN expression. Conclusions Based on the data a new mechanism is proposed where glucocorticoids treat asthma partly through up-regulation of PTEN expression. The in vitro studies also suggest that the PTEN pathway may be involved in human asthma.

  3. Aspectos ultra-sonográficos dos hamartomas dos ductos biliares (complexo de von Meyenburg: resultado de uma busca ativa de oito anos Ultrasonography findings in patients with bile duct hamartomas (von Meyenburg complex: result of an active search of eight years

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    Márcio Martins Machado

    2003-06-01

    Full Text Available A correta identificação de tumores hepáticos benignos é importante, pois a maioria não necessita de conduta intervencionista. Os autores relatam os aspectos ultra-sonográficos dos hamartomas de ductos biliares (complexo de von Meyenburg em 16 pacientes estudados prospectivamente, resultados de uma busca ativa de oito anos. Em 14 pacientes foram identificadas múltiplas lesões menores ou iguais a 0,8 cm, e em dois, apenas duas lesões em cada (medindo de 0,4 cm a 1,3 cm. O aspecto ultra-sonográfico que predominou foi o de múltiplas pequenas imagens hiperecogênicas com ou sem reverberação sonora posterior e margens irregulares (14 pacientes. Menos comumente, foi encontrado o aspecto "em alvo", com centro com maior ecogenicidade que a periferia (dois pacientes com duas lesões cada e margens bem definidas.The recognition and identification of benign liver tumors is important since most of these tumors do not require any intervention. The authors report the ultrasonography findings in 16 patients with bile duct hamartomas (von Meyenburg complex that were evaluated prospectively by an active search of eight years. Multiple lesions with size equal or less than 0.8 cm were identified in 14 patients. Two other patients had only two lesions measuring 0.4 cm to 1.3 cm. The most common ultrasonographic pattern was that of multiple small hyperechogenic lesions (with or without posterior acoustic reverberation with irregular margins (14 patients. A less common finding (two patients with two lesions each was the "target" pattern with echogenic center and well defined limits.

  4. Clinical study of preoperative selective arterial embolization combined with laparoscopic enucleation of tumor in treatment of renal hamartoma%术前选择性动脉栓塞联合腹腔镜肿瘤剜除术治疗肾错构瘤

    Institute of Scientific and Technical Information of China (English)

    林明恩; 洪英楷; 何学军; 张炜

    2016-01-01

    s:Objective To study the clinical effect of preoperative selective arterial embolization(SAE)and laparoscopic enucleation of tumor surgery on renal angiomyolipoma(RAML).Methods The clinical data of 52 patients with RAML hospitalized from January 2014 to January 2016 in our hospital were respectively analyzed,of which 22 cases were treated by retroperitoneal laparoscopic enucleation 24 hours after SAE(group SAE),30 cases received laparoscopic enucleation of tumor treatment(non SAE group).The clinical effect of patients be-tween two groups were compared.Results The success rate of tumor enucleating of SAE group was 100%(22/22),which was higher than 66.67%(20/30)of non SAE group,and the difference had statistical significance(P0.05),the Scr of SAE group was significantly lower than that of non SAE group,the difference was significant(P0.05).All of 52 patietns were followed up from 6 months to 24 months,no tumor recurrence after surgery was found.Conclusion SAE combined with laparoscopic enucleation in treatment of RAML can reduce the surgical trauma,improve postoperative rehabilitation and protect renal function,which was safe application.%目的:探讨肾错构瘤(RAML)采用术前选择性动脉栓塞术(SAE)与腹腔镜肿瘤剜除术治疗的临床效果。方法回顾分析2014年1月至2016年1月我院收治的52例RAML患者的临床资料,其中22例患者术前行SAE后24 h内腹腔镜肿瘤剜除术(SAE组),30例患者未行SAE直接行腹腔镜肿瘤剜除术治疗(非SAE组),对比2组的临床效果。结果 SAE组的肿瘤剜除术成功率为100%(22/22),高于非SAE组的66.67%(20/30),差异有统计学意义(P<0.05)。SAE组的术中出血量、手术时间、肾动脉阻断时间、胃肠功能恢复时间均少于非SAE组,差异具有统计学意义(P<0.05),住院时间明显长于非SAE组,差异有统计学意义(P<0.05)。术后3个月,2组eGFR比较

  5. Urgent resection of bleeding congenital mesenchymal chest wall hamartoma in an infant

    OpenAIRE

    Bieda, Jan-Christoph; Tröbs, Ralf-Bodo; Roll, Claudia; Wunsch, Rainer; Neid, Matthias

    2013-01-01

    We report a case with prenatally diagnosed large cystic-solid mesenchymal chest wall hamartoma. An attempt of conservative management was made however repeated intralesional hemorrhage led to enlargement and severe anemia which required urgent resection at the age of 8 weeks. The infant had an unimpaired development over a follow-up of 4 years. Wir berichten über ein Neugeborenes mit einem bereits pränatal diagnostizierten, ausgedehnten Thoraxwand-Hamartom von zystisch-solider Beschaffen...

  6. KRAS and BRAF Mutations and PTEN Expression Do Not Predict Efficacy of Cetuximab-Based Chemoradiotherapy in Locally Advanced Rectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Erben, Philipp, E-mail: philipp.erben@medma.uni-heidelberg.de [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Stroebel, Philipp [Pathologisches Institut, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Horisberger, Karoline [Chirurgische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Popa, Juliana; Bohn, Beatrice; Hanfstein, Benjamin [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Kaehler, Georg; Kienle, Peter; Post, Stefan [Chirurgische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Wenz, Frederik [Klinik fuer Strahlentherapie und Radioonkologie, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Hochhaus, Andreas [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Klinik fuer Innere Medizin II, Abteilung Haematologie/Onkologie, Universitaetsklinikum Jena, Jena (Germany); Hofheinz, Ralf-Dieter [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany)

    2011-11-15

    Purpose: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown. Methods and Materials: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan-Meier method. Results: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. Conclusions: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS.

  7. Cisplatin Induces Overactivation of the Dormant Primordial Follicle through PTEN/AKT/FOXO3a Pathway which Leads to Loss of Ovarian Reserve in Mice

    Science.gov (United States)

    Chang, Eun Mi; Lim, Eunjin; Yoon, Sookyoung; Jeong, Kyungah; Bae, Sijeong; Lee, Dong Ryul; Yoon, Tae Ki

    2015-01-01

    Cisplatin is a first-line chemotherapeutic agent for ovarian cancer that acts by promoting DNA cross links and adduct. However drug resistance and considerable side effects including reproductive toxicity remain a significant challenge. PTEN is well known as a tumor suppressor function which plays a fundamental role in the regulation of the cell cycle, apoptosis and development of cancer. At the same time PTEN has been revealed to be critically important for the maintenance of the primordial follicle pool. In this study, we investigated the role of PTEN/Akt/FOXO3 pathway in cisplatin-induced primordial follicle depletion. Cisplatin induced ovarian failure mouse model was used to evaluate how this pathway involves. In vitro maturation was used for oocyte rescue after cisplatin damage. We found that cisplatin treatment decreased PTEN levels, leading to a subsequent increase in the phosphorylation of key molecules in the pathway. The activation of the PTEN/Akt/FOXO3 pathway cascade increased cytoplasmic translocation of FOXO3a in cisplatin-treated follicles, which in turn increased the pool size of growing follicles, and rapidly depleted the number of dormant follicles. Once activated, the follicles were more prone to apoptosis, and their cumulus cells showed a loss of luteinizing hormone (LH) receptor expression, which leads to failure during final maturation and ovulation. In vitro maturation to rescue oocytes in a cisplatin-treated mouse model resulted in successful maturation and fertilization. This study is the first to show the involvement of the PTEN/Akt/FOXO3 pathway in premature ovarian failure after cisplatin treatment and the possibility of rescue through in vitro maturation. PMID:26656301

  8. Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

    Science.gov (United States)

    Rangel, Roberto; Lee, Song-Choon; Hon-Kim Ban, Kenneth; Guzman-Rojas, Liliana; Mann, Michael B.; Newberg, Justin Y.; McNoe, Leslie A.; Selvanesan, Luxmanan; Ward, Jerrold M.; Rust, Alistair G.; Chin, Kuan-Yew; Black, Michael A.; Jenkins, Nancy A.; Copeland, Neal G.

    2016-01-01

    Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC. PMID:27849608

  9. Neurons and tumor suppressors.

    Science.gov (United States)

    Zochodne, Douglas W

    2014-08-20

    Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, we review how two brakes, PTEN (phosphatase and tensin homolog deleted on chromosome 10) and retinoblastoma emerge as new and exciting knockdown targets to enhance neuron plasticity and improve outcome from damage or disease.

  10. Neurons and Tumor Suppressors

    OpenAIRE

    Douglas W Zochodne

    2014-01-01

    Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, we review how two brakes, PTEN (phosphatase and tensin homolog deleted on chromosome 10) and retinoblastoma emerge as new and exciting knockdown targets to e...

  11. Multiorgan involvements of cowden disease in 50-year-old woman: A case report and literature overview

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eun Jae; Jung, Won Sang; Ko, Jeong Min; Park, Hyun Jin [Dept. of Radiology, St. Vincent' s Hospital, The Catholic University of Korea College of Medicine, Suwon (Korea, Republic of)

    2013-09-15

    Cowden disease is the prototype of phosphate and, tensin homologue deleted on the chromosome 10 (PTEN) hamartoma tumor syndrome caused by germline mutations in the tumor suppressor PTEN, which is characterized by multiple developmentally disorganized benign growths, hamartomas, with an increased risk of both benign and malignant tumors. We present another case of Cowden disease in a 50-year-old woman. Besides the diagnostic criteria of Cowden disease, she had various manifestations in thyroid, lung, spleen, liver, pancreas, and muscle. As far as we know, it is the first case showing radiographic findings of hamartomatous lesions in thyroid, spleen, and pancreas, associated with Cowden disease.

  12. Fibrolipomatous hamartoma and macrodystrofia lipomatosa: imaging and clinical data analysis of four cases and review of the literature; Hamartoma fibrolipomatoso e macrodistrofia lipomatosa: analise dos achados clinicos e de imagem em quatro casos, com revisao da literatura

    Energy Technology Data Exchange (ETDEWEB)

    Coelho, Rafael Darahem de Souza; Simao, Marcelo Novelino; Trad, Clovis Simao [Sao Paulo Univ., Ribeirao Preto, SP (Brazil). Faculdade de Medicina. Hospital das Clinicas]. E-mail: rdarahem@terra.com.br

    2002-10-01

    Fibrolipomatous hamartoma of nerve and macrodystrophia lipomatosa are rare conditions that present characteristic imaging findings. The plain films, magnetic resonance imaging studies and medical records of four patients were reviewed. The lesion was resected in one patient allowing histological confirmation of the diagnosis. Diagnosis was based on imaging and clinical findings in three patients who had unavailable biopsy data. We describe two cases of isolated macrodystrophia lipomatosa, one case of fibrolipomatous hamartoma and one case where both conditions were found. In the macrodystrophia lipomatosa cases plain films demonstrated enlargement of osseous and soft tissue structures in the affected limbs, with fatty streaks interspersed along the muscle fibers. The median nerve was affected in the cases of fibrolipomatous hamartoma. Magnetic resonance imaging findings included nerve fascicle thickening characterized by low signal on both T1 and T2-weighted sequences, and surrounding fat, which appears as high signal on T1 and low signal on T2-weighted sequences with fat saturation. Both nerves had a coaxial cable appearance on axial images. The fibrolipomatous hamartoma extended to the nerve branches, which is a typical finding. The typical imaging findings of macrodystrophia lipomatosa and fibrolipomatous hamartoma of nerve, particularly at magnetic resonance imaging examination, allowed a reliable diagnosis of these frequently coexistent conditions. (author)

  13. Differential activation of Wnt-β-catenin pathway in triple negative breast cancer increases MMP7 in a PTEN dependent manner.

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    Nandini Dey

    Full Text Available Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012. Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP, including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54. The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25% and High Rd (74% in clinical stage T3 pathologic response in contrast to the high pCR (40% and low residual disease (RD (60% of the low MMP7 group.

  14. Differential Activation of Wnt-β-Catenin Pathway in Triple Negative Breast Cancer Increases MMP7 in a PTEN Dependent Manner

    Science.gov (United States)

    Dey, Nandini; Young, Brandon; Abramovitz, Mark; Bouzyk, Mark; Barwick, Benjamin; De, Pradip; Leyland-Jones, Brian

    2013-01-01

    Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC) deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012). Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP), including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide) and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54). The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25%) and High Rd (74%) in clinical stage T3 pathologic response in contrast to the high pCR (40%) and low residual disease (RD) (60%) of the low MMP7 group. PMID:24143235

  15. Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways.

    Science.gov (United States)

    Qian, Liqiang; Liu, Yan; Xu, Yang; Ji, Weidan; Wu, Qiuye; Liu, Yongjing; Gao, Quangen; Su, Changqing

    2015-11-01

    Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C30N4H40SO5F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo, and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment.

  16. Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN: an imaging demonstration

    Directory of Open Access Journals (Sweden)

    Yang ZS

    2014-03-01

    Full Text Available Zhuo-Shun Yang,1,* Xiang-Jun Tang,2,* Xing-Rong Guo,1 Dan-Dan Zou,1 Xu-Yong Sun,3 Jing-Bo Feng,1 Jie Luo,1 Long-Jun Dai,1,4 Garth L Warnock4 1Hubei Key Laboratory of Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 3Guangxi Key Laboratory for Transplant Medicine, 303 Hospital of PLA, Nanning, People’s Republic of China; 4Department of Surgery, University of British Columbia, Vancouver, BC, Canada *These authors contributed equally to this work Background: Mesenchymal stem cells (MSCs have been considered to hold great potential as ideal carriers for the delivery of anticancer agents since the discovery of their tumor tropism. This study was performed to demonstrate the effects of phosphatase and tensin homolog (PTEN engineering on MSCs’ capacity for cancer cell-oriented migration. Methods: MSCs were engineered with a PTEN-bearing plasmid and the expression was confirmed with Western blotting. A human glioma cell line (DBTRG was used as the target cell; DBTRG cell-oriented migration of MSCs was monitored with a micro speed photographic system. Results: The expression of transfected PTEN in MSCs was identified by immunoblotting analysis and confirmed with cell viability assessment of target cells. The DBTRG cell-oriented migration of PTEN-engineered MSCs was demonstrated by a real-time dynamic monitoring system, and a phagocytosis-like action of MSCs was also observed. Conclusion: MSCs maintained their capacity for cancer cell-directed migration after they were engineered with anticancer genes. This study provides the first direct evidence of MSCs’ tropism post-anticancer gene engineering. Keywords: gene therapy, mesenchymal stem cells, phosphatase and tensin homolog, cancer

  17. Molecular Mechanism of Nkx3.1 Deregulation and its Function in Murine Pten Prostate Cancer Model

    Science.gov (United States)

    2006-09-01

    hybridization , post hybridization , and analyses following standard laboratory procedure. The probe cocktail contained 20 differentially labeled chromosome...contain near tetraploid chromosome number, with 65-84 chromosomes in PTEN-P2 and 76-80 chromosomes in PTEN-CaP2; PTEN- P8 and PTEN-CaP8 have near 6N

  18. Cell surface area and membrane folding in glioblastoma cell lines differing in PTEN and p53 status.

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    Simon Memmel

    Full Text Available Glioblastoma multiforme (GBM is characterized by rapid growth, invasion and resistance to chemo-/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM, the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT technique. The osmotic stability and volume regulation of GBM cells were analyzed by video microscopy. The expression of PTEN, p53, mTOR and several other marker proteins involved in cell growth and membrane synthesis were examined by Western blotting. The combined SEM, ROT and osmotic data provided independent lines of evidence for a large variability in membrane area and folding among tested GBM lines. Thus, DK-MG cells (wild type p53 and wild type PTEN exhibited the lowest degree of membrane folding, probed by the area-specific capacitance C m = 1.9 µF/cm(2. In contrast, cell lines carrying mutations in both p53 and PTEN (U373-MG and SNB19 showed the highest C m values of 3.7-4.0 µF/cm(2, which corroborate well with their heavily villated cell surface revealed by SEM. Since PTEN and p53 are well-known inhibitors of mTOR, the increased membrane area/folding in mutant GBM lines may be related to the enhanced protein and lipid synthesis due to a deregulation of the mTOR-dependent downstream signaling pathway. Given that membrane folds and extensions are implicated in tumor cell motility and metastasis, the dielectric approach presented here provides a rapid and simple tool for screening the biophysical cell properties in studies on targeting chemo- or radiotherapeutically the

  19. Subcellular targeting and dynamic regulation of PTEN: Implications for neuronal cells and neurological disorders

    Directory of Open Access Journals (Sweden)

    Patricia eKreis

    2014-04-01

    Full Text Available PTEN is a lipid and protein phosphatase that regulates a diverse range of cellular mechanisms. PTEN is mainly present in the cytosol and transiently associates with the plasma membrane to dephosphorylate PI(3,4,5P3, thereby antagonizing the PI3-Kinase signaling pathway. Recently, PTEN has been shown to associate also with organelles such as the endoplasmic reticulum, the mitochondria or the nucleus, and to be secreted outside of the cell. In addition, PTEN dynamically localizes to specialized sub-cellular compartments such as the neuronal growth cone or dendritic spines. The diverse localizations of PTEN imply a tight temporal and spatial regulation, orchestrated by mechanisms such as posttranslational modifications, formation of distinct protein-protein interactions or the activation/recruitment of PTEN downstream of external cues. The regulation of PTEN function is thus not only important at the enzymatic activity level, but is also associated to its spatial distribution. In this review we will summarize (i recent findings that highlight mechanisms controlling PTEN movement and sub-cellular localization, and (ii current understanding of how PTEN localization is achieved by mechanisms controlling posttranslational modification, by association with binding partners and by PTEN structural or activity requirements. Finally, we will discuss the possible roles of compartmentalized PTEN in developing and mature neurons in health and disease.

  20. Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases

    DEFF Research Database (Denmark)

    Miletic, Ana V; Anzelon-Mills, Amy N; Mills, David M

    2010-01-01

    results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP(-/-)) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently......, follicular or centroblastic lymphoma. bPTEN/SHIP(-/-) B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27(kip1) and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP(-/-) B cells...... proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP(-/-) B cells. This study reveals that PTEN and SHIP act cooperatively...

  1. Fibrous hamartoma of infancy in the hand: unusual location and MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Song, You Seon; Lee, In Sook [Pusan National University School of Medicine, Department of Radiology, Busan (Korea); Pusan National University School of Medicine, Medical Research Institute, Busan (Korea); Kim, Hui Taek [Pusan National University Hospital, Department of Orthopaedic Surgery, Busan (Korea); Choi, Kyung-Un [Pusan National University School of Medicine, Medical Research Institute, Busan (Korea); Pusan National University Hospital, Department of Pathology, Busan (Korea); Song, Jong Woon [Inje University Pusan Paik Hospital, Department of Radiology, Busan (Korea)

    2010-10-15

    Fibrous hamartomas of infancy (FHIs) are benign, poorly-circumscribed, soft tissue growths presenting during the first 2 years of life and characteristically affecting the axilla, upper arm, upper trunk, inguinal region, and external genital area. Involvement of the hands and feet is extremely rare. We report a case of FHI unusually occurring in a deep portion of the hand. MRI revealed atypical features similar to that of a vascular malformation, hemangioma, fibromatosis, or neurofibromatosis of the hand. Partial resection of the mass was performed to correct the contracture of the second finger and an additional operation was not performed because of the benign nature of FHIs. (orig.)

  2. MR imaging findings of an atypical pulmonary hamartoma in a 12-year-old child

    Energy Technology Data Exchange (ETDEWEB)

    Alexopoulou, Efthymia; Economopoulos, Nikos; Kelekis, Nikolaos L. [National and Kapodistrian University of Athens, Department of Radiology, General University Hospital Attikon, Athens (Greece); Priftis, Kostas N. [Penteli Children' s Hospital, Department of Allergology-Pulmonology, Athens (Greece); Tsigka, Alexia [Athens Medical Centre, Pathology Department, Athens (Greece)

    2008-10-15

    We present the MR imaging findings in an atypical pulmonary hamartoma in a 12-year-old boy. CT showed no evidence of fat or calcifications in the tumour. It demonstrated peripheral rim enhancement on arterial-phase MR images due to a compressed respiratory epithelium, and progression to nearly homogeneous contrast enhancement on delayed-phase images. Small cystic spaces were identified on MR hydrographic and contrast-enhanced images formed by invaginating respiratory epithelium, a unique imaging finding in this condition. (orig.)

  3. Angiomyomatous hamartoma: a rare case report with review of the literature

    Directory of Open Access Journals (Sweden)

    Naseem Ansari

    2009-12-01

    Full Text Available Normal 0 false false false EN-GB X-NONE X-NONE MicrosoftInternetExplorer4 Angiomyomatous hamartoma of the lymph node is a benign vascular disorder of unknown aetiology, first described in 1991. However, to the best of our knowledge, it still remains a rare entity with only 17 cases reported so far. We report a case in an 82 year old male, present a review of literature, and stress the importance of diagnosis of this benign condition which obviates the need for unnecessary and extensive surgical resection.

  4. TMPRSS2-ERG and PTEN loss in prostate cancer.

    Science.gov (United States)

    Squire, Jeremy A

    2009-05-01

    Two studies show that the common recurrent gene fusion between TMPRSS2 and ERG promotes prostate cancer in both mouse and humans when PTEN is concurrently lost. In human prostate cancer, the presence of both these aberrations may be indicative of poor prognosis, suggesting that preclinical therapeutic research should target both of these pathways.

  5. Comparison of Color Fundus Photography, Infrared Fundus Photography, and Optical Coherence Tomography in Detecting Retinal Hamartoma in Patients with Tuberous Sclerosis Complex

    Institute of Scientific and Technical Information of China (English)

    Da-Yong Bai; Xu Wang; Jun-Yang Zhao; Li Li; Jun Gao; Ning-Li Wang

    2016-01-01

    Background:A sensitive method is required to detect retinal hamartomas in patients with tuberous sclerosis complex (TSC).The aim of the present study was to compare the color fundus photography,infrared imaging (IFG),and optical coherence tomography (OCT) in the detection rate of retinal hamartoma in patients with TSC.Methods:This study included 11 patients (22 eyes) with TSC,who underwent color fundus photography,IFG,and spectral-domain OCT to detect retinal hamartomas.TSC1 and TSC2 mutations were tested in eight patients.Results:The mean age of the 11 patients was 8.0 ± 2.1 years.The mean spherical equivalent was-0.55 ± 1.42 D by autorefraction with cycloplegia.In 11 patients (22 eyes),OCT,infrared fundus photography,and color fundus photography revealed 26,18,and 9 hamartomas,respectively.The predominant hamartoma was type I (55.6%).All the hamartomas that detected by color fundus photography or IFG can be detected by OCT.Conclusion:Among the methods of color fundus photography,IFG,and OCT,the OCT has higher detection rate for retinal hamartoma in TSC patients;therefore,OCT might be promising for the clinical diagnosis of TSC.

  6. Actin cytoskeleton organization, cell surface modification and invasion rate of 5 glioblastoma cell lines differing in PTEN and p53 status

    Energy Technology Data Exchange (ETDEWEB)

    Djuzenova, Cholpon S., E-mail: djuzenova_t@ukw.de [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Fiedler, Vanessa [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Memmel, Simon [Lehrstuhl für Biotechnologie und Biophysik, Universität Würzburg, Biozentrum Am Hubland, 97070 Würzburg (Germany); Katzer, Astrid; Hartmann, Susanne [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Krohne, Georg [Elektronenmikroskopie, Biozentrum, Universität Würzburg, Am Hubland, 97070 Würzburg (Germany); Zimmermann, Heiko [Hauptabteilung Biophysik and Kryotechnologie, Fraunhofer-Institut für Biomedizinische Technik, Lehrstuhl für Molekulare und Zelluläre Biotechnologie/Nanotechnologie, Universität des Saarlandes, Ensheimer Strasse 48, 66386 St. Ingbert (Germany); Scholz, Claus-Jürgen [Interdisciplinary Center for Clinical Research, University Hospital, Versbacher Strasse 7, 97078 Würzburg (Germany); Polat, Bülent; Flentje, Michael [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); and others

    2015-01-15

    Glioblastoma cells exhibit highly invasive behavior whose mechanisms are not yet fully understood. The present study explores the relationship between the invasion capacity of 5 glioblastoma cell lines differing in p53 and PTEN status, expression of mTOR and several other marker proteins involved in cell invasion, actin cytoskeleton organization and cell morphology. We found that two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) exhibited the highest invasion rates through the Matrigel or collagen matrix. In DK-MG (p53wt/PTENwt) and GaMG (p53mut/PTENwt) cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG (p53wt/PTENmut), U373-MG and SNB19 (both p53mut/PTENmut) cells preferentially expressed F-actin in filopodia and lamellipodia. Scanning electron microscopy confirmed the abundant filopodia and lamellipodia in the PTEN mutated cell lines. Interestingly, the gene profiling analysis revealed two clusters of cell lines, corresponding to the most (U373-MG and SNB19, i.e. p53 and PTEN mutated cells) and less invasive phenotypes. The results of this study might shed new light on the mechanisms of glioblastoma invasion. - Highlights: • We examine 5 glioblastoma lines on the invasion capacity and actin cytoskeleton. • Glioblastoma cell lines mutated in both p53 and PTEN were the most invasive. • Less invasive cells showed much less lamellipodia, but more actin stress fibers. • A mechanism for the differences in tumor cell invasion is proposed.

  7. Mutations of the KIT gene and loss of heterozygosity of the PTEN region in a primary malignant melanoma arising from a mature cystic teratoma of the ovary.

    Science.gov (United States)

    Tate, Genshu; Tajiri, Takuma; Suzuki, Takao; Mitsuya, Toshiyuki

    2009-04-01

    A tumor suppressor gene at 10q23.3, designated PTEN, encoding a dual-specificity phosphatase with lipid and protein phosphatase activity, has been shown to play a pivotal role in the pathogenesis of a variety of human cancers. A frequent loss of heterozygosity (LOH) at 10q is found in melanoma; however, little is known about the role of PTEN in the pathogenesis of a primary malignant melanoma derived from ovarian mature cystic teratoma, which is an extremely rare melanoma. This study examined the genetic alterations involved in the mitogen-activated protein kinase and phosphatidylinositol 3 kinase pathways in an ovarian malignant melanoma. A LOH analysis revealed hemizygous deletion around and in the PTEN gene not only in the ovarian melanoma but also in a mature cystic teratoma. Another case of ovarian mature cystic teratomas in the absence of melanoma also showed allelic loss of the PTEN region. To date, mutations of BRAF, NRAS, and KIT genes have been reported in malignant melanomas. In the present study, D816H and K558E mutations of the KIT gene were revealed in the melanoma arising from a mature cystic teratoma, but not in a mature cystic teratoma. No mutations of the BRAF and NRAS genes were found in the melanoma. These results indicate that LOH of the PTEN region is one of the molecular alterations of an ovarian mature cystic teratoma and a KIT mutation is an additional promotional event associated with the oncogenesis of a melanoma arising from an ovarian mature cystic teratoma.

  8. Involvement of IGF-2, IGF-1R, IGF-2R and PTEN in development of human tooth germ – an immunohistochemical study

    Science.gov (United States)

    Kero, Darko; Cigic, Livia; Medvedec Mikic, Ivana; Galic, Tea; Cubela, Mladen; Vukojevic, Katarina; Saraga-Babic, Mirna

    2016-01-01

    ABSTRACT Insulin-Like Growth Factor 2 (IGF-2) is a peptide hormone essential for prenatal growth and development. IGF-2 exerts its mitogenic effects via Insulin-Like Growth Factor 1 Receptor (IGF-1R), and is eliminated by binding to Insulin-Like Growth Receptor 2 (IGF-2R). IGF-2 is also negatively regulated by Phosphatase and Tensin Homolog (PTEN), a phosphatase mutated in various tumors. Not much is known about the interplay between these factors during human odontogenesis. In this study, expression patterns of IGF-2, IGF-1R, IGF-2R and PTEN were analyzed by double immunofluorescence in incisor human tooth germs during the foetal period of development between the 7th and 20th gestational week. Throughout the investigated period, IGF-2 was mostly expressed in enamel organ, whereas mild to moderate expression of PTEN could be seen in dental papilla and parts of enamel organ. Expression of IGF-1R was ubiquitous and displayed strong intensity throughout the entire enamel organ. In contrast, expression of IGF-2R had rather erratic pattern in enamel organ and dental papilla alike. Expression patterns of IGF-2, IGF-1R, IGF-2R and PTEN in highly proliferative cervical loops, as well as in differentiating pre-ameloblasts and pre-odontoblasts of cusp tip region during the early and late bell stages when enamel organ acquires definitive shape, indicate importance of these factors in crown morphogenesis of human incisor. Taken together, our data suggest the involvement of IGF-2, IGF-1R, IGF-2R and PTEN in temporo-spatial patterning of basic cellular processes (proliferation, differentiation) during normal tooth development. They are also relevant for improving knowledge of molecular basis of human odontogenesis. PMID:27326759

  9. Involvement of IGF-2, IGF-1R, IGF-2R and PTEN in development of human tooth germ - an immunohistochemical study.

    Science.gov (United States)

    Kero, Darko; Cigic, Livia; Medvedec Mikic, Ivana; Galic, Tea; Cubela, Mladen; Vukojevic, Katarina; Saraga-Babic, Mirna

    2016-07-02

    Insulin-Like Growth Factor 2 (IGF-2) is a peptide hormone essential for prenatal growth and development. IGF-2 exerts its mitogenic effects via Insulin-Like Growth Factor 1 Receptor (IGF-1R), and is eliminated by binding to Insulin-Like Growth Receptor 2 (IGF-2R). IGF-2 is also negatively regulated by Phosphatase and Tensin Homolog (PTEN), a phosphatase mutated in various tumors. Not much is known about the interplay between these factors during human odontogenesis. In this study, expression patterns of IGF-2, IGF-1R, IGF-2R and PTEN were analyzed by double immunofluorescence in incisor human tooth germs during the foetal period of development between the 7(th) and 20(th) gestational week. Throughout the investigated period, IGF-2 was mostly expressed in enamel organ, whereas mild to moderate expression of PTEN could be seen in dental papilla and parts of enamel organ. Expression of IGF-1R was ubiquitous and displayed strong intensity throughout the entire enamel organ. In contrast, expression of IGF-2R had rather erratic pattern in enamel organ and dental papilla alike. Expression patterns of IGF-2, IGF-1R, IGF-2R and PTEN in highly proliferative cervical loops, as well as in differentiating pre-ameloblasts and pre-odontoblasts of cusp tip region during the early and late bell stages when enamel organ acquires definitive shape, indicate importance of these factors in crown morphogenesis of human incisor. Taken together, our data suggest the involvement of IGF-2, IGF-1R, IGF-2R and PTEN in temporo-spatial patterning of basic cellular processes (proliferation, differentiation) during normal tooth development. They are also relevant for improving knowledge of molecular basis of human odontogenesis.

  10. Genetic aberration of PTEN in peripheral T cell lymphoma, not otherwise specified%非特指外周T细胞淋巴瘤中PTEN的改变

    Institute of Scientific and Technical Information of China (English)

    朱文娟; 张建中

    2012-01-01

    目的 观察非特指外周T细胞淋巴瘤(peripheral T cell lymphoma,not otherwise specified,PTCL-NOS)中抑癌基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)的改变情况,探讨其与肿瘤生物学行为的关系,为阐明PTCL-NOS的发生、发展机制提供科学依据.方法应用间期双色荧光原位杂交(fluorescence in situ hybridization,FISH)技术检测36例PTCL-NOS石蜡包埋组织中PTEN基因的改变情况,分析其改变与各临床参数的关系.结果 36例PTCL-NOS中8例出现PTEN杂合性缺失(loss of heterozygosity,LOH);Kaplan-Meier生存分析显示该基因异常组较正常组生存期明显缩短(P0.05).结论 PTCL-NOS存在的抑癌基因PTEN杂合性缺失,在PTCL-NOS发生、发展中可能起重要作用,是评估该肿瘤预后的重要指标.%Purpose To investigate the genetic changes of tumor suppressor gene PTEN in PTCL-NOS, and to explore its relationship with the development of PTCL-NOS and other clinicopathological parameters. Methods Thirty-six cases of PTCL-NOS were studied by fluorescence in-situ hybridization ( FISH ) using interphase dual-colour probes. The probes were generated from BAC clones RP11 - 380G5 corresponding to PTEN gene. Correlation of the genetic changes with patients prognosis and other clinical parameters was analyzed. Results Loss of heterozygosity ( LOH ) of PTEN presented in 8/36 cases; Kaplan-Meier survival analysis indicated there was a trend that the group with PTEN gene change had a poorer prognosis than the group without PTEN gene change ( P 0. 05 ). Conclusion A significant percentage of PTCL-NOS carry the genetic alteration of PTEN that may play an important role in the pathogenesis of PTCL-NOS and the e-valuation of the patient' s prognosis.

  11. Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy.

    Science.gov (United States)

    Hildebrand, Michael S; Griffin, Nicole G; Damiano, John A; Cops, Elisa J; Burgess, Rosemary; Ozturk, Ezgi; Jones, Nigel C; Leventer, Richard J; Freeman, Jeremy L; Harvey, A Simon; Sadleir, Lynette G; Scheffer, Ingrid E; Major, Heather; Darbro, Benjamin W; Allen, Andrew S; Goldstein, David B; Kerrigan, John F; Berkovic, Samuel F; Heinzen, Erin L

    2016-08-01

    Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.

  12. PTEN蛋白磷酸酶活性的作用%The Function of PTEN's Protein Phosphatase Activity

    Institute of Scientific and Technical Information of China (English)

    郝礼森; 刘小娟; 张晓岚

    2012-01-01

    PTEN一个具有磷酸酶活性的肿瘤抑制基因,是编码具有脂质磷酸酶活性和蛋白磷酸酶活性的双重特异性磷酸酶,其缺失或功能异常与人类恶性肿瘤的发生发展密切相关.PTEN的脂质磷酸酶活性和蛋白磷酸酶活性在调控肿瘤细胞的生物学行为、维持细胞正常的生理活动中均发挥了重要作用.但二者的作用重点及机制仍有不同,其蛋白磷酸酶活性主要侧重于调控细胞的黏附迁移及侵袭.为更好地认识PTEN蛋白磷酸酶活性的作用,该文对PTEN蛋白磷酸酶活性的作用及其机制作一简要综述.%Phosphatase and tensin homolog deleted on chromosome ten (PTEN), a tumor suppressorgene found to exhibit a dual specificity protein and lipid phosphatase activity, occurs deletion or dysfunction in a wide range of advanced cancers. Both lipid phosphatase activity and protein phosphatase activity of PTEN play an important role in regulating the biological behavior of tumor cell and maintaining normal cellular physiologic function. However, there are differences between lipid phosphatase activity and protein phosphatase activity in the focal point and mechanism of the function. And the function of its protein phosphatase activity is mainly to regulate the adhesion, migration and invasion of cell. In this article, the funcion of PTEN's protein phosphatase activity and its mechanisms were briefly summarized for a better understanding of its role.

  13. Human eccrine hamartoma of the forearm-antebrachial organ of the ringtailed lemur (Lemur catta). A possible phylogenetic relationship?

    Science.gov (United States)

    Kopera, D; Soyer, H P; Kerl, H

    1994-06-01

    A 31-year-old woman presented with a clinically otherwise unsuspicious area of profuse sweating on her right forearm. Without triggering agents, sweating attacks producing a clear, serous fluid were observed daily. Histopathologic examination of a biopsy specimen showed hyperplastic eccrine glands with pale, stippled cytoplasm characteristic of eccrine hamartoma. No explanation, however, has been given for the fact that several authors observed eccrine hamartomas in the same anatomical location. Adolescent lemurs of the species catta (ringtailed lemur) are equipped with a pair of antebrachial cutaneous glands located on the volar surface of the wrist. They exude a clear secretion enabling them to "brachial branch mark" their territories. Histopathologic findings in the ringtailed lemur's antebrachial organ show characteristics of both apocrine and eccrine glands. In contrast to normal apocrine glands, however, the antebrachial organs of ringtailed lemurs reach the epidermis directly and are not connected to hair follicles. According to the "biogenetic law" of Ernst Haeckel, stating that ontogeny has to be seen as a short and incomplete repetition of phylogeny, a human fetus passes all evolutional stages from a single cell via amphibians and mammals to a human being. Thus, the antebrachial organ of the ringtailed lemur may be the "phylogenetic explanation" for eccrine hamartomas of the forearm in humans. The histopathologic findings of the antebrachial organ and of eccrine hamartomas are in accordance with this hypothesis.

  14. Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene

    Directory of Open Access Journals (Sweden)

    Ohtoshi Akihira

    2008-10-01

    Full Text Available Abstract To investigate the roles of Pten and β-Catenin in the midbrain, either the Pten gene or the β-catenin gene was conditionally ablated, using Dmbx1 (diencephalon/mesencephalon-expressed brain homeobox gene 1-Cre mice. Homozygous disruption of the Pten or β-catenin gene in Dmbx1-expressing cells caused severe hydrocephalus and mortality during the postnatal period. Conditional deletion of Pten resulted in enlargement of midbrain structures. β-catenin conditional mutant mice showed malformation of the superior and inferior colliculi and stenosis of the midbrain aqueduct. These results demonstrate that both Pten and β-Catenin are essential for proper midbrain development, and provide the direct evidence that mutations of both Pten and β-catenin lead to hydrocephalus.

  15. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils.

    Science.gov (United States)

    Heit, Bryan; Robbins, Stephen M; Downey, Charlene M; Guan, Zhiwen; Colarusso, Pina; Miller, B Joan; Jirik, Frank R; Kubes, Paul

    2008-07-01

    Neutrophils encounter and 'prioritize' many chemoattractants in their pursuit of bacteria. Here we tested the possibility that the phosphatase PTEN is responsible for the prioritization of chemoattractants. Neutrophils induced chemotaxis by two separate pathways, the phosphatidylinositol-3-OH kinase (PI(3)K) phosphatase and tensin homolog (PTEN) pathway, and the p38 mitogen-activated protein kinase pathway, with the p38 pathway dominating over the PI(3)K pathway. Pten(-/-) neutrophils could not prioritize chemoattractants and were 'distracted' by chemokines when moving toward bacterial chemoattractants. In opposing gradients, PTEN became distributed throughout the cell circumference, which inhibited all PI(3)K activity, thus permitting 'preferential' migration toward bacterial products via phospholipase A(2) and p38. Such prioritization was defective in Pten(-/-) neutrophils, which resulted in defective bacterial clearance in vivo. Our data identify a PTEN-dependent mechanism in neutrophils to prioritize, 'triage' and integrate responses to multiple chemotactic cues.

  16. Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Joshi, Ayesha; Ellenson, Lora Hedrick, E-mail: lora.ellenson@med.cornell.edu

    2011-07-01

    Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten{sup +/-} mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten{sup +/-} mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ER{alpha} as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

  17. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Bergmann, Troels K; Henrichsen-Schnack, Tine

    2014-01-01

    BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS......-RAF-MAPK and PI3K-AKT-mTOR pathways in colorectal cancer is uncertain, which led us to systematically review the impact of alterations in KRAS (outside of exon 2), NRAS, BRAF, PIK3CA and PTEN in relation to the clinical benefit from anti-EGFR treatment. METHODS: In total, 22 studies that include 2395 patients......, NRAS, BRAF and PIK3CA and non-functional PTEN predict resistance to anti-EGFR therapies and demonstrates that biomarker analysis beyond KRAS exon 2 should be implemented for prediction of clinical benefit from anti-EGFR antibodies in metastatic colorectal cancer....

  18. PTEN, Stem Cells, and Cancer Stem Cells*S⃞

    OpenAIRE

    Hill, Reginald; Wu, Hong

    2009-01-01

    Like normal stem cells, “cancer stem cells” have the capacity for indefinite proliferation and generation of new cancerous tissues through self-renewal and differentiation. Among the major intracellular signaling pathways, WNT, SHH, and NOTCH are known to be important in regulating normal stem cell activities, and their alterations are associated with tumorigenesis. It has become clear recently that PTEN (phosphatase and tensin homologue) is also critical for stem cell...

  19. Expression of PPARγ and PTEN in human colorectal cancer: An immunohistochemical study using tissue microarray methodology.

    Science.gov (United States)

    Lin, Mao Song; Huang, Jun Xing; Chen, Wei Chang; Zhang, Bao Feng; Fang, Jing; Zhou, Qiong; Hu, Ying; Gao, Heng Jun

    2011-11-01

    Although aberrations of peroxisome proliferator-activated receptor γ (PPARγ) and phosphatase and tensin homolog (PTEN) expression have been identified in several other cancer types, certain previous studies have revealed that PPARγ is abundant in normal and malignant tissue in the colon. The question of whether aberrant PTEN is involved in the initial stage or is a later event during colorectal carcinogenesis remains controversial. Relatively few studies have focused on the correlation of expression of PPARγ and PTEN in various tissues. In the present study, paraffin-embedded blocks from 139 patients with CRC, 18 adenomatous polyps and 50 paired paracancerous benign mucosas were selected and analysed in 4 tissue microarray (TMA) blocks comprising 104, 72, 130 and 54 cores, respectively. Expression of PPARγ and PTEN was examined using immunohistochemical staining on TMAs. There were no significant differences in the expression of PPARγ (P=0.055) and PTEN (P=0.100) between the colorectal cancers, adenomas and paracancerous mucosas. However, correlations of PPARγ expression with clinical stage (P=0.004) and PTEN expression with histological grade (P=0.006) and distant metastasis (P=0.015) were demonstrated in the CRC specimens. Although the differences in PPARγ and PTEN protein expression in human colorectal cancer may not be considered as early diagnostic markers, our results indicate that CRCs with a low expression or deletion of PTEN may progress towards invasion and even metastasis; thus, PTEN may have potential as a prognostic marker in human CRC.

  20. Fetal intracranial tumors: a review of 27 cases

    Energy Technology Data Exchange (ETDEWEB)

    Cassart, M.; Avni, F. [Erasme University Hospital, Department of Medical Imaging, Brussels (Belgium); Bosson, N.; Garel, C. [Hopital d' Enfants Armand-Trousseau, Department of Medical Imaging, Paris (France); Eurin, D. [Charles Nicolle Hospital, Department of Pediatric Imaging, Rouen (France)

    2008-10-15

    Fetal intracranial tumors are rare. The diagnosis is generally made on histology after birth. The aim of this study was to analyze clinical and imaging data in a series of fetal intracranial tumors and emphasize the findings that may help approach the diagnosis antenatally. We retrospectively analyzed imaging and clinical findings in 27 cases of fetal intracranial tumors assessed by ultrasound (27/27) and MR imaging (24/27). A histological diagnosis was always obtained. Main diagnoses included 15 germinal tumors (13 teratomas), 4 glial tumors, 2 craniopharyngiomas and 3 hamartomas. Average gestational age at diagnosis was 27 weeks for teratomas, 21 weeks for hamartomas and 34 weeks for glial tumors. All tumors but one were supra tentorial, and the lesion extended in the posterior fossa in two teratomas. A heterogeneous pattern, which was more frequently seen in teratomas, was better visualized by MR than US imaging. In addition, in two cases of teratomas, MR imaging better assessed the extension of the tumor. Teratomas and gliomas are the most frequent brain tumors in the fetus. US and MR imagings appear complementary in the prenatal assessment of these lesions. (orig.)

  1. Pedunculated Brunner's gland hamartoma of the duodenum causing upper gastrointestinal hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Shoji Hirasaki; Motoharu Kubo; Atsushi Inoue; Yasuyuki Miyake; Hisako Oshiro

    2009-01-01

    A case of pedunculated Brunner's gland hamartoma (BGH) of the duodenum causing upper gastrointestinal (GI) hemorrhage is reported. The patient was a 47-year-old man who visited our hospital for further evaluation of tarry stools and shortness of breath.Endoscopic examination of the upper digestive tract revealed a large peduncular polyp with bleeding,about 30 mm in diameter, arising from the wall of the second portion of the duodenum. GI bleeding occurred from the base of the stalk of the polyp. Endoscopic polypectomy was performed. Histological examination of the specimen revealed that the main body of the polyp contained several lobules of mature Brunner'gland with areas of cystic dilatation. The surface epithelium consisted of normal duodenal mucosa with areas of focal ulceration. This polyp was diagnosed as a BGH. The symptom of tarry stools resolved after endoscopic resection. Our case shows that treatment is necessary for duodenal BGH if GI bleeding occurs.

  2. Oral leiomyomatous hamartoma of the median maxillary gingiva: a case report and review of the literature.

    Science.gov (United States)

    ALQahtani, Dalal; Qannam, Ahmed

    2013-08-01

    Oral leiomyomatous hamartoma (OLH) is a rare lesion seen in the oral cavity. It mainly presents on the median maxilla and tongue. In the literature in English, there are only 10 reported cases of OLH of the median maxilla. Most of the cases were found in patients of Japanese and Latin American origin. We report a case of OLH in an 18-month-old boy of Middle Eastern ancestry. The lesion presented as a pedunculated, light pink, soft swelling that was located on the labial gingiva of tooth number 21. Microscopically, it showed proliferative smooth-muscle fascicles dispersed in loose fibrous stroma and multiple small vessels. The lesional cells looked mature and elongated and were deeply eosinophilic spindle cells with basophilic, central "cigar-shaped" nuclei. The diagnosis of OLH was supported by positive immunohistochemical reactivity of smooth-muscle actin and desmin. To our knowledge, this is the first reported case of OLH in a Middle Eastern patient.

  3. MiR-26a inhibits proliferation and migration of HaCaT keratinocytes through regulating PTEN expression.

    Science.gov (United States)

    Yu, Nanze; Yang, Yang; Li, Xiongwei; Zhang, Mingzi; Huang, Jiuzuo; Wang, Xiaojun; Long, Xiao

    2016-12-05

    MicroRNAs (miRNAs) have been shown to be associated with differentiation, migration and apoptosis in keratinocyte. Although it has been reported that microRNA-26a (miR-26a) plays important roles in tumor cells, its biological functions in keratinocytes are still not well elucidated. In this study, we confirmed expression of miR-26a in human keratinocytes using RT-PCR and further studied the role of miR-26a in cell proliferation and cell migration. Ectopic expression of MiR-26a mimic or inhibitor increased or decreased miR-26a expression respectively in HaCaT cells. Proliferation of HaCaT keratinocyte can be suppressed or promoted by overexpression or down-expression of miR-26a. In scratch wound-healing assay and Boyden chamber cell migration assay, upregulating miR-26a expression blocked cell migration, while downregulating miR-26a expression enhanced the migration. Using quantitative RT-PCR (qRT-PCR) and western blot, we further discovered that both mRNA and protein level of phosphatase and tensin homolog deleted from chromosome 10(PTEN) were regulated by miR-26a in HaCaT cells. Meanwhile the level of active form of AKT was also regulated by the miR-26a. In rescue experiment, knockdown of PTEN in the miR-26a mimic transduced cells recovered the migration ability of HaCaT cells. Together these results suggest that miR-26a modulates the proliferation and migration of keratinocytes via regulating PTEN/AKT signaling pathway.

  4. Cell-Type Specific Roles for PTEN in Establishing a Functional Retinal Architecture

    Science.gov (United States)

    Cantrup, Robert; Dixit, Rajiv; Palmesino, Elena; Bonfield, Stephan; Shaker, Tarek; Tachibana, Nobuhiko; Zinyk, Dawn; Dalesman, Sarah; Yamakawa, Kazuhiro; Stell, William K.; Wong, Rachel O.; Reese, Benjamin E.; Kania, Artur; Sauvé, Yves; Schuurmans, Carol

    2012-01-01

    Background The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture. Methodology/Principal Findings In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam. Conclusions/Significance We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular

  5. Cell-type specific roles for PTEN in establishing a functional retinal architecture.

    Directory of Open Access Journals (Sweden)

    Robert Cantrup

    Full Text Available BACKGROUND: The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture. METHODOLOGY/PRINCIPAL FINDINGS: In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam. CONCLUSIONS/SIGNIFICANCE: We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected

  6. Rescue of glandular dysmorphogenesis in PTEN-deficient colorectal cancer epithelium by PPARγ-targeted therapy.

    Science.gov (United States)

    Jagan, I; Fatehullah, A; Deevi, R K; Bingham, V; Campbell, F C

    2013-03-07

    Disruption of glandular architecture associates with poor clinical outcome in high-grade colorectal cancer (CRC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN) regulates morphogenic growth of benign MDCK (Madin Darby Canine Kidney) cells through effects on the Rho-like GTPase cdc42 (cell division cycle 42). This study investigates PTEN-dependent morphogenesis in a CRC model. Stable short hairpin RNA knockdown of PTEN in Caco-2 cells influenced expression or localization of cdc42 guanine nucleotide exchange factors and inhibited cdc42 activation. Parental Caco-2 cells formed regular hollow gland-like structures (glands) with a single central lumen, in three-dimensional (3D) cultures. Conversely, PTEN-deficient Caco-2 ShPTEN cells formed irregular glands with multiple abnormal lumens as well as intra- and/or intercellular vacuoles evocative of the high-grade CRC phenotype. Effects of targeted treatment were investigated. Phosphatidinylinositol 3-kinase (PI3K) modulating treatment did not affect gland morphogenesis but did influence gland number, gland size and/or cell size within glands. As PTEN may be regulated by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ), cultures were treated with the PPARγ ligand rosiglitazone. This treatment enhanced PTEN expression, cdc42 activation and rescued dysmorphogenesis by restoring single lumen formation in Caco-2 ShPTEN glands. Rosiglitazone effects on cdc42 activation and Caco-2 ShPTEN gland development were attenuated by cotreatment with GW9662, a PPARγ antagonist. Taken together, these studies show PTEN-cdc42 regulation of lumen formation in a 3D model of human CRC glandular morphogenesis. Treatment by the PPARγ ligand rosiglitazone, but not PI3K modulators, rescued colorectal glandular dysmorphogenesis of PTEN deficiency.

  7. Hyperactivity of Newborn Pten Knock-out Neurons Results from Increased Excitatory Synaptic Drive

    Science.gov (United States)

    Williams, Michael R.; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T.

    2015-01-01

    Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either “birthdate” or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. PMID:25609613

  8. Cdc6 and Cyclin E2 Are PTEN-Regulated Genes Associated with Human Prostate Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zhong Wu

    2009-01-01

    Full Text Available Phosphatase and tensin homolog deleted on chromosome 10 (PTEN is frequently inactivated in metastatic prostate cancer, yet the molecular consequences of this and their association with the metastatic phenotype are incompletely understood. We performed transcriptomic analysis and identified genes altered by conditional PTEN reexpression in C4-2, a human metastatic prostate cancer cell line with inactive PTEN. PTEN-regulated genes were disproportionately represented among genes altered in human prostate cancer progression and metastasis but not among those associated with tumorigenesis. From the former set, we identified two novel putative PTEN targets, cdc6 and cyclin E2, which were overexpressed in metastatic human prostate cancer and up-regulated as a function of PTEN depletion in poorly metastatic DU145 human prostate cancer cells harboring a wild type PTEN. Inhibition of cdc6 and cyclin E2 levels as a consequence of PTEN expression was associated with cell cycle G1 arrest, whereas use of PTEN activity mutants revealed that regulation of these genes was dependent on PTEN lipid phosphatase activity. Computational and promoter-reporter evaluations implicated the E2F transcription factor in PTEN regulation of cdc6 and cyclin E2 expression. Our results suggest a hypothetical model whereby PTEN loss upregulates cell cycle genes such as cdc6 and cyclin E2 that in turn promote metastatic colonization at distant sites.

  9. Studies of variability in the PTEN gene among Danish caucasian patients with Type II diabetes mellitus

    DEFF Research Database (Denmark)

    Hansen, L; Jensen, J N; Ekstrøm, C T

    2001-01-01

    Phosphatase and tensin homologue deleted from chromosome ten (PTEN) has recently been characterized as a novel member in the expanding network of proteins regulating the intracellular effects of insulin. By dephosphorylation of phosphatidyl-inositol-(3, 4, 5)-trisphosphate (PIP3) the PTEN protein...

  10. Systematic analysis of the PTEN 5' leader identifies a major AUU initiated proteoform.

    Science.gov (United States)

    Tzani, Ioanna; Ivanov, Ivaylo P; Andreev, Dmitri E; Dmitriev, Ruslan I; Dean, Kellie A; Baranov, Pavel V; Atkins, John F; Loughran, Gary

    2016-05-01

    Abundant evidence for translation within the 5' leaders of many human genes is rapidly emerging, especially, because of the advent of ribosome profiling. In most cases, it is believed that the act of translation rather than the encoded peptide is important. However, the wealth of available sequencing data in recent years allows phylogenetic detection of sequences within 5' leaders that have emerged under coding constraint and therefore allow for the prediction of functional 5' leader translation. Using this approach, we previously predicted a CUG-initiated, 173 amino acid N-terminal extension to the human tumour suppressor PTEN. Here, a systematic experimental analysis of translation events in the PTEN 5' leader identifies at least two additional non-AUG-initiated PTEN proteoforms that are expressed in most human cell lines tested. The most abundant extended PTEN proteoform initiates at a conserved AUU codon and extends the canonical AUG-initiated PTEN by 146 amino acids. All N-terminally extended PTEN proteoforms tested retain the ability to downregulate the PI3K pathway. We also provide evidence for the translation of two conserved AUG-initiated upstream open reading frames within the PTEN 5' leader that control the ratio of PTEN proteoforms.

  11. Dynamic computed tomography findings of atypical pulmonary hamartoma and it's pathologic correlations: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Seung Baek; Jeong Yeon Joo Lee, Gee Won; Kim, Yeong Dae; Ahn, Hyo Yeong; Lee, Chang Hoon; Kim, Ah Rong; Lee, Ji Won [Medical Research Institute, Pusan National University Hospital, Busan (Korea, Republic of)

    2016-04-15

    We present the dynamic contrast-enhanced computed tomography (CT) findings of atypical pulmonary hamartoma with a rare histologic pattern in a 20-year-old male. CT showed a 3.4 cm lobulated mass with a 'tip of the iceberg' appearance in the medium bronchus of the right lower lobe. Dynamic contrast-enhanced CT demonstrated a heterogeneously and persistently enhancing mass. The CT Hounsfield unit (HU) measurements were: 17 HU pre-contrast, 32 HU at 1 minute, 44 HU at 2 minutes, 51 HU at 4 minutes, and 64 HU at 15 minutes. Pathologic examination after video-assisted thoracoscopic surgery disclosed a pulmonary hamartoma with a predominant fibroblastic component.

  12. MiR-21 inhibitor suppressed the progression of retinoblastoma via the modulation of PTEN/PI3K/AKT pathway.

    Science.gov (United States)

    Gui, Fu; Hong, Zhengdong; You, Zhipeng; Wu, Hongxi; Zhang, Yulan

    2016-12-01

    MicroRNA-21 (miR-21) was reported to act as an oncogene during the development of many human tumors. However, little was revealed about the function of miR-21 in retinoblastoma (RB). In this study, we examined the expression of miR-21 in RB tissues and explored the relationship between miR-21 and phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-OH kinase (PI3K)/AKT signal. Quantitative real-time PCR (qRT-PCR) results showed that the level of miR-21 in RB tissues was higher than that in retinal normal tissues. In Weri-Rb-1 cells, miR-21 inhibitor suppressed the expression of miR-21 and cell viability, but improved cell apoptotic rates by modulating the levels of PDCD4, Bax, and Bcl-2. Meanwhile, miR-21 inhibitor suppressed cell migration and invasion via inhibiting the protein levels of MMP2 and MMP9 and significantly affected the expression of PTEN, PI3K, and p-AKT. Taken together, miR-21 inhibitor suppressed cell proliferation, migration, and invasion via the PTEN/PI3K/AKT signal. These findings revealed the molecular basis of miR-21 functioning in the progression of RB and provided a new means for cell therapy in RB.

  13. MicroRNA-130b targets PTEN to mediate drug resistance and proliferation of breast cancer cells via the PI3K/Akt signaling pathway

    Science.gov (United States)

    Miao, Yuan; Zheng, Wei; Li, Nana; Su, Zhen; Zhao, Lifen; Zhou, Huimin; Jia, Li

    2017-01-01

    Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among breast cancer patients. This study was aimed to investigate the possible mechanism by which microRNA-130b-3p (miR-130b) mediates the chemoresistance and proliferation of breast cancer. MiR-130b was found to be up-regulated in tumor tissues versus adjacent tissues of breast cancer, as well as in adriamycin (ADR) resistant breast cancer cell line (MCF-7/ADR) versus its parental line (MCF-7) and the non-malignant breast epithelial cell line (MCF-10A), demonstrating its crucial relevance for breast cancer biology. We identified that PTEN was a direct target of miR-130b and inversely correlated with miR-130b expression in breast cancer. Moreover, over-expression of miR-130b promoted drug resistance, proliferation and decreased apoptosis of MCF-7 cells, while suppression of miR-130b enhanced drug cytotoxicity and apoptosis, as well as reduced proliferation of MCF-7/ADR cells in vitro and in vivo. Particularly, miR-130b mediated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway as well as the chemoresistance and proliferation of breast cancer cell lines, which was partially blocked following knockdown of PTEN. Altogether, miR-130b targets PTEN to induce MDR, proliferation, and apoptosis via PI3K/Akt signaling pathway. This provides a novel promising candidate for breast cancer therapy. PMID:28165066

  14. Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE), and neuromuscular and vascular hamartoma (NMVH): two sides of the same coin?

    Science.gov (United States)

    Setaffy, Lisa; Osuna, María José Martín; Plieschnegger, Wolfgang; del Pino Florez Rial, María; Geboes, Karel; Langner, Cord

    2015-04-01

    Multifocal stenosing enteritis, not related to Crohn's disease or drug intake, has been described under two different terms: "cryptogenic multifocal ulcerous stenosing enteritis" (CMUSE) and "neuromuscular and vascular hamartoma" (NMVH). We present three new cases of this condition and argue that the two terms reflect the same disease entity. Although etiology and pathogenesis of the disease remain largely unclear, obliterative vascular changes may play an important role.

  15. Casos Clínicos Hamartoma hipotalámico, una causa de pubertad precoz: Caso clínico

    OpenAIRE

    Alvarado R,José; López M,José Manuel

    2001-01-01

    Hypothalamic hamartomas are non neoplastic lesions that may cause precocious puberty with or without complex seizures, personality disorders and mental retardation. We report a 14 years old male that had a precocious puberty at the age of 11 and a prolonged episode of altered sensorium with automatism, that was diagnosed as a complex seizure. Physical examination showed a sexual development classified as Tanner stage III-IV, a height of 168 cm and a weight of 61 kg. Neurological examination w...

  16. Tramadol regulates proliferation, migration and invasion via PTEN/PI3K/AKT signaling in lung adenocarcinoma cells.

    Science.gov (United States)

    Xia, M; Tong, J-H; Ji, N-N; Duan, M-L; Tan, Y-H; Xu, J-G

    2016-06-01

    Tramadol is used mainly for the treatment of moderate to severe chronic cancer pain. However, the effect of tramadol on lung cancer remains unclear. Therefore, it is important to explore the mechanism accounting for the function of tramadol on lung cancer. We investigated the effects of tramadol on the proliferation, migration and invasion in human lung adenocarcinoma cells in vitro by CCK-8 assay, wound healing assay and Transwell assay, respectively. We also explored the potential mechanism of tramadol on lung cancer cells by Western blotting. A549 and PC-9 cells were incubated with 2 µM tramadol for different time (0, 7, 14 and 28 d). The in vitro experiments showed that tramadol treatment significantly inhibited cell proliferation, migration and invasion in a time-dependent manner. Moreover, administration of tramadol suppressed tumor growth in vivo. The data also revealed that tramadol could up-regulate the protein expression level of PTEN and consistently inhibit the phosphorylation level of PI3K and Akt, whereas the total level of PI3K and Akt remain unchanged. These findings indicated that tramadol inhibited proliferation, migration and invasion of human lung adenocarcinoma cells through elevation of PTEN and inactivation of PI3K/Akt signaling.

  17. Activation of miR-21 by STAT3 induces proliferation and suppresses apoptosis in nasopharyngeal carcinoma by targeting PTEN gene.

    Directory of Open Access Journals (Sweden)

    Hesheng Ou

    Full Text Available The present study is to investigate the role of microRNA-21 (miR-21 in nasopharyngeal carcinoma (NPC and the mechanisms of regulation of PTEN by miR-21. Fifty-four tissue samples were collected from 42 patients with NPC and 12 healthy controls. Human NPC cell lines CNE-1, CNE-2, TWO3 and C666-1 were used for cell assays. To investigate the expression of miR-21, RT-PCR was employed. RT-PCR, Western blotting, and immunohistochemistry were used to measure the expression of STAT3 mRNA and STAT3 protein. To test the effect of miR-21 on the cell growth and apoptosis of NPC cells in vitro, transfection of CNE1 and CNE2 cell lines and flow cytometry were performed. TUNEL assay was used to detect DNA fragmentation. To validate whether miR-21 directly recognizes the 3'-UTRs of PTEN mRNA, luciferase reporter assay was employed. miR-21 expression was increased in NPC tissues compared with control and the same result was found in NPC cell lines. Notably, increased expression of miR-21 was directly related to advanced clinical stage and lymph node metastasis. STAT3, a transcription factor activated by IL-6, directly activated miR-21 in transformed NPC cell lines. Furthermore, miR-21 markedly inhibited PTEN tumor suppressor, leading to increased AKT activity. Both in vitro and in vivo assays revealed that miR-21 enhanced NPC cell proliferation and suppressed apoptosis. miR-21, activated by STAT3, induced proliferation and suppressed apoptosis in NPC by targeting PTEN-AKT pathway.

  18. Downregulation of PTEN at Corneal Wound Sites Accelerates Wound Healing through Increased Cell Migration

    Science.gov (United States)

    Cao, Lin; Graue-Hernandez, Enrique O.; Tran, Vu; Reid, Brian; Pu, Jin; Mannis, Mark J.

    2011-01-01

    Purpose. The PI3K/Akt pathway is required for cell polarization and migration, whereas the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has inhibitory effects on the PI3K/Akt pathway. The authors therefore hypothesized that wounding would downregulate PTEN and that this downregulation would enhance wound healing. Methods. In human corneal epithelial (HCE) cell monolayer and rat cornea scratch wound models, the authors investigated PTEN and Akt expression using Western blot and immunofluorescence analyses. The effects of PTEN and PI3K inhibitors dipotassium bisperoxo (picolinato) oxovanadate (bpv(pic)) and LY294002 on cell migration and wound closure were investigated using time-lapse imaging. Finally, the authors investigated the effect of PTEN inhibition on wound healing in whole rat eyes. Results. In HCE cell monolayer and rat cornea, PTEN was downregulated at the wound edges within 30 minutes of wounding. The downregulation of PTEN was causal in a simultaneous increase in Akt activation, which was responsible for a significant increase in individual cell migration rate from 8.8 μm/h to 17.3 μm/h. An increased migration rate was maintained for 20 hours. PTEN inhibition significantly enhanced the wound healing rate in the HCE cell monolayer from 10 minutes onward after treatment and reduced the healing time in eye organ culture from 30 to 20 hours. Conclusions. Injury to the corneal epithelium downregulates the expression of PTEN at wound edges, allowing increased PI3K/Akt signaling, thereby contributing to a significant enhancement of cell migration and wound healing. These results suggest that PTEN inhibition may be an effective treatment for corneal injury. PMID:21212174

  19. Triptolide inhibits the growth of osteosarcoma by regulating microRNA-181a via targeting PTEN gene in vivo and vitro.

    Science.gov (United States)

    Jiang, Chunming; Fang, Xiang; Zhang, Hongxu; Wang, Xuepeng; Li, Maoqiang; Jiang, Wu; Tian, Fei; Zhu, Liulong; Bian, Zhenyu

    2017-04-01

    We aimed to study the anti-tumor effects of triptolide on osteosarcoma and the related molecular mechanisms. The cell viability, apoptosis portion, tumor size, tumor weight, and invasion of osteosarcoma cells were determined. The relative level of microRNA-181 in osteosarcoma tissues and the adjacent tissues was determined by quantitative real-time reverse transcription polymerase chain reaction. The target gene of microRNA-181a was determined and verified by luciferase report assay. At last, osteosarcoma cells were treated with triptolide and triptolide + microRNA-181a mimics to verify the relationship between triptolide and microRNA-181a. Triptolide inhibited the cell viability, promoted the apoptosis, decreased the tumor size and weight, and reduced the invasion of osteosarcoma cells. The level of microRNA-181a in osteosarcoma cells decreased significantly after treating with triptolide, and the relative level of microRNA-181a in osteosarcoma tissues was markedly higher than that in the adjacent tissues. PTEN was reported and verified the direct target gene of microRNA-181a. The overexpression of microRNA-181a decreased the inhibition of triptolide on osteosarcoma proliferation and promotion on osteosarcoma apoptosis. In conclusion, triptolide inhibited cell growth and invasion of osteosarcoma by regulating microRNA-181a via targeting PTEN gene in vivo and vitro.

  20. Detecting PTEN and PI3K signaling in brain

    Science.gov (United States)

    Zhu, Guo; Baker, Suzanne J.

    2016-01-01

    Summary The central nervous system is comprised of multiple cell types including neurons, glia and other supporting cells that may differ dramatically in levels of signaling pathway activation. Immunohistochemistry in conjunction with drug interference are powerful tools that allow evaluation of signaling pathways in different cell types of the mouse central nervous system in vivo. Here we provide detailed protocols for immunohistochemistry to evaluate three essential components in the PI3K pathway in mouse brain: Pten, p-Akt and p-4ebp1, and for rapamycin treatment to modulate mTOR signaling in vivo. PMID:27033070

  1. Antagonism of miR-21 reverses epithelial-mesenchymal transition and cancer stem cell phenotype through AKT/ERK1/2 inactivation by targeting PTEN.

    Directory of Open Access Journals (Sweden)

    Mingli Han

    Full Text Available BACKGROUND: Accumulating evidence suggested that epithelial-mesenchymal transition (EMT and cancer stem cell (CSC characteristics, both of which contribute to tumor invasion and metastasis, are interrelated with miR-21. MiR-21 is one of the important microRNAs associated with tumor progression and metastasis, but the molecular mechanisms underlying EMT and CSC phenotype during miR-21 contributes to migration and invasion of breast cancer cells remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, MDA-MB-231/anti-miR-21 cells were established by transfected hsa-miR-21 antagomir into breast cancer MDA-MB-231 cells. EMT was evaluated by the changes of mesenchymal cell markers (N-cadherin, Vimentin, and alpha-SMA, epithelial cell marker (E-cadherin, as well as capacities of cell migration and invasion; CSC phenotype was measured using the changes of CSC surface markers (ALDH1 and CD44, and the capacity of sphereforming (mammospheres. We found that antagonism of miR-21 reversed EMT and CSC phenotype, accompanied with PTEN up-regulation and AKT/ERK1/2 inactivation. Interestingly, down-regulation of PTEN by siPTEN suppressed the effects of miR-21 antagomir on EMT and CSC phenotype, confirming that PTEN is a target of miR-21 in reversing EMT and CSC phenotype. The inhibitors of PI3K-AKT and ERK1/2 pathways, LY294002 and U0126, both significantly suppressed EMT and CSC phenotype, indicating that AKT and ERK1/2 pathways are required for miR-21 mediating EMT and CSC phenotype. CONCLUSIONS/SIGNIFICANCE: In conclusion, our results demonstrated that antagonism of miR-21 reverses EMT and CSC phenotype through targeting PTEN, via inactivation of AKT and ERK1/2 pathways, and showed a novel mechanism of which might relieve the malignant biological behaviors of breast cancer.

  2. Expression of DNA ligase IV is linked to poor prognosis and characterizes a subset of prostate cancers harboring TMPRSS2:ERG fusion and PTEN deletion.

    Science.gov (United States)

    Grupp, Katharina; Roettger, Laura; Kluth, Martina; Hube-Magg, Claudia; Simon, Ronald; Lebok, Patrick; Minner, Sarah; Tsourlakis, Maria Christina; Koop, Christina; Graefen, Markus; Adam, Meike; Haese, Alexander; Wittmer, Corinna; Sauter, Guido; Wilczak, Waldemar; Huland, Hartwig; Schlomm, Thorsten; Steurer, Stefan; Krech, Till

    2015-09-01

    DNA ligases are essential for the maintenance of genome integrity as they are indispensable for DNA replication, recombination and repair. The present study was undertaken to gain insights into the prevalence and clinical significance of ligase IV (LIG4) expression in prostate cancer. A total of 11,152 prostate cancer specimens were analyzed by immunohistochemistry for LIG4 expression. Results were compared to follow-up data, ERG status and deletions at PTEN, 3p13, 5q21 and 6q15. LIG4 expression was predominantly localized in the nucleus of the cells with increased intensities in malignant as compared to benign prostate epithelium. In prostate cancer, LIG4 expression was found in 91% of interpretable tumors, including 12% cancers with weak, 23% with moderate and 56% with strong LIG4 positivity. Strong LIG4 expression was tightly linked to advanced Gleason score (P<0.0001) and positive nodal involvement (P=0.03). There was a remarkable accumulation of strong LIG4 expression in tumors harboring TMPRSS2:ERG fusion and PTEN deletions (P<0.0001 each). High LIG4 expression was also tightly related to early biochemical recurrence when all tumors (P<0.0001) or the subsets of ERG-negative (P=0.0004) or ERG-positive prostate cancers (P=0.006) were analyzed. Multivariate analysis including parameters that are available before surgery demonstrated independent association with biochemical recurrence for advanced Gleason grade on biopsy, high preoperative PSA level, high clinical stage (P<0.0001 each) and for LIG4 immunostaining (P=0.03). Our study identifies LIG4 as a predictor of an increased risk for early PSA recurrence in prostate cancer. Moreover, the strong association with TMPRSS2:ERG fusion and PTEN deletions suggest important interactions between these pathways in prostate cancers.

  3. Ginkgolic Acid C 17:1, Derived from Ginkgo biloba Leaves, Suppresses Constitutive and Inducible STAT3 Activation through Induction of PTEN and SHP-1 Tyrosine Phosphatase

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    Seung Ho Baek

    2017-02-01

    Full Text Available Ginkgolic acid C 17:1 (GAC 17:1 extracted from Ginkgo biloba leaves, has been previously reported to exhibit diverse antitumor effect(s through modulation of several molecular targets in tumor cells, however the detailed mechanism(s of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3 is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy. We determined the anti-tumor mechanism of GAC 17:1 with respect to its effect on STAT3 signaling pathway in multiple myeloma cell lines. We found that GAC 17:1 can inhibit constitutive activation of STAT3 through the abrogation of upstream JAK2, Src but not of JAK1 kinases in U266 cells and also found that GAC can suppress IL-6-induced STAT3 phosphorylation in MM.1S cells. Treatment of protein tyrosine phosphatase (PTP inhibitor blocked suppression of STAT3 phosphorylation by GAC 17:1, thereby indicating a critical role for a PTP. We also demonstrate that GAC 17:1 can induce the substantial expression of PTEN and SHP-1 at both protein and mRNA level. Further, deletion of PTEN and SHP-1 genes by siRNA can repress the induction of PTEN and SHP-1, as well as abolished the inhibitory effect of drug on STAT3 phosphorylation. GAC 17:1 down-regulated the expression of STAT3 regulated gene products and induced apoptosis of tumor cells. Overall, GAC 17:1 was found to abrogate STAT3 signaling pathway and thus exert its anticancer effects against multiple myeloma cells.

  4. Immunohistochemical expression of PTEN in normal, hyperplastic and endometrial carcinoma of endometrium

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    IzadiMood

    2008-08-01

    Full Text Available "nBackground: Endometrial carcinoma is the most common malignancy of the female genital tract. Different molecular alterations have been described in endometrioid endometrial carcinoma that, the most frequently altered gene is mutations of PTEN. Up to 50-83% of endometrioid carcinoma reveal altered PTEN characterized by loss of expression. In endometrial hyperplasia, which are precursors of endometrioid carcinoma, loss of PTEN expression is 30-63%."n"nMethods: Immunohistochemical staining was performed on 90 cases of endometrial curettage including: 30 proliferative endometrium, 30 hyperplastic endometrium and 30 endometroid carcinoma."n"nImmunohistochemical specimens were graded semiquatitatively by considering the percentage of staining with two cut-point 10% & 50% on the whole section for each specimen."n"nResults: loss of PTEN expression was observed 0%, 0%, 30% of 51.7% in proliferative, simple hyperplasia, complex hyperplasia and endometrioid carcinoma respectively with cut-point 10% and 0%, 5.3%, 30%, 52.2% in endometrioid carcinoma respectively with cut-point 50%. Also there was no difference in PTEN expression between atypical complex hyperplasia and endometrioid carcinoma but there was significant difference between simple hyperplasia and proliferative with endometrioid carcinoma & atypical complex hyperplasia."n"nConclusion: These results show loss of PTEN expression in endmetrioid carcinoma and no differences between endometrioid carcinoma and atypical complex hyperplasia. Therefore, assessment of PTEN expression by negative immunostaining and matched with routine hematoxylin and eosin stained can be a new tool for diagnosis of endometrioid carcinoma.

  5. PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential.

    Science.gov (United States)

    Wartenberg, Martin; Centeno, Irene; Haemmig, Stefan; Vassella, Erik; Zlobec, Inti; Galván, José A; Neuenschwander, Maja; Schlup, Cornelia; Gloor, Beat; Lugli, Alessandro; Perren, Aurel; Karamitopoulou, Eva

    2016-09-01

    Neoplastic stroma is believed to influence tumour progression. Here, we examine phosphatase and tensin homolog deleted on chromosome ten (PTEN) status in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) focussing especially at the stromal cells. We asses PTEN at protein, messenger RNA and DNA level using a well-characterised PDAC cohort (n = 117). miR-21, known to target PTEN, is assessed after RNA extraction from different laser-capture-microdissected cell populations, including cancer cells and juxta-tumoural and tumour-remote stroma. PTEN deletion was the most frequent cause of PTEN protein loss in PDAC cells (71%) and correlated with vascular invasion (p = 0.0176) and decreased overall survival (p = 0.0127). Concomitant PTEN protein loss in tumour and juxta-tumoural stroma, found in 21.4% of PDACs, correlated with increased distant metastasis (p = 0.0045). Stromal cells with PTEN protein loss frequently showed PTEN genetic aberrations, including hemizygous PTEN deletion (46.6%) or chromosome 10 monosomy (40%). No alterations were found in the tumour-remote stroma. miR-21 was overexpressed by cancer- and juxta-tumoural stromal cells, in some cases without simultaneous PTEN gene alterations. No PTEN mutations or promoter methylation were detected. We find various mechanisms of PTEN protein loss in the different tumour cell populations, including allelic PTEN deletions, gross chromosomal 10 aberrations and altered miR-21 expression. PTEN deletion is a major cause of PTEN protein loss in PDAC and correlates with aggressive characteristics and worse outcome. PTEN protein loss in juxta-tumoural stromal cells is mostly due to PTEN haplo-insufficiency and characterises a subgroup of PDACs with enhanced metastatic potential. In the tumour microenvironment of the invasive front, PTEN silencing by miR-21 in cancer and surrounding stromal cells acts not only cooperatively but also independently of the genetic aberrations to precipitate PTEN

  6. SPLUNC1 regulates cell progression and apoptosis through the miR-141-PTEN/p27 pathway, but is hindered by LMP1.

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    Pan Chen

    Full Text Available Little is known about the role of the host defensive protein short palate, lung and nasal epithelium clone 1 (SPLUNC1 in the carcinogenesis of nasopharyngeal carcinoma (NPC. Here we report that SPLUNC1 plays a role at a very early stage of NPC carcinogenesis. SPLUNC1 regulates NPC cell proliferation, differentiation and apoptosis through miR-141, which in turn regulates PTEN and p27 expression. This signaling axis is negatively regulated by the EBV-coded gene LMP1. Therefore we propose that SPLUNC1 suppresses NPC tumor formation and its inhibition by LMP1 provides a route for NPC tumorigenesis.

  7. Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide

    Energy Technology Data Exchange (ETDEWEB)

    Ohno, Kazuki; Okuda, Kosaku; Uehara, Takashi, E-mail: uehara@pharm.okayama-u.ac.jp

    2015-01-02

    Highlights: • PTEN is S-sulfhydrated endogenously in SH-SY5Y human neuroblastoma cells. • Preventing this modification by knocking down CBS renders PTEN sensitive to NO. • pAkt levels are increased significantly in CBS siRNA-transfected cells. • H{sub 2}S functions as an endogenous regulator of PTEN in neuronal cells. - Abstract: Hydrogen sulfide (H{sub 2}S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H{sub 2}S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H{sub 2}S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S-sulfhydration. Further, the knockdown of cystathionine β-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H{sub 2}S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H{sub 2}S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions.

  8. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Zuurbier, Linda; Petricoin, Emanuel F.; Vuerhard, Maartje J.; Calvert, Valerie; Kooi, Clarissa; Buijs-Gladdines, Jessica G.C.A.M.; Smits, Willem K.; Sonneveld, Edwin; Veerman, Anjo J.P.; Kamps, Willem A.; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

    2012-01-01

    Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors. PMID:22491738

  9. Tumor suppression by miR-26 overrides potential oncogenic activity in intestinal tumorigenesis

    Science.gov (United States)

    Zeitels, Lauren R.; Acharya, Asha; Shi, Guanglu; Chivukula, Divya; Chivukula, Raghu R.; Anandam, Joselin L.; Abdelnaby, Abier A.; Balch, Glen C.; Mansour, John C.; Yopp, Adam C.; Richardson, James A.

    2014-01-01

    Down-regulation of miR-26 family members has been implicated in the pathogenesis of multiple malignancies. In some settings, including glioma, however, miR-26-mediated repression of PTEN promotes tumorigenesis. To investigate the contexts in which the tumor suppressor versus oncogenic activity of miR-26 predominates in vivo, we generated miR-26a transgenic mice. Despite measureable repression of Pten, elevated miR-26a levels were not associated with malignancy in transgenic animals. We documented reduced miR-26 expression in human colorectal cancer and, accordingly, showed that miR-26a expression potently suppressed intestinal adenoma formation in Apcmin/+ mice, a model known to be sensitive to Pten dosage. These studies reveal a tumor suppressor role for miR-26 in intestinal cancer that overrides putative oncogenic activity, highlighting the therapeutic potential of miR-26 delivery to this tumor type. PMID:25395662

  10. Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers.

    Science.gov (United States)

    Certal, Victor; Halley, Frank; Virone-Oddos, Angela; Delorme, Cécile; Karlsson, Andreas; Rak, Alexey; Thompson, Fabienne; Filoche-Rommé, Bruno; El-Ahmad, Youssef; Carry, Jean-Christophe; Abecassis, Pierre-Yves; Lejeune, Pascale; Vincent, Loic; Bonnevaux, Hélène; Nicolas, Jean-Paul; Bertrand, Thomas; Marquette, Jean-Pierre; Michot, Nadine; Benard, Tsiala; Below, Peter; Vade, Isabelle; Chatreaux, Fabienne; Lebourg, Gilles; Pilorge, Fabienne; Angouillant-Boniface, Odile; Louboutin, Audrey; Lengauer, Christoph; Schio, Laurent

    2012-05-24

    Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.

  11. Mesenchymal Hamartoma of Chest Wall in an Infant: Mimicking Persistent Pneumonia.

    Science.gov (United States)

    Singh, Amitabh; Seth, Rachna; Pai, Gautham; Dawman, Lesa; Satapathy, Amit

    2015-09-01

    Mesenchymal Hamartoma of the chest wall (MHCW) is a very rare benign tumour. They are usually discovered in infancy. Spontaneous regression is known to occur in this benign condition. Management is surgical removal of mass if respiratory compromise is present. Conservative management is preferred modality in asymptomatic children as malignant transformation is not reported. Herein, we present a case of MHCW in a 5 month old infant presenting with acute respiratory distress with history of respiratory problem at 3 months of age. Child was suspected to have persistent pneumonia in view of radiological findings. Child's respiratory distress improved with antibiotics and bronchodilators. Respiratory symptoms in MHCW are due to extrinsic compression of lung parenchyma. Present case had respiratory symptoms with persistent radiological findings leading to suspicion of persistent pneumonia. His respiratory symptoms and exacerbation on follow up was attributed to hyper reactive airway disease and MHCW was managed conservatively. The non-neoplastic nature, characteristic presentation, histopathology, imaging modality and management options of MHCW are discussed.

  12. Correlation between PTEN Expression and PI3K/Akt Signal Pathway in Endometrial Carcinoma

    Institute of Scientific and Technical Information of China (English)

    Qinglei GAO; Fei YE; Xi XIA; Hui XING; Yunping LU; Jianfeng ZHOU; Ding MA

    2009-01-01

    In order to investigate the role of the PTEN expression in carcinogenesis and develop-ment of endometrial carcinoma and clarify whether and how PTEN and PI3K/Akt pathway relate to endometrial carcinoma,the expression of PTEN and phospho-Akt was detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) methods and Western-blot from 24 cases of endomctrial carcinoma,10 cases of endometrial atypical hyperplasia,10 cases of endometrial hy-perplasia,and 10 cases of normal endometrium.SP immunohistochemical methods were used to measure levels of PTEN protein expression in following 5 study groups:31 cases of endometrium in proliferative phase,30 cases of endometrium in secretory phase,71 cases of endometrial hyperplasia,25 cases of atypical hyperplasia and 73 cases of endometrial carcinoma.Immunostaining score of PTEN was 3.39±0.15 in proliferative phase,1.90±0.21 in secretory phase,3.34~0.29 in endometrial hyperplasia,0.624±0.11 in atypical hyperplasia,and 0.74±0.19 in endometrial carcinoma,respectively.PTEN mRNA relative value in normal endometrium,endometrial hyperplasia,endometrial atypical hyperplasia,and endometrial carcinoma was 2.45±0.51,2.32±0.32,0.46±0.11,and 0.35±0.13 respec-tively.The expression levels of PTEN mRNA and protein in patients with endometrial carcinoma and atypical hyperplasia were significantly lower than in those of proliferative phase and with endo-metrial hyperplasia.The level of PTEN expression in patients with endometrial carcinoma was sig-nificantly related to tissue type (P0.05).Western blot analysis revealed that Phospho-Akt level in PTEN negative cases was significantly higher,and there was a negative correlation between PTEN and phospho-Akt (r=- 0.8973,P<0.0001).It was suggested that loss of PTEN expression was an early event in endometrial tumorigenesis.The phosphorylation of Akt induced by the loss of PTEN took part in the tumorigenesis and development of endometrial carcinoma.

  13. Pten Regulates Retinal Amacrine Cell Number by Modulating Akt, Tgfβ, and Erk Signaling.

    Science.gov (United States)

    Tachibana, Nobuhiko; Cantrup, Robert; Dixit, Rajiv; Touahri, Yacine; Kaushik, Gaurav; Zinyk, Dawn; Daftarian, Narsis; Biernaskie, Jeff; McFarlane, Sarah; Schuurmans, Carol

    2016-09-07

    All tissues are genetically programmed to acquire an optimal size that is defined by total cell number and individual cellular dimensions. The retina contains stereotyped proportions of one glial and six neuronal cell types that are generated in overlapping waves. How multipotent retinal progenitors know when to switch from making one cell type to the next so that appropriate numbers of each cell type are generated is poorly understood. Pten is a phosphatase that controls progenitor cell proliferation and differentiation in several lineages. Here, using a conditional loss-of-function strategy, we found that Pten regulates retinal cell division and is required to produce the full complement of rod photoreceptors and amacrine cells in mouse. We focused on amacrine cell number control, identifying three downstream Pten effector pathways. First, phosphoinositide 3-kinase/Akt signaling is hyperactivated in Pten conditional knock-out (cKO) retinas, and misexpression of constitutively active Akt (Akt-CA) in retinal explants phenocopies the reduction in amacrine cell production observed in Pten cKOs. Second, Akt-CA activates Tgfβ signaling in retinal explants, which is a negative feedback pathway for amacrine cell production. Accordingly, Tgfβ signaling is elevated in Pten cKO retinas, and epistatic analyses placed Pten downstream of TgfβRII in amacrine cell number control. Finally, Pten regulates Raf/Mek/Erk signaling levels to promote the differentiation of all amacrine cell subtypes, which are each reduced in number in Pten cKOs. Pten is thus a positive regulator of amacrine cell production, acting via multiple downstream pathways, highlighting its diverse actions as a mediator of cell number control. Despite the importance of size for optimal organ function, how individual cell types are generated in correct proportions is poorly understood. There are several ways to control cell number, including readouts of organ function (e.g., secreted hormones reach functional

  14. Molecular and genetic aspects of odontogenic tumors: a review

    Directory of Open Access Journals (Sweden)

    Kavita Garg

    2015-06-01

    Full Text Available Odontogenic tumors contain a heterogeneous collection of lesions that are categorized from hamartomas to benign and malignant neoplasms of inconstant aggressiveness. Odontogenic tumors are usually extraordinary with assessed frequency of short of 0.5 cases/100,000 population for every year. The lesions such as odontogenic tumors are inferred from the components of the tooth-structuring contraption. They are discovered solely inside the maxillary and mandibular bones. This audit speaks to experiences and cooperation of the molecular and genetic variations connected to the development and movement of odontogenic tumors which incorporate oncogenes, tumor-silencer genes, APC gene, retinoblastoma genes, DNA repair genes, onco-viruses, development components, telomerase, cell cycle controllers, apoptosis-related elements, and regulators/controllers of tooth development. The reasonable and better understanding of the molecular components may prompt new ideas for their detection and administrating a better prognosis of odontogenic tumors.

  15. An unusual cuticular tumor-like growth on the abdomen of a lobster, Homarus americanus.

    Science.gov (United States)

    Shields, Jeffrey D; Small, Hamish J

    2013-11-01

    Tumors are rare in crustaceans, and whereas a few have been reported from the lobster Homarus americanus none have been adequately described. A lobster with an unusual, large, blue-colored tumor-like growth projecting laterally outward from the first abdominal somite was caught off Stonington, Maine, USA. The growth was rugose and covered by a relatively normal appearing cuticle with dispersed focal melanization. The underlying stroma consisted of an internal area of rescaffolded fibrous connective tissue, restructured muscle fibers, few arterioles, and an epidermal area comprised of columnar, highly vacuolated epithelial cells. No infectious pathogens or unusual inclusions were observed with microscopy and no eukaryotic pathogens were detected via molecular sequencing. Given the nature of the histology and the appearance of the growth, we identify the mass as a benign papilliform hamartoma that likely originated as a result of abnormal wound repair possibly initiated around ecdysis. This represents the first tumor-like hamartoma reported from a lobster, and the second hamartoma reported from a crustacean.

  16. TGFβ-stimulated microRNA-21 utilizes PTEN to orchestrate AKT/mTORC1 signaling for mesangial cell hypertrophy and matrix expansion.

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    Nirmalya Dey

    Full Text Available Transforming growth factor-β (TGFβ promotes glomerular hypertrophy and matrix expansion, leading to glomerulosclerosis. MicroRNAs are well suited to promote fibrosis because they can repress gene expression, which negatively regulate the fibrotic process. Recent cellular and animal studies have revealed enhanced expression of microRNA, miR-21, in renal cells in response to TGFβ. Specific miR-21 targets downstream of TGFβ receptor activation that control cell hypertrophy and matrix protein expression have not been studied. Using 3'UTR-driven luciferase reporter, we identified the tumor suppressor protein PTEN as a target of TGFβ-stimulated miR-21 in glomerular mesangial cells. Expression of miR-21 Sponge, which quenches endogenous miR-21 levels, reversed TGFβ-induced suppression of PTEN. Additionally, miR-21 Sponge inhibited TGFβ-stimulated phosphorylation of Akt kinase, resulting in attenuation of phosphorylation of its substrate GSK3β. Tuberin and PRAS40, two other Akt substrates, and endogenous inhibitors of mTORC1, regulate mesangial cell hypertrophy. Neutralization of endogenous miR-21 abrogated TGFβ-stimulated phosphorylation of tuberin and PRAS40, leading to inhibition of phosphorylation of S6 kinase, mTOR and 4EBP-1. Moreover, downregulation of miR-21 significantly suppressed TGFβ-induced protein synthesis and hypertrophy, which were reversed by siRNA-targeted inhibition of PTEN expression. Similarly, expression of constitutively active Akt kinase reversed the miR-21 Sponge-mediated inhibition of TGFβ-induced protein synthesis and hypertrophy. Furthermore, expression of constitutively active mTORC1 prevented the miR-21 Sponge-induced suppression of mesangial cell protein synthesis and hypertrophy by TGFβ. Finally, we show that miR-21 Sponge inhibited TGFβ-stimulated fibronectin and collagen expression. Suppression of PTEN expression and expression of both constitutively active Akt kinase and mTORC1 independently reversed this

  17. The Involvement of Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN in the Regulation of Inflammation Following Coronary Microembolization

    Directory of Open Access Journals (Sweden)

    Jiangyou Wang

    2014-06-01

    Full Text Available Background/Aims: Growing evidence shows that phosphatase and tensin homolog deleted on chromosome ten (PTEN is involved in regulating inflammation in different pathological conditions. Therefore, we hypothesized that the upregulation of PTEN correlates with the impairment of cardiac function in swine following coronary microembolization (CME. Methods: To possibly disclose an anti-inflammatory effect of PTEN, we induced swine CME by injecting inertia plastic microspheres (42 μm in diameter into the left anterior descending coronary artery and analyzed the myocardial tissue by immunochemistry, qRT-PCR and western blot analyses. In addition, we downregulated PTEN using siRNA. Results: Following CME, PTEN mRNA and protein levels were elevated as early as 3 h, peaked at 12 h, and then continuously decreased at 24 h and 48 h but remained elevated. Through linear correlation analysis, the PTEN protein level positively correlated with cTnI and TNF-α but was negatively correlated with LVEF. Furthermore, PTEN siRNA reduced the microinfarct volume, improved cardiac function (LVEF, reduced the release of cTnI, and suppressed PTEN and TNF-α protein expression. Conclusion: This study demonstrated, for the first time, that PTEN is involved in CME-induced inflammatory injury. The data generated from this study provide a rationale for the development of PTEN-based anti-inflammatory strategies.

  18. Lipofibromatous hamartoma of the median nerve: report of a case and review of the literature; Hamartoma fibrolipomatoso del nervio mediano: descripcion de un caso y revision de la bibliografia

    Energy Technology Data Exchange (ETDEWEB)

    Lopez, G.; Ruiz, F.; Rodriguez, C.; Carcia, E. [Hospital Universitario Virgen de las Nieves. Granada (Spain)

    2001-07-01

    Lipofibromatous hamartoma is a rare benign lesion that affects peripheral nerves. The predominant site is median nerve, although it has been reported in other locations. It usually presents prior to the third decade of life, and is associated with motor cycled in up to one third of cases. We describe a case involving median nerve in a 24-year-old man who underwent ultrasound and magnetic resonance, followed by surgical confirmation of the diagnosis. A brief review of the literature is also provided. The magnetic resonance findings are virtually pathognomonic of this disease and, thus, the diagnosis can be reached without the need to perform biopsy. (Author) 12 refs.

  19. The effects of antisense PTEN gene transfection on the growth and invasion of glioma cells

    Institute of Scientific and Technical Information of China (English)

    CHEN Hong-jie; ZHENG Zhao-cong; WANG Ru-mi; WANG Shou-sen; YANG Wei-zhong

    2006-01-01

    Objective:To study the effects of antisense PTEN gene on the growth and invasion of glioma cells. Methods:A pcDNA3. 1/Hygro (-) recombinant plasmid containing antisense PTEN gene fragment was constructed. Glioma cells of primary culture were transfected with antisense PTEN gene vector and stably transfected clones were selected. Then, the different growth and invasion abilities and the different MMP9 mRNA expressions of three kinds of cells were observed, including the transfected cells, untransfected cells and the cells transfected with empty vector. Results :The abilities of growth and invasion of the transfected cells and the expressions of MMP9 mRNA were obviously enhanced. Conclusion: Antisense PTEN gene could have a negative impact on the growth and invasion of primary culture glioma cells.

  20. A common variation of the PTEN gene is associated with peripheral insulin resistance

    DEFF Research Database (Denmark)

    Grinder-Hansen, L; Ribel-Madsen, R; Wojtaszewski, Jørgen

    2016-01-01

    . RESULTS: The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single...... nucleotide polymorphism was not associated with either PI3K or Akt activities. CONCLUSION: A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling......AIM: Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated...

  1. Expression and significance of PTEN and PCNA in human laryngeal squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    李长青; 文莲姬; 金春顺; 崔树勋

    2004-01-01

    Objective: To elucidate the expression and significance of PTEN and PCNA in human laryngeal squamous cell carcinoma. Methods: Immunochemical method was used to study 60 cases of laryngeal carcinoma, 20 cases of normal laryngeal tissues which were closely adjacent to carcinoma and 10 cases of normal laryngeal tissues. Results: It was showed that PTEN gene was expressed in 85 % laryngeal carcinoma tissues. The percentage of lymph node metastasis of laryngeal carcinoma which were negative or positive of PTEN protein was 77.8 % and 33.3 % respectively, and the difference was significance ( P < 0.05). Conclusion: Expression of PTEN in laryngeal carcinoma was different from that of normal laryngeal tissues. It may play a role but not important in the tumorigenesis and development of laryngeal carcinoma.

  2. Advances in folliculosebaceous cystic hamartoma%毛囊皮脂腺囊性错构瘤研究进展

    Institute of Scientific and Technical Information of China (English)

    郑力强; 韩向春

    2011-01-01

    Clinically, folliculosebaceous cystic hamartoma (FSCH)is uncommon and lacks distinct features. It often manifests as asymptomatic, skin-colored papules or nodules mostly distributed on the face. Histopathologically, it is a kind of hamartoma of skin appendages mainly characterized by the hyperplasia of folliculosebaceous units and mesenchymal tissues. The differential diagnosis mainly includes sebaceous trichofolliculoma and dermoid cyst. Its immunohistochemical manifestations are unspecific and associated with epithelial and non-epithelial component within the hamartoma. This paper presents an update on the knowledge about clinical and immunohistochemical manifestation of, diagnostic criteria and treatment for FSCH.%临床上,毛囊皮脂腺囊性错构瘤比较少见,缺乏典型特征,是一种不对称,好发于面部的肤色丘疹或结节。病理学上是以毛囊皮脂腺组织和间叶细胞成分增生为主的皮肤附属器错构瘤,主要与皮脂腺毛囊瘤、皮样囊肿相鉴别。免疫组化结果与瘤体内上皮或非上皮成分有关,无特异性。概述毛囊皮脂腺囊性错构瘤的临床表现、诊断标准、免疫组化及治疗方面的研究进展。

  3. PTEN phosphatase-independent maintenance of glandular morphology in a predictive colorectal cancer model system.

    Science.gov (United States)

    Jagan, Ishaan C; Deevi, Ravi K; Fatehullah, Aliya; Topley, Rebecca; Eves, Joshua; Stevenson, Michael; Loughrey, Maurice; Arthur, Kenneth; Campbell, Frederick Charles

    2013-11-01

    Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na(+)/H(+) exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

  4. MicroRNA-21 regulates hTERT via PTEN in hypertrophic scar fibroblasts.

    Directory of Open Access Journals (Sweden)

    Hua-Yu Zhu

    Full Text Available BACKGROUND: As an important oncogenic miRNA, microRNA-21 (miR-21 is associated with various malignant diseases. However, the precise biological function of miR-21 and its molecular mechanism in hypertrophic scar fibroblast cells has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR analysis revealed significant upregulation of miR-21 in hypertrophic scar fibroblast cells compared with that in normal skin fibroblast cells. The effects of miR-21 were then assessed in MTT and apoptosis assays through in vitro transfection with a miR-21 mimic or inhibitor. Next, PTEN (phosphatase and tensin homologue deleted on chromosome ten was identified as a target gene of miR-21 in hypertrophic scar fibroblast cells. Furthermore, Western-blot and qRT-PCR analyses revealed that miR-21 increased the expression of human telomerase reverse transcriptase (hTERT via the PTEN/PI3K/AKT pathway. Introduction of PTEN cDNA led to a remarkable depletion of hTERT and PI3K/AKT at the protein level as well as inhibition of miR-21-induced proliferation. In addition, Western-blot and qRT-PCR analyses confirmed that hTERT was the downstream target of PTEN. Finally, miR-21 and PTEN RNA expression levels in hypertrophic scar tissue samples were examined. Immunohistochemistry assays revealed an inverse correlation between PTEN and hTERT levels in high miR-21 RNA expressing-hypertrophic scar tissues. CONCLUSIONS/SIGNIFICANCE: These data indicate that miR-21 regulates hTERT expression via the PTEN/PI3K/AKT signaling pathway by directly targeting PTEN, therefore controlling hypertrophic scar fibroblast cell growth. MiR-21 may be a potential novel molecular target for the treatment of hypertrophic scarring.

  5. DNA Mismatch Repair Deficiency Accelerates Endometrial Tumorigenesis in Pten Heterozygous Mice

    OpenAIRE

    Hong WANG; Douglas, Wayne; Lia, Marie; Edelmann, Winfried; Kucherlapati, Raju; Podsypanina, Katrina; Parsons, Ramon; Ellenson, Lora Hedrick

    2002-01-01

    PTEN mutation and microsatellite instability are two of the most common genetic alterations in uterine endometrioid carcinoma. Furthermore, previous studies have suggested an association between the two alterations, however the basis and consequence of the association is not understood. Recently it has been shown that 100% of female Pten+/− mice develop complex atypical hyperplasia by 32 weeks of age that progresses to endometrial carcinoma in ∼20 to 25% of mice at 40 weeks. In an attempt to ...

  6. PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

    Directory of Open Access Journals (Sweden)

    Ishaan C. Jagan

    2013-11-01

    Full Text Available Organotypic models may provide mechanistic insight into colorectal cancer (CRC morphology. Three-dimensional (3D colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN coupling of cell division cycle 42 (cdc42 to atypical protein kinase C (aPKC. This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3 were ineffective. The isolated PTEN C2 domain (C2 accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na+/H+ exchanger regulatory factor-1 (NHERF-1 in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

  7. Giant notochordal hamartoma of intraosseous origin: a newly reported benign entity to be distinguished from chordoma. Report of two cases

    Energy Technology Data Exchange (ETDEWEB)

    Mirra, J.M. [Dept. of Orthopaedic Pathology, Orthopaedic Hospital, Los Angeles, CA (United States); Brien, E.W. [Dept. of Musculoskeletal Tumors, Orthopaedic Hospital, Los Angeles, CA (United States)

    2001-12-01

    Two cases are reported of a newly described intraosseous entity of vertebral bodies deemed ''giant notochordal hamartoma of intraosseous origin''. This entity is commonly mistaken for chordoma and must be distinguished from it as the consequences of misinterpretation may be serious. The clinical, radiological and histologic criteria that can be used to distinguish these two entities are emphasized. Included is a proposed pathogenesis for this lesion, its probable notochordal origin, and a review of other probable cases. (orig.)

  8. Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling

    Institute of Scientific and Technical Information of China (English)

    Zan Tong; Yan Fan; Weiqi Zhang; Jun Xu; Jing Cheng; Mingxiao Ding; Hongkui Deng

    2009-01-01

    PTEN, a negative regulator of the phosphatidylinositol-3-kinase/AKT pathway, is an important modulator of insu-lin signaling. To determine the metabolic function of pancreatic Pten, we generated pancreas-specific Pten knockout (PPKO) mice. PPKO mice had enlarged pancreas and elevated proliferation of acinar cells. They also exhibited hy-poglycemia, hypoinsulinemia, and altered amino metabolism. Notably, PPKO mice showed delayed onset of strepto-zotocin (STZ)-induced diabetes and sex-biased resistance to high-fat-diet (HFD)-induced diabetes. To investigate the mechanism for the resistance to HFD-induced hyperglycemia in PPKO mice, we evaluated AKT phosphorylation in major insulin-responsive tissues: the liver, muscle, and fat. We found that Pten loss in the pancreas causes the eleva-tion of AKT signaling in the liver. The phosphorylation of AKT and its downstream substrate GSK3β was increased in the liver of PPKO mice, while PTEN level was decreased without detectable excision of Pten allele in the liver of PPKO mice. Proteomics analysis revealed dramatically decreased level of 78-kDa glucose-regulated protein (GRP78) in the liver of PPKO mice, which may also contribute to the lower blood glucose level of PPKO mice fed with HFD. Together, our findings reveal a novel response in the liver to pancreatic defect in metabolic regulation, adding a new dimension to understanding diabetes resistance.

  9. Exogenous PTEN Gene Induces Apoptosis in Breast Carcinoma Cell Line MDA468

    Institute of Scientific and Technical Information of China (English)

    CHEN Qingyong; WANG Chunyou; JIANG Chunfang; CHEN Daoda

    2007-01-01

    The effects and mechanisms of exogenous phosphatase and tensin homolog deleted from chromosome ten (PTEN) gene on phosphatase activity-dependent apoptosis of breast cancer cell line MDA468 were investigated. PTEN gene packaged with lipofectin was transferred into breast cancer cell line MDA468 and parental MDA468 cells served as controls. RT-PCR and Western blot were done to detect the expression of target genes. The expression of phosphospecific protein kinase B (PKB/Akt) and focal adhesion kinase (FAK) protein stimulated by epidermal growth factor (EGF) was also detected. Apoptosis was determined by flow cytometry with a double-staining method using FITC-conjugated annexin V and PI. MDA468 cells transfected with PTEN gene could express PTEN mRNA and protein. PTEN decreased the phosphorylation level of AKT protein and down-regulated FAK protein expression in MDA468 stimulated by EGF. The apoptosis rate was 21.68%. PTEN induced breast cancer apoptosis phosphatase activity-dependently. The mechanism is possibly relatedwith phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/AKT signaling pathway. Those results may provide new clues on the gene therapy in breast cancer.

  10. Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.

    Science.gov (United States)

    Yue, Shi; Rao, Jianhua; Zhu, Jianjun; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

    2014-06-01

    Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation.

  11. Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas.

    Science.gov (United States)

    Wu, Jie; Gao, Ming; Rice, Stephen G; Tsang, Candy; Beggs, John; Turner, Dharshaun; Li, Guohui; Yang, Bo; Xia, Kunkun; Gao, Fenfei; Qiu, Shenfeng; Liu, Qiang; Kerrigan, John F

    2016-06-01

    Human hypothalamic hamartoma (HH) is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36) and connexin-43 (Cx43) in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA) neurons observed with whole-cell patch-clamp recordings from the same patient's HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients.

  12. Gap Junctions Contribute to Ictal/Interictal Genesis in Human Hypothalamic Hamartomas

    Directory of Open Access Journals (Sweden)

    Jie Wu

    2016-06-01

    Full Text Available Human hypothalamic hamartoma (HH is a rare subcortical lesion associated with treatment-resistant epilepsy. Cellular mechanisms responsible for epileptogenesis are unknown. We hypothesized that neuronal gap junctions contribute to epileptogenesis through synchronous activity within the neuron networks in HH tissue. We studied surgically resected HH tissue with Western-blot analysis, immunohistochemistry, electron microscopy, biocytin microinjection of recorded HH neurons, and microelectrode patch clamp recordings with and without pharmacological blockade of gap junctions. Normal human hypothalamus tissue was used as a control. Western blots showed increased expression of both connexin-36 (Cx36 and connexin-43 (Cx43 in HH tissue compared with normal human mammillary body tissue. Immunohistochemistry demonstrated that Cx36 and Cx43 are expressed in HH tissue, but Cx36 was mainly expressed within neuron clusters while Cx43 was mainly expressed outside of neuron clusters. Gap-junction profiles were observed between small HH neurons with electron microscopy. Biocytin injection into single recorded small HH neurons showed labeling of adjacent neurons, which was not observed in the presence of a neuronal gap-junction blocker, mefloquine. Microelectrode field recordings from freshly resected HH slices demonstrated spontaneous ictal/interictal-like discharges in most slices. Bath-application of gap-junction blockers significantly reduced ictal/interictal-like discharges in a concentration-dependent manner, while not affecting the action-potential firing of small gamma-aminobutyric acid (GABA neurons observed with whole-cell patch-clamp recordings from the same patient's HH tissue. These results suggest that neuronal gap junctions between small GABAergic HH neurons participate in the genesis of epileptic-like discharges. Blockade of gap junctions may be a new therapeutic strategy for controlling seizure activity in HH patients.

  13. 肾脏巨大错构瘤的超声诊断探讨%Discussion on the diagnosisudy of giant renal hamartoma with color Doppler ultrasound

    Institute of Scientific and Technical Information of China (English)

    张清连; 张灌生; 钟跃

    2012-01-01

    Objective To discuss the value of color Doppler ultrasound on the diagnosis of giant (larger than 10cm) renal hamartoma (GRH). Methods Ultrasonic images of 9 cases with GRH confirmed by pathology after operation were retrospectively studied. Results 7 cases were diagnosed correctly by ultrasound (7/9), 1 case were mistaken as renal carcinoma (1/9) and 1 case was mistaken as adrenal gland fat tumor (1/9) in ultrasound diagnosis. The GRH shape was ellipse with clear margins. The GRH were showed high echo in 6 cases, middle echo in 2 cases and low echo in 1 case. That high alternate with low echoes were composed "stripe sign" were observed in all high echo and middle echo GRH, and there were a few bloodstream signal in these masses. The low echo GRH were not observed "stripe sign", and there were more bloodstream signal. That the protruding parts of GRH pressed the kidneys to form "press sign" were observed in all cases. The GRH with spontaneous rupture were observed cystic area in 2 cases. Both kidneys had many high echo small hamartoma sign in 6 cases. Conclusion The GRH has some features in ultrasonic images, color Doppler ultrasound has important diagnostic value for GRH, it could be considered as the first diagnostic method before operation.%目的 探讨彩色多普勒超声诊断肾脏巨大错构瘤(最大径线大于10cm)的临床应用价值.方法 回顾性分析经手术病理证实的9例肾脏巨大错构瘤的超声检查资料,并对其超声表现特征进行分析.结果 9例肾脏巨大错构瘤超声诊断正确7例(77.78%),1例误诊为肾癌(11.11%),1例误诊为肾上腺脂肪瘤(11.11%).肾脏巨大错构瘤的声像大致呈椭圆形,轮廓清晰,6例呈高回声,2例呈中等回声,1例呈低回声.高回声及中等回声肿块内皆观察到了高低回声相间的“条纹征”,且肿块内血流稀少.低回声肿块内未见“条纹征”,血流较多.9例肾脏巨大错构瘤皆观察到了肿瘤的外突部分对

  14. Up-regulation of Biglycan is Associated with Poor Prognosis and PTEN Deletion in Patients with Prostate Cancer

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    Frank Jacobsen

    2017-09-01

    Full Text Available Biglycan (BGN, a proteoglycan of the extracellular matrix, is included in mRNA signatures for prostate cancer aggressiveness. To understand the impact of BGN on prognosis and its relationship to molecularly defined subsets, we analyzed BGN expression by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Seventy-eight percent of 11,050 interpretable cancers showed BGN expression, which was considered as low intensity in 47.7% and as high intensity in 31.1% of cancers. BGN protein expression rose with increasing pathological tumor stage, Gleason grade, lymph node metastasis and early PSA recurrence (P < .0001 each. Comparison with our molecular database attached to the TMA revealed that BGN expression was linked to presence of TMPRRS2:ERG fusion and PTEN deletion (P < .0001 each. In addition, BGN was strongly linked to androgen-receptor (AR levels (P < .0001, suggesting a hormone-depending regulation of BGN. BGN up-regulation is a frequent feature of prostate cancer that parallels tumor progression and may be useful to estimate tumor aggressiveness particularly if combined with other molecular markers.

  15. A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

    Energy Technology Data Exchange (ETDEWEB)

    Christensen, Michael, E-mail: mechristense@uwalumni.com [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Najy, Abdo J. [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Snyder, Michael; Movilla, Lisa S. [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Kim, Hyeong-Reh Choi [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States)

    2014-01-01

    Purpose: Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. Methods and Materials: PTEN wild-type (PTEN{sup +/+}) and PTEN knockout (PTEN{sup −/−}) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN{sup −/−} cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. Results: PTEN{sup −/−} cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN{sup −/−} cells demonstrated increased clonogenic survival in vitro compared to PTEN{sup +/+}, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN{sup −/−} cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN{sup −/−} cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. Conclusions: We propose

  16. Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism.

    Science.gov (United States)

    Takeuchi, Koichi; Gertner, Michael J; Zhou, Jing; Parada, Luis F; Bennett, Michael V L; Zukin, R Suzanne

    2013-03-19

    The phosphoinositide signaling system is a crucial regulator of neural development, cell survival, and plasticity. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates phosphatidylinositol 3-kinase signaling and downstream targets. Nse-Cre Pten conditional knockout mice, in which Pten is ablated in granule cells of the dentate gyrus and pyramidal neurons of the hippocampal CA3, but not CA1, recapitulate many of the symptoms of humans with inactivating PTEN mutations, including progressive hypertrophy of the dentate gyrus and deficits in hippocampus-based social and cognitive behaviors. However, the impact of Pten loss on activity-dependent synaptic plasticity in this clinically relevant mouse model of Pten inactivation remains unclear. Here, we show that two phosphatidylinositol 3-kinase- and protein synthesis-dependent forms of synaptic plasticity, theta burst-induced long-term potentiation and metabotropic glutamate receptor (mGluR)-dependent long-term depression, are dysregulated at medial perforant path-to-dentate gyrus synapses of young Nse-Cre Pten conditional knockout mice before the onset of visible morphological abnormalities. In contrast, long-term potentiation and mGluR-dependent long-term depression are normal at CA3-CA1 pyramidal cell synapses at this age. Our results reveal that deletion of Pten in dentate granule cells dysregulates synaptic plasticity, a defect that may underlie abnormal social and cognitive behaviors observed in humans with Pten inactivating mutations and potentially other autism spectrum disorders.

  17. Clinicopathological significance of combined immunohistochemical analysis of PTEN, p53 and EGFR in breast carcinoma%联合检测乳腺癌组织中 PTEN、p53和 EGFR表达的临床病理意义

    Institute of Scientific and Technical Information of China (English)

    李新军; 付丽梅; 付明霞; 薛栋

    2015-01-01

    目的:探讨PTEN、p53和上皮生长因子受体( epidermal growth factor receptor, EGFR)在乳腺癌中表达的临床病理意义及其相关性。方法采用免疫组化MaxVision两步法检测209例乳腺浸润性导管癌和40例良性乳腺病变中PTEN、p53、EGFR蛋白的表达。结果 PTEN、p53和EGFR在乳腺癌中的过表达率为57.9%、55.0%和38.3%,与良性乳腺病变间差异有显著性(P均<0.05)。 PTEN、p53及EGFR蛋白表达均与肿瘤大小、组织学分级、淋巴结转移、ER和PR状态、分子分型有显著相关性(P均<0.05);PTEN、p53表达与TNM分期有显著相关性;PTEN、EGFR表达与HER-2状态有显著相关性。 EGFR、p53表达与PTEN呈显著负相关(P均<0.01),p53表达与EGFR呈显著正相关(P=0.000)。 PTEN、EGFR表达与乳腺癌预后相关,但不是独立的预后因子。具有PTEN-/p53+/EGFR+组合表达的乳腺癌生存率低于其他组合(P=0.008)。结论 PTEN低或失表达、p53突变和EGFR过表达可能协同参与乳腺癌的发生、发展,三者联合检测对乳腺癌的治疗和预后可能具有指导作用。%Purpose To study clinical pathological significance of the expression of PTEN, p53 and epidermal growth factor receptor ( EGFR) in breast carcinoma and their correlation. Methods Immunohistochemical MaxVision method was used to detect the expres-sion of PTEN, p53, EGFR in 209 cases of infiltrating ductal carcinoma of breast and 40 cases of benign breast diseases. Results The over-expression rate of PTEN, p53 and EGFR protein in breast carcinoma was 57. 9%, 55. 0% and 38. 3% respectively, which was significantly different from those in benign breast diseases (P<0. 05). The expression of PTEN, p53 and EGFR in breast cancer was correlated with tumor size, histological grade, lymph node metastasis, ER status, PR status and molecular subtype (P<0. 05). There was an association between PTEN or p53 and TNM stage, PTEN or EGFR and HER-2 status. There was a

  18. Gastric Smooth Muscle Hamartomas Mimicking Polyps in a Dog: A Case Description and a Review of the Literature

    Directory of Open Access Journals (Sweden)

    Marian A. Taulescu

    2013-01-01

    Full Text Available This report presents a case of two smooth muscle hamartomas of the stomach in a 10-year-old male Boxer. The clinical history of the animal was of chronic vomiting, weight loss, and intermittent gastric distension, and it died because of chronic and congestive heart failure. Gross, histology, and immunohistochemistry (IHC exams were performed. On necropsy, in the pyloric region of the stomach, two closely related polypoid growths between 10 and 15 mm in diameter were identified. On the cut sections, both polyps presented white to gray color, with homogenous architecture and well-defined limits. The thickness of the submucosal layer was seen to be increased to 1 cm. No other gastric alterations were identified by the necropsy exam. Histologically, both masses growth consisted of hyperplastic glands lined by foveolar epithelium, arranged in a papillary or branching pattern, and supported by a core of well-vascularised and marked smooth muscle tissue interspersed between glands. No dysplastic cells and mitotic figures were observed in these lesions. Immunohistochemistry revealed a strong cytoplasm labelling for smooth muscle actin of the bundles around the mucosal glands. To our knowledge, this is the first report of smooth muscle hamartomas mimicking multiple gastric polyps in dogs.

  19. CT and MR Findings of Multiple Bile Duct Hamartomas%胆管错构瘤的CT、MRI表现

    Institute of Scientific and Technical Information of China (English)

    冯廷越; 陈天忠; 唐建桥

    2015-01-01

    Objective To summarize computed tomography (CT) and magnetic resonance (MR) imaging features of multiple bile duct hamartomas (BDH) and analysis changes of lesions with concurrent infection before and after treatment on MRI and CT to improve understanding of the imaging findings of the disease.Methods This retrospective study reviewed CT and MR imaging findings of ten patients with multiple bile duct hamartomas in our hospital and compared the difference of imaging findings before and after therapy in those with infection.Results Non-contrasted enhanced CT images of multiple bile duct hamartomas showed scattered or diffuse low density lesions with no enhancement; T2 weighted imaging (T2WI) was sensitivity to detect cystic lesion with significantly higher signal. Diffuse liver disease could be well displayed by Magnetic Resonance Cholangiopancreatography (MRCP), and all lesions were without intrahepatic biliary communication and have irregular borders when concurrent infection.Conclusion CT examination is limited in the diagnosis of biliary hamartomas, and conventional non-contrasted MRI and MRCP examinations have great value and show some advantages in the diagnosis of multiple bile duct hamartomas compared to CT, while we should pay more attention to the change of imaging findings of those with concurrent infection.%目的:总结胆管错构瘤的CT及MRI表现,对比分析并发感染病例病灶的治疗前后改变,以提高对该病影像检查及诊断的认识。方法回顾性研究我院诊治的10例胆管错构瘤患者的资料,分析胆管错构瘤病变的CT、MRI表现特点,对并发感染病例的治疗前后变化进行对比分析。结果胆管错构瘤的CT平扫表现为散在或弥漫性分布的低密度灶,增强扫描无强化;MRI平扫T2WI序列能敏感的显示呈明显高信号的囊性病变;MRCP立体的显示弥漫性病变,所有病变与肝内胆管树不相通;并发感染后病灶边界变模糊。结论单

  20. PTEN coding product:a new marker for tumorigenesis and progession of endometrial carcinoma

    Institute of Scientific and Technical Information of China (English)

    Gao Qinglei; Li Jing; Xing Hui; Lu Yunping; Zhou Jianfeng; Ma Ding

    2008-01-01

    Objective :To investigate the expression of PTEN in carcinogenesis and development of endometrial carcinoma.Methods: The expression of PTEN was detected by reverse transcription-polymerase chain reaction(RT-PCR) methods from 24 cases with endometrial carcinoma,10 cases with endometrial atypical hyperplasia,I0 eases with endometrial hyperplasia and I0 cases with normal endometrium and by SP immunohistochemical methods from 73 cases with endometrial carcinoma,25 cases with endometrial atypical hyperplasia,71 cases with endometrial hyperplasia and 31 cases with normal endometrium.Results:PTEN expression of both RNA and protein in patients with endometrial carcinoma and endometrial atypical hyperplasia was significantly lower than that of patients with endometrial hyperplasia and normal endometriurn.mRNA relative value was 0.35±0.13,0.46±0.11,2.32±0.32,2.45±0.51,respectively.Loss of PTEN expression rates were 66.67% (38/57) ,76.00% ( 19/25 ) ,5.63% (4/71 ) ,0 (0/31 ),repeetively.The results were also compared with clinical parameters.Loss of PTEN expression in patients with endometrial carcinoma was significantly related to histological classification ( P < 0.0001 ) and differentiation ( P < 0.05 ).It was not related to depth of myometrium invasion and clinical stage( P >0.05 ).Conclusion:Loss of PTEN expression is an early event in endometrial tumorigenesis.Detection of PTEN protein may be a diagnostic biomarker for endometrial precancers and adenocareinoma.

  1. Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology.

    Science.gov (United States)

    Choi, Jaesung Peter; Zheng, Yu; Handelsman, David J; Simanainen, Ulla

    2016-05-01

    Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n=8) and ugeARKO (n=7) uteri. Uterine weight was significantly (P=0.002) increased in ugePTENARKO (374±97 mg (mean±s.e.)) compared with WT (97±6 mg), ugeARKO (94±12 mg), and ugePTENKO (205±33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.

  2. Downregulation of miR-382 by propranolol inhibits the progression of infantile hemangioma via the PTEN-mediated AKT/mTOR pathway.

    Science.gov (United States)

    Li, Dongfan; Li, Peng; Guo, Zhengtuan; Wang, Huaijie; Pan, Weikang

    2017-03-01

    Approximately 10% of infantile hemangiomas (IHs) are the most common vascular tumors affecting children and are characterized by rapid growth, and can have destructive, disfiguring and even life-threatening consequences. Currently, propranolol is considered to be a safe and effective treatment option for problematic proliferating IHs. Recent studies have also revealed that microRNAs (miRNAs or miRs) play important roles in the regulation of angiogenesis. In this study, XPTS‑1 cells were used as a hemangioma-derived endothelial cell line constructed in our laboratory. Through a series of experiments, we discovered that miR‑382 is a novel miRNA associated with IHs, which was overexpressed in XPTS‑1 cells and was conversely downregulated by treatment with propranolol. In addition, we found that miR‑382 contributes to the progression of IHs. Our results revealed that propranolol inhibited XPTS‑1 cell migration and proliferation, and promoted apoptosis, and these effects were reversed by the restoration of miR‑382 expression by transfection of the cells with an miR‑382 overexpression vector. Further experiments revealed that the above-mentioned effects were associated with the phosphatase and tensin homolog (PTEN)-mediated AKT/mammalian target of rapamycin (mTOR) signaling pathway. The expression of PTEN was upregulated, while that of p-AKT, p-mTOR and p-p70S6K was downregulated by propranolol; these effects were partly reversed by the overexpression of miR‑382. On the whole, our study identified that the downregulation of miR‑382 by propranolol inhibits the progression of IHs via the PTEN-mediated AKT/mTOR pathway.

  3. Differential diagnosis and management of liver tumors in infants

    Institute of Scientific and Technical Information of China (English)

    Israel; Fernez-Pineda; Rosa; Cabello-Laureano

    2014-01-01

    During the first year of life, most of the liver neoplasms are benign in origin, but some of these histologically benign lesions may be challenging in their management. Although most hepatic hemangiomas can be safely observed until involution is documented, some patients will need treatment due to progressive hepatomegaly, hypothyroidism and/or cardiac failure. Large mesenchymal hamartomas may require extensive hepatic resection and an appropriate surgical plan is critical to obtain good results. For malignant neoplasms such as hepatoblastoma, complete surgical resection is the mainstay of curative therapy. The decision about whether to perform an upfront or delayed resection of a primary liver malignant tumor is based on many considerations, including the ease of resection, surgical expertise, tumor histology and stage, and the likely chemosensitivity of the tumor. This article reviews the initial management of the more common hepatic tumors of infancy, focusing on the differential diagnosis and treatment options.

  4. Expression and significance of PTEN, hypoxia-inducible factor-1 alpha in colorectal adenoma and adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    Ying-An Jiang; Li-Fang Fan; Chong-Qing Jiang; You-Yuan Zhang; He-Sheng Luo; Zhi-Jiao Tang; Dong Xia; Ming Wang

    2003-01-01

    AIM: To investigate the expression and significance of PTEN,hypoxia-inducible factor-1 alpha (HIF-1α), and targeting gene VEGF during colorectal carciogenesis.METHODS: Total 71 cases colorectal neoplasms (9 cases of colorectal adenoma and 62 colorectal adenocarcinoma)were formalin fixed and paraffin-embedded, and all specimens were evaluated for PTEN mRNA, HIF-1α mRNA and VEGF protein expression. PTEN mRNA, HIF-1α mRNA were detected by in situ hybridization. VEGF protein was identified by citrate-microwave SP immunohistochemical method.RESULTS: There were significant differences in PTEN, HIF1α and VEGF expression between colorectal adenomas and colorectal adenocarcinoma (P<0.05). The level of PTEN expression decreased as the pathologic stage increased.Conversely, HIF-1α and VEGF expression increased with the Dukes stage as follows: stage A (0.1029±0.0457:0.1207± 0.0436), stage B (0.1656±0.0329: 0.1572±0.0514),and stage C+D (0.2335±0.0748: 0.2219±0.0803). For PTEN expression, there was a significant difference among Dukes stage A, B, and C+D, and the level of PTEN expression was found to be significant higher in Dukes stage A or B than that of Dukes stage C or D. For HIF-1α expression,there was a significant difference between Dukes stage A and B, and the level of HIF-1α expression was found to be significantly higher in Dukes stage C+D than that of Dukes stage A or B. The VEGF expression had similar results as HIF-1α expression. In colorectal adenocarcinoma,decreased levels of PTEN were significantly associated with increased expression of HIF-1α mRNA (r=-0.36, P<0.05)and VEGF protein (r=-0.48, P<0.05) respectively. The levels of HIF-1 were positively correlated with VEGF expression (r=0.71, P<0.01).CONCLUSION: Loss of PTEN expression and increased levels of HIF-1α and VEGF may play an important role in carcinogenesis and progression of colorectal adenocarcinoma.

  5. Combined Phosphatase and Tensin Homolog (PTEN Loss and Fatty Acid Synthase (FAS Overexpression Worsens the Prognosis of Chinese Patients with Hepatocellular Carcinoma

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    Xuehua Zhu

    2012-08-01

    Full Text Available We aimed to investigate the expression pattern of phosphatase and tensin homolog (PTEN, to evaluate the relationship between PTEN expression and clinicopathological characteristics, including fatty acid synthase (FAS expression, and to determine the correlations of PTEN and FAS expression with survival in Chinese patients with hepatocellular carcinoma (HCC. The expression patterns of PTEN and FAS were determined using tissue microarrays and immunohistochemistry. The expression of PTEN was compared with the clinicopathological characteristics of HCC, including FAS expression. Receiver operator characteristic curves were used to calculate the clinical sensitivity and specificity of PTEN expression. Kaplan-Meier survival curves were constructed to evaluate the correlations of PTEN loss and FAS overexpression with overall survival. We found that the loss of PTEN expression occurred predominantly in the cytoplasm, while FAS was mainly localized to the cytoplasm. Cytoplasmic and total PTEN expression levels were significantly decreased in HCC compared with adjacent non-neoplastic tissue (both, p < 0.0001. Decreased cytoplasmic and total PTEN expression showed significant clinical sensitivity and specificity for HCC (both, p < 0.0001. Downregulation of PTEN in HCC relative to non-neoplastic tissue was significantly correlated with histological grade (p = 0.043 for histological grades I–II versus grade III. Loss of total PTEN was significantly correlated with FAS overexpression (p = 0.014. Loss of PTEN was also associated with poor prognosis of patients with poorly differentiated HCC (p = 0.049. Moreover, loss of PTEN combined with FAS overexpression was associated with significantly worse prognosis compared with other HCC cases (p = 0.011. Our data indicate that PTEN may serve as a potential diagnostic and prognostic marker of HCC. Upregulating PTEN expression and inhibiting FAS

  6. Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥ 2 line cetuximab-based therapy of colorectal cancer patients.

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    Zacharenia Saridaki

    Full Text Available BACKGROUND: To investigate the predictive significance of KRAS, BRAF, PIK3CA mutational status, AREG- EREG mRNA expression, PTEN protein expression and skin rash in metastatic colorectal cancer (mCRC patients treated with cetuximab containing salvage chemotherapy. METHODS: Primary tumors from 112 mCRC patients were analyzed. The worst skin toxicity during treatment was recorded. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 37 (33%, 8 (7.2% and 11 (9.8% cases, respectively, PTEN was lost in 21 (19.8% cases, AREG and EREG were overexpressed in 48 (45% and 51 (49% cases. In the whole study population, time to tumor progression (TTP and overall survival (OS was significantly lower in patients with KRAS (p = 0.001 and p = 0.026, respectively or BRAF (p = 0.001 and p<0.0001, respectively mutant tumors, downregulation of AREG (p = 0.018 and p = 0.013, respectively or EREG (p = 0.002 and p = 0.004, respectively and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively. In KRAS wt patients TTP and OS was significantly lower in patients with BRAF (p = 0.0001 and p<0.0001, respectively mutant tumors, downregulation of AREG (p = 0.021 and p = 0.004, respectively or EREG (p = 0.0001 and p<0.0001, respectively and grade 0-1 skin rash (p<0.0001 and p<0.0001, respectively. TTP was significantly lower in patients with PIK3CA mutations (p = 0.01 or lost PTEN (p = 0.002. Multivariate analysis revealed KRAS (Hazard Ratio [HR] 4.3, p<0.0001, BRAF mutation (HR: 5.1, p<0.0001, EREG low expression (HR: 1.6, p = 0.021 and absence of severe/moderate skin rash (HR: 4.0, p<0.0001 as independent prognostic factors for decreased TTP. Similarly, KRAS (HR 2.9, p = 0.01, BRAF mutation (HR: 3.0, p = 0.001, EREG low expression (HR: 1.7, p = 0.021, absence of severe/moderate skin rash (HR: 3.7, p<0.0001 and the presence of undifferantited tumours (HR: 2.2, p = 0.001 were revealed as independent prognostic factors for decreased OS. CONCLUSIONS: These results

  7. Prognostic Significance of mTOR and PTEN in Patients with Esophageal Squamous Cell Carcinoma

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    Jianjun Lu

    2015-01-01

    Full Text Available The prognostic value of mTOR in ESCC is much controversial; this study aimed to determine the prognostic importance of mTOR and PTEN in patients with ESCC. A total of 148 consecutive patients who underwent esophagectomy from 2010 to 2012 were included in this study, tested by western bolt and immunohistochemistry for mTOR and PTEN expression. Correlation coefficient was calculated using Pearson’s correlation test. The 3-year overall survival (OS and disease-free survival (DFS were calculated in relation to the two markers. 94 (63.5% of 148 were mTOR high expression, and PTEN high expression was detected in 46 (31.1% of the 148 patients with ESCC. The Pearson correlation coefficient revealed a significant negative correlation in two proteins (correlation coefficient = −0.189, P<0.005. The 3-year OS and DFS time in the mTOR-high group was 23.9 and 18.4 months, respectively, and the time in the mTOR-low group was 33.9 months and 31.4 months, respectively. The difference of survival rate between the two groups remained statistically significant. mTOR-low or PTEN-high patients had better 3-year rates of OS and DFS than mTOR-high or PTEN-low group (P<0.001 by the log-rank test. This study also found that mTOR was an independence prognostic factor by multivariate analysis.

  8. Cystic tumors of the liver: A practical approach

    Institute of Scientific and Technical Information of China (English)

    Paolo Del Poggio; Marco Buonocore

    2008-01-01

    Biliary cyst tumors (cystadenoma and cystadenocarcinoma) are an indication for liver resection. They account for only 5% of all solitary cystic lesions of the liver, but differential diagnosis with multiloculated or complicated biliary cysts, atypical hemangiomas, hamartomas and lymphangiomas may be difficult. The most frequent challenge is to differentiate biliary cyst tumors from hemorrhagic cysts. Computerized tomography (CT) and magnetic resonance imaging (MRI) are often not diagnostic and in these cases fine needle aspiration (FNA) is used to confirm the presence of atypical biliary cells. FNA, however, lacks adequate sensitivity and specificity and should always be used in conjunction with imaging. Pre-operative differentiation of cystadenoma from cystadenocarcinoma is impossible and surgery must be performed if a biliary cyst tumor is suspected. When multiple cystic lesions are observed throughout the liver parenchyma, it is important to exclude liver metastasis, of which colonic cancer is the most common primary site. Multiple biliary hamartomas (von Meyenburg complex) can appear as a mixture of solid and cystic lesions and can be confused with cystic metastasis. Strong and uniform T2 hyperintensity on MRI is usually diagnostic, but occasionally a percutaneous biopsy may be required.

  9. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

    Science.gov (United States)

    Milella, Michele; Falcone, Italia; Conciatori, Fabiana; Matteoni, Silvia; Sacconi, Andrea; De Luca, Teresa; Bazzichetto, Chiara; Corbo, Vincenzo; Simbolo, Michele; Sperduti, Isabella; Benfante, Antonina; Del Curatolo, Anais; Cesta Incani, Ursula; Malusa, Federico; Eramo, Adriana; Sette, Giovanni; Scarpa, Aldo; Konopleva, Marina; Andreeff, Michael; McCubrey, James Andrew; Blandino, Giovanni; Todaro, Matilde; Stassi, Giorgio; De Maria, Ruggero; Cognetti, Francesco; Del Bufalo, Donatella; Ciuffreda, Ludovica

    2017-01-01

    Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies. PMID:28220839

  10. PTEN, a widely known negative regulator of insulin/PI3K signaling, positively regulates neuronal insulin resistance

    Science.gov (United States)

    Gupta, Amit; Dey, Chinmoy Sankar

    2012-01-01

    Lipid and protein tyrosine phosphatase, phosphatase and tension homologue (PTEN), is a widely known negative regulator of insulin/phosphoinositide 3-kinase signaling. Down-regulation of PTEN is thus widely documented to ameliorate insulin resistance in peripheral tissues such as skeletal muscle and adipose. However, not much is known about its exact role in neuronal insulin signaling and insulin resistance. Moreover, alterations of PTEN in neuronal systems have led to discovery of several unexpected outcomes, including in the neurodegenerative disorder Alzheimer's disease (AD), which is increasingly being recognized as a brain-specific form of diabetes. In addition, contrary to expectations, its neuron-specific deletion in mice resulted in development of diet-sensitive obesity. The present study shows that PTEN, paradoxically, positively regulates neuronal insulin signaling and glucose uptake. Its down-regulation exacerbates neuronal insulin resistance. The positive role of PTEN in neuronal insulin signaling is likely due to its protein phosphatase actions, which prevents the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), the kinases critically involved in neuronal energy impairment and neurodegeneration. Results suggest that PTEN acting through FAK, the direct protein substrate of PTEN, prevents ERK activation. Our findings provide an explanation for unexpected outcomes reported earlier with PTEN alterations in neuronal systems and also suggest a novel molecular pathway linking neuronal insulin resistance and AD, the two pathophysiological states demonstrated to be closely linked. PMID:22875989

  11. Análise do gene PTEN por hibridização in situ fluorescente no carcinoma de células renais

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    Eurico Cleto Ribeiro de Campos

    Full Text Available OBJETIVO: avaliar a frequência de deleção do gene PTEN no carcinoma de células renais e o impacto da deleção nas taxas de sobrevida global e livre de doença. MÉTODOS: foram analisados 110 pacientes portadores de carcinoma de células renais submetidos à nefrectomia radical ou parcial entre os anos de 1980 e 2007. Em 53 casos foi possível a análise do gene PTEN pelo método de hibridização in situ fluorescente através da técnica de "tissue microarray". Para a análise estatística, os pacientes foram classificados em dois grupos, de acordo com a presença ou ausência de deleção. RESULTADOS: o tempo médio de seguimento foi de 41,9 meses. Deleção hemizigótica foi identificada em 18 pacientes (33,9%, ao passo que deleção homozigótica esteve presente em três (5,6%. Em aproximadamente 40% dos casos analisados havia deleção. Monossomia e trissomia foram detectadas, respectivamente, em nove (17% e dois pacientes (3,8%. Em 21 pacientes (39,6%, a análise por hibridização in situ do gene PTEN foi normal. Não houve diferenças estatisticamente significativas nas taxas de sobrevida global (p=0,468 e livre de doença (p=0,344 entre os pacientes portadores ou não de deleção. Foram fatores independentes para a sobrevida global: estádio clínico TNM, sintomatologia ao diagnóstico, alto grau de Fuhrmann performance status (Ecog e recorrência tumoral. A livre de doença foi influenciada unicamente pelo estádio clínico TNM. CONCLUSÃO: deleção do gene PTEN no CCR foi detectada com frequência de aproximadamente 40% e sua presença não foi determinante de menores taxas de sobrevida, permanecendo os fatores prognósticos tradicionais como determinantes da evolução dos pacientes.

  12. [Pseudo-tumoral lesions of dense conjuntival tissue. Attempt at pathogenic interpretation].

    Science.gov (United States)

    Bonenfani, J L; Lagacé, R

    1975-01-01

    The histogenesis of pseudotumors of dense connective tissue has been studied. These lesions may be classified as mucoid (synovial cyst and periungueal myxoma), collagenous (desmoid tumor, desmoid fibroblastoma and fibromatosis colli), elastic (elastofibroma dorsi), cellular (fibroblastic: fibromatosis, fasciitis and myositis; histiocytic: giant-cell tumor of tendon sheath, fibrous histiocytoma and atypical fibroxanthoma), metaplastic (ossifying fasciitis, ossifying myositis and juvenile chondroid fibroma) and hamartomatous nature (fibrous hamartoma). It must be emphasized that these lesions show a variable and polymorphouse cellular composition and then can simulate sarcoma.

  13. Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss

    Science.gov (United States)

    Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen; Zhao, Jean J; Roberts, Thomas M

    2016-01-01

    We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110α and p110β. We found that p110β localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110β to rafts alleviated the requirement for p110β-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110β dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110β. DOI: http://dx.doi.org/10.7554/eLife.17635.001

  14. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations.

    Science.gov (United States)

    Kar, Souvik; Samii, Amir; Bertalanffy, Helmut

    2015-04-01

    Cerebral cavernous malformations (CCM) are common vascular malformation of the brain and are associated with abnormal angiogenesis. Although the exact etiology and the underlying molecular mechanism are still under investigation, recent advances in the identification of the mutations in three genes and their interactions with different signaling pathways have shed light on our understanding of CCM pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression. Here, we provide an update literature review on the current knowledge of the PTEN/PI3K/Akt/VEGF signaling in angiogenesis, more importantly in CCM pathogenesis. In addition to reviewing the current literatures, this article will also focus on the structural domain of the three CCM proteins and their interacting partners. Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment.

  15. PTEN基因对慢性粒细胞白血病Survivin、Xiap、Smac调控的研究%Regulation of wild type PTEN gene on Survivin, Xiap and Smac in chronic leukemia cells

    Institute of Scientific and Technical Information of China (English)

    成志勇; 万建设; 王亚丽; 梁丽青; 梁文同; 穆敬; 芦希; 潘崚

    2011-01-01

    Objective To explore the effects of tumor-suppressing gene wild type PTEN on the cell proliferation,apoptosis and the possible regulations of apoptosis-related molecules Survivin,Xiap and Smac gene in human chronic myeloid leukemia(CML)and cell line K562 cells.Methods(1)The recombinant adenovirus containing green fluorescent protein(GFP)and PTEN(Ad-PTEN-GFP)or empty vector(AdGFP)was transfected into K562 cells.The growth of K562 cells was observed by MTT assay while cell cycle and apoptotic rate were assessed by flow cytometry(FCM).PTEN,Survivin,Xiap and Smac mRNA levels were detected by real-time fluorescent relative-quantification reverse transcriptional PCR(FQ-PCR)while PTEN protein levels analyzed by Western blot.(2)The expression levels of PTEN,Survivin,Xiap and Smac mRNA were detected in 10 chronic myelogenous leukemia(CML)patients in chronic phase(CML-CP),10 CML patients in blast crises(CML-BC)and 10 normal control marrow mononuclear cells(MMNC).Results The growth of K562 cells was suppressed markedly.And the maximal growth inhibition rate was 38.6% after the tranfection of PTEN.Survivin,Xiap,Smac mRNA expression levels were down-regulated by around 6.14,7.44 and 2.95 folds respectively(0.0700 ±0.0059,0.0089 ±0.0006,0.0600 ±0.0039 vs 0.4370 ± 0.0790,0.0661 ± 0.0072,0.1580 ± 0.0078 vs 0.4530 ± 0.0810,0.0700 ± 0.0079.0.1770 ±0.0085,all P < 0.01).The mRNA expression level of PTEN in CML-BC patients was lower than that in CML-CP patients and normal control.But Survivin,Xiap,Smae mRNA expression levels were higher in CML-BC patients than those in CML-CP and normal control.Conclusion The over-expression of PTEN gene may inhibit the proliferation of K562 cells and promote cell apoptosis via the regulation of Survivin,Xiap and Smac genes.%目的 探讨肿瘤抑制基因PTEN对人慢性粒细胞白血病(CML)中生存素(Survivin)、X连锁凋亡抑制蛋白(Xiap)、线粒体促凋亡蛋白(Smac)调控的作用.方法(1)将携带有野生型PTEN和绿

  16. Collision Tumor Composed of Meningioma and Cavernoma

    Science.gov (United States)

    Weigel, Jens; Neher, Markus; Schrey, Michael; Wünsch, Peter H.; Steiner, Hans-Herbert

    2017-01-01

    A true collision tumor is a rare entity composed of two histologically distinct neoplasms coinciding in the same organ. This paper reports a unique case of cerebral collision tumor consisting of two benign components. On the first hand, meningioma which is usually a benign lesion arising from the meningothelial cell in the arachnoidal membrane. On the other, cerebral cavernoma which is a well-circumscribed, benign vascular hamartoma within the brain. To our knowledge, there is no previously documented case of cerebral collision tumor consisting of two benign components. A 56-year-old Caucasian male suffered in 2002 from an atypical meningioma WHO II° located in the left lateral ventricle. Three years after the tumor extirpation, the patient suffered from a hematoma in the fourth ventricle due to a recurrently haemorrhaged cavernoma. In 2008, a recurrence of the tumor in the left lateral ventricle was discovered. Additionally, another tumor located in the quadrigeminal lamina was detected. After surgical resection of the tumor in the left lateral ventricle, the pathological examination confirmed the diagnosis of a collision tumor consisting of components of a meningioma WHO II° and a cavernoma. Postoperatively, no adjuvant treatment was needed and no tumor recurrence is discovered up to the present. A possible explanation for the collision of those two different tumors may be migration of tumor cells mediated by the cerebrospinal fluid. After 5-years of follow-up, there is no sign of any tumor recurrence; therefore, surgical tumor removal without adjuvant therapy seems to be the treatment of choice. PMID:28061500

  17. [Combined hamartoma of the retina and retinal pigment epithelium. Anti-VEGF treatment of the associated choroidal neovascular membranes].

    Science.gov (United States)

    Echevarría, L; Villena, O; Nievas, T; Bellido, R

    2015-02-01

    A 58 year-old female was diagnosed with a juxtapapillary combined hamartoma of the retina and retinal pigment epithelium (CHR-RPE) in her left eye 14 years ago. Her visual acuity in that eye was 20/20. Recently, she came to our department with a sudden visual loss and metamorphopsis in her left eye. After performing funduscopy, angiography and OCT, she was diagnosed with choroidal neovascular membrane (CNVM) at lesion border, and started on antiangiogenic therapy. CHR-RPE, despite being a benign condition, may become complicated with severe visual impairment. Antiangiogenic therapy provides a good alternative to photodynamic therapy or laser photocoagulation for treatment of CNVM, avoiding adding iatrogenesis from these treatment to the complications associated with this pathology. Copyright © 2014 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  18. Research of expression and clinical significance of p53, PCNA and PTEN in gastric cancer%p53、PCNA和PTEN在胃癌组织中的表达及其临床意义

    Institute of Scientific and Technical Information of China (English)

    贾海江; 戴林

    2012-01-01

    目的 探讨p53、PCNA和PTEN蛋白在胃癌组织中的表达及其临床意义.方法 随访经手术治疗的胃癌患者,应用免疫组织化学染色方法,检测有随访资料的胃癌组织中p53、PCNA和PTEN的表达情况.结果 胃癌组织中,p53阳性表达率58.2%,PCNA强阳性表达率52.7%,PTEN表达缺失率52.7%;p53、PCNA和PTEN的表达与胃癌浸润深度、有无淋巴结转移有关(P0.05);胃癌患者术后5年生存率比较:p53阳性表达患者低于阴性表达患者(P0. 05). Gastric cancer patients with p53 expression had less probability of 5-year survival than patients with negative expression; gastric cancer patients with strong PCNA expression had less probability of 5-year survival than patients with weakly expression; gastric cancer patients with PTEN expression had more probability of 5 years survival than patients with negative expression. The differences were all statistically significant (P<0. 05). Conclusions Expression of p53, PCNA and PTEN are all related to the depth of tumor invasion and metastasis of lymph node. Gastric cancer patients with positive expression of p53, strong positive of expression PCNA or negative expression of PTEN have poor prognosis. The detections of p53, PCNA and PTEN expression in gastric cancer specimens might be used as one of the indicators to determine the prognosis of gastric cancer patients.

  19. BMP-2 up-regulates PTEN expression and induces apoptosis of pulmonary artery smooth muscle cells under hypoxia.

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    Weifeng Pi

    Full Text Available AIM: To investigate the role of bone morphogenetic protein 2 (BMP-2 in regulation of phosphatase and tensin homologue deleted on chromosome ten (PTEN and apoptosis of pulmonary artery smooth muscle cells (PASMCs under hypoxia. METHODS: Normal human PASMCs were cultured in growth medium (GM and treated with BMP-2 from 5-80 ng/ml under hypoxia (5% CO(2+94% N(2+1% O(2 for 72 hours. Gene expression of PTEN, AKT-1 and AKT-2 were determined by quantitative RT-PCR (QRT-PCR. Protein expression levels of PTEN, AKT and phosph-AKT (pAKT were determined. Apoptosis of PASMCs were determined by measuring activities of caspases-3, -8 and -9. siRNA-smad-4, bpV(HOpic (PTEN inhibitor and GW9662 (PPARγ antagonist were used to determine the signalling pathways. RESULTS: Proliferation of PASMCs showed dose dependence of BMP-2, the lowest proliferation rate was achieved at 60 ng/ml concentration under hypoxia (82.2±2.8%. BMP-2 increased PTEN gene expression level, while AKT-1 and AKT-2 did not change. Consistently, the PTEN protein expression also showed dose dependence of BMP-2. AKT activity significantly reduced in BMP-2 treated PASMCs. Increased activities of caspase-3, -8 and -9 of PASMCs were found after cultured with BMP-2. PTEN expression remained unchanged when Smad-4 expression was inhibited by siRNA-Smad-4. bpV(HOpic and GW9662 (PPARγ inhibitor inhibited PTEN protein expression and recovered PASMCs proliferation rate. CONCLUSION: BMP-2 increased PTEN expression under hypoxia in a dose dependent pattern. BMP-2 reduced AKT activity and increased caspase activity of PASMCs under hypoxia. The increased PTEN expression may be mediated through PPARγ signalling pathway, instead of BMP/Smad signalling pathway.

  20. Establishment and antitumor effects of dasatinib and PKI-587 in BD-138T, a patient-derived muscle invasive bladder cancer preclinical platform with concomitant EGFR amplification and PTEN deletion

    Science.gov (United States)

    Lim, Joung Eun; Jeong, Da Eun; Song, Hye Jin; Kim, Sudong; Nam, Do-Hyun; Sung, Hyun Hwan; Jeong, Byong Chang; Seo, Seong Il; Jeon, Seong Soo; Lee, Hyun Moo; Choi, Han-Yong; Jeon, Hwang Gyun

    2016-01-01

    Muscle-invasive bladder cancer (MIBC) consists of a heterogeneous group of tumors with a high rate of metastasis and mortality. To facilitate the in-depth investigation and validation of tailored strategies for MIBC treatment, we have developed an integrated approach using advanced high-throughput drug screening and a clinically relevant patient-derived preclinical platform. We isolated patient-derived tumor cells (PDCs) from a rare MIBC case (BD-138T) that harbors concomitant epidermal growth factor receptor (EGFR) amplification and phosphatase and tensin homolog (PTEN) deletion. High-throughput in vitro drug screening demonstrated that dasatinib, a SRC inhibitor, and PKI-587, a dual PI3K/mTOR inhibitor, exhibited targeted anti-proliferative and pro-apoptotic effects against BD-138T PDCs. Using established patient-derived xenograft models that successfully retain the genomic and molecular characteristics of the parental tumor, we confirmed that these anti-tumor responses occurred through the inhibition of SRC and PI3K/AKT/mTOR signaling pathways. Taken together, these experimental results demonstrate that dasatinib and PKI-587 might serve as promising anticancer drug candidates for treating MIBC with combined EGFR gene amplification and PTEN deletion. PMID:27438149

  1. EGFR- and AKT-mediated reduction in PTEN expression contributes to tyrphostin resistance and is reversed by mTOR inhibition in endometrial cancer cells.

    Science.gov (United States)

    Li, Tian; Yang, Yuebo; Li, Xiaomao; Xu, Chengfang; Meng, Lirong

    2012-02-01

    Loss or mutation of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene is associated with resistance to epidermal growth factor receptor (EGFR) inhibitors. However, the mechanism underlying remains elusive. In this study, we aimed to explore whether sensitivity to the EGFR tyrosine kinase inhibitor (TKI) is affected by PTEN status in endometrial cancer cells. PTEN siRNA and the PTEN gene were transfected into HEC-1A and Ishikawa endometrial cancer cells using lentiviral vectors. Cells were treated under various concentrations of RG14620 and rapamycin, which are EGFR and mammalian target of rapamycin (mTOR) inhibitors, respectively. The IC(50) of RG16420 was determined by using the MTT method. Cell apoptosis and the cell cycle were studied, and activation of EGFR, AKT, and p70S6 were detected by Western blot analysis. Loss of PTEN promoted cell proliferation and led to significant increases in the levels of EGFR, phospho-EGFR, AKT, phospho-AKT, and phospho-mTOR proteins. Ishikawa and HEC-1A(PTENkd) cells that displayed loss and inactivation of PTEN function were resistant to RG14620. HEC-1A and Ishikawa(PTEN) cells with intact PTEN were sensitive to RG14620. The combination of two inhibitors was more effective than both monotherapies, particularly in carcinoma cells with PTEN dysfunction. Decreased phospho-EGFR protein expression was observed in all cell lines that were sensitive to RG14620. Decreased phospho-AKT and phospho-p70S6 protein expression was observed in PTEN-intact cells that were sensitive to RG14620. PTEN loss results in resistance to EGFR TKI, which was reversed by PTEN reintroduction or mTOR inhibitor treatment. The combined treatment of EGFR TKI and the mTOR inhibitor provided a synergistic effect by promoting cell death in PTEN-deficient and PTEN-intact endometrial cancer cells, particularly in PTEN-deficient carcinoma cells with up-regulated EGFR activation.

  2. Resveratrol reverses Doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer.

    Science.gov (United States)

    Xu, Jiahui; Liu, Deying; Niu, Huilin; Zhu, Guifang; Xu, Yangwei; Ye, Danli; Li, Jian; Zhang, Qingling

    2017-01-26

    Gastric cancer is one of the major causes of cancer-related mortality worldwide. Most of patients presenting with inoperable gastric cancers rely on systemic chemotherapy for prolongation of survival. Doxorubicin (DOX) is one of the important agents against gastric cancer. Acquired DOX-resistance severely impedes the chemotherapeutic effect, invariably leading to poor prognosis. Resveratrol (RES) as a kind of phytoalexin has demonstrated anti-tumor functions in breast cancer and myeloid leukemia, but its function and mechanism are still unknown in gastric cancer treatment. CCK8 assay was used to detect the cytotoxicity of DOX and RES to gastric cancer cells. DOX-resistant subclone cell line (SGC7901/DOX) was derived from SGC7901 cells exposed to stepwise increasing concentrations of DOX treatment. We measured the migratory capabilities of SGC7901/DOX cells by Cell scratch test and Transwell assay. SGC7901/DOX cells were treated with DOX, RES, neither or both. Then we analyzed cell survival by CCK8 assay, colony formation by Colony-forming assay, cell apoptosis by Annexin-V-FITC and PI dual staining assay and cell migration by Cell scratch test and Transwell assay. Western blotting was conducted to detect the protein expressions of PTEN/Akt signaling pathway and EMT-related markers. Immunofluorescence was performed to confirm the EMT-related markers expressions. The xenograft model was used to assess the effect of DOX and RES in vivo. The key molecules associated with proliferation, apoptosis and EMT were evaluated by immunohistochemistry in tumor specimens. SGC7901/DOX cells acquired drug resistance and enhancive migratory capability. RES enabled SGC7901/DOX cells to regain DOX sensitivity, mitigated the aggressive biological features, promoted cell apoptosis in vitro and inhibited tumor growth in vivo. Mechanistic studies revealed that SGC7901/DOX cells underwent epithelial-mesenchymal transition (EMT) which was induced by Akt activation, and through activating

  3. Review of spectral domain-enhanced depth imaging optical coherence tomography of tumors of the retina and retinal pigment epithelium in children and adults

    Directory of Open Access Journals (Sweden)

    Carol L Shields

    2015-01-01

    Full Text Available Background: Spectral domain (SD enhanced depth imaging optical coherence tomography (EDI-OCT is a useful tool for anatomic, cross-sectional imaging of retinal conditions. Aims: The aim was to identify characteristic patterns of retinal and retinal pigment epithelial tumors on EDI-OCT in children and adults. Settings and Design: Retrospective review. Materials and Methods: Analysis of published reports and personal observations using office-based EDI-OCT for adults and portable hand-held SD OCT for infants and children. Results: Using EDI-OCT, retinal tumors such as small retinoblastoma, astrocytic hamartoma, and hemangioblastoma arose abruptly from the retina, immediately adjacent to normal retina. Small exophytic retinoblastoma and retinal hemangioblastoma showed the full-thickness, homogeneous retinal disorganization with surrounding normal retina "draping" over the margins. Retinoblastoma occasionally had intralesional cavities and surrounding subretinal fluid. Hemangioblastoma often had adjacent intraretinal edema and subretinal fluid. Astrocytic hamartoma arose within the nerve fiber layer and sometimes with a "moth-eaten" or cavitary appearance. Retinal pigment epithelial (RPE lesions such as congenital hypertrophy of RPE appeared flat with shadowing, occasional subretinal cleft, and abrupt photoreceptor loss. Congenital simple hamartoma showed an abrupt elevation from the inner retina with crisp, dark posterior shadowing. Combined hamartoma of the retina/RPE showed vitreoretinal traction causing "sawtooth mini-peak" or gently "maxi-peak" folding of the retina. RPE adenoma often produces remote macular edema or epiretinal membrane and the tumor has an irregular, "rugged" surface with deep shadowing. Conclusions: Enhanced depth imaging optical coherence tomography shows characteristic patterns that are suggestive of certain retinal and RPE tumors.

  4. [Mixed epithelial and stromal tumor growing with polypoid pattern in the renal pelvis].

    Science.gov (United States)

    Yamasaki, Toshinari; Yagihashi, Yuusuke; Iwamura, Hiroshi; Shirahase, Toshiaki; Hashimura, Takayuki; Katsura, Yoshitaka

    2004-01-01

    A 68-year-old woman was found incidentally to have right hydronephrosis and a renal pelvic mass by abdominal ultrasonography. Radiographic examinations revealed a heterogeneous renal pelvic tumor, and right nephroureterectomy was performed. The tumor was well circumscribed yellow-whitish solid mass with scattered cysts. Histologically, the tumor was composed of both mesenchymal and epithelial components. The mesenchymal elements consisted of fibroblasts and smooth muscle cells, and the epithelial elements of cystic and tubular structures lined by cuboidal epithelium. Atypia and mitoses were not identified. The patient was free of recurrence 42 months postoperatively. Mixed epithelial and stromal tumor of the kidney is a recently recognized neoplasm that occurs almost exclusively in perimenopausal woman. Similar tumors have been reported previously under various names, including adult mesoblastic nephroma and cystic hamartoma of the renal pelvis. Histogenesis of the tumor is still controversial.

  5. Hemorragia digestiva alta secundária a hamartoma de glândulas de Brunner: relato de caso e revisão da literatura = Upper gastrintestinal bleeding due to Brunner’s gland hamartoma: case report and literature review

    Directory of Open Access Journals (Sweden)

    Lul, Rodrigo Mayer

    2013-01-01

    Conclusões: Apesar do hamartoma de glândulas de Brunner ser uma lesão benigna e rara, de crescimento indolente e comumente assintomática, pode provocar quadros graves como o descrito neste relato, devendo ser sempre lembrado como diagnóstico diferencial em casos de hemorragia digestiva alta

  6. Extra-hepatic bile duct hamartoma in a 10-month-old with a morgagni hernia and multiple anatomical anomalies: a rare and incidental finding.

    Science.gov (United States)

    Shah, Adil A; Karass, Michael; Page, Andrew J; Shehata, Bahig M; Durham, Megan M

    2013-07-01

    Von Meyenburg complexes (VMCs), also known as bile duct hamartomas, are a part of a group of ductal plate malformations. They are typically present intrahepatically. In this case, we present to our knowledge the first report of an extra-hepatic VMC in the pediatric population. The patient presented as a 10-month-old infant with a weeklong history of progressive breathing difficulty. A chest radiograph was obtained, showing intestinal loops in the thoracic cavity consistent with a Morgagni's hernia, unrelated to his breathing difficulty. The patient then underwent an elective repair of his congenital diaphragmatic defect. During the operation, the bile duct hamartoma was found adherent to the accessory lobe of the liver, present to the left of the ligamentum teres.

  7. Ameloblastic fibroma in six–year-old male: Hamartoma or a true neoplasm

    Science.gov (United States)

    Jindal, Chhavi; Bhola, Reena Sarkar

    2011-01-01

    Ameloblastic fibroma (AF) is an uncommon true mixed odontogenic tumor with a relative frequency between 1.5% and 4.5%. Recently, it has been proposed that two subtypes of AF exist: A neoplasm and a hamartomatous lesion. We report a case of AF in left mandibular posterior region in a 6-year-old male patient. The tumor showed unusual and aggressive features that suggested it was a true neoplasm. PMID:22144834

  8. Ameloblastic fibroma in six-year-old male: Hamartoma or a true neoplasm.

    Science.gov (United States)

    Jindal, Chhavi; Bhola, Reena Sarkar

    2011-09-01

    Ameloblastic fibroma (AF) is an uncommon true mixed odontogenic tumor with a relative frequency between 1.5% and 4.5%. Recently, it has been proposed that two subtypes of AF exist: A neoplasm and a hamartomatous lesion. We report a case of AF in left mandibular posterior region in a 6-year-old male patient. The tumor showed unusual and aggressive features that suggested it was a true neoplasm.

  9. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities.

    Directory of Open Access Journals (Sweden)

    Janice B B Lam

    Full Text Available BACKGROUND: Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1 and thioredoxin reductase (TrxR1 were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1. CONCLUSION: Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K

  10. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors

    Directory of Open Access Journals (Sweden)

    Mitrou Panagiota N

    2011-04-01

    Full Text Available Abstract Background The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. Methods 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Results Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05. PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04. Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02 and poor differentiation (p PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55. Conclusion These data demonstrated the frequent occurrence (34.9% of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.

  11. Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

    Science.gov (United States)

    Revandkar, Ajinkya; Perciato, Maria Luna; Toso, Alberto; Alajati, Abdullah; Chen, Jingjing; Gerber, Hermeto; Dimitrov, Mitko; Rinaldi, Andrea; Delaleu, Nicolas; Pasquini, Emiliano; D'Antuono, Rocco; Pinton, Sandra; Losa, Marco; Gnetti, Letizia; Arribas, Alberto; Fraering, Patrick; Bertoni, Francesco; Nepveu, Alain; Alimonti, Andrea

    2016-01-01

    Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients. PMID:27941799

  12. Overexpression of LRIG1 regulates PTEN via MAPK/MEK signaling pathway in esophageal squamous cell carcinoma

    Science.gov (United States)

    Jiang, Xiaofang; Li, Huiwu

    2016-01-01

    The present study aimed to evaluate the role of leucine-rich repeats and immunoglobulin-like domain protein 1 (LRIG1) in the regulation of phosphatase and tensin homolog (PTEN) expression in esophageal carcinogenesis. LRIG1 was overexpressed in esophageal squamous cell carcinoma (ESCC) cell lines, and the effect of LRIG1 overexpression on the mRNA and protein expression levels of PTEN was evaluated by reverse transcription-quantitative polymerase chain reaction and western blotting. Furthermore, the effects of LRIG1 overexpression on the cell cycle distribution and apoptosis of ESCC cells were examined by flow cytometry. Various cell signaling pathway inhibitors were used to assess the effects of LRIG1 on downstream signaling in ESCC cell lines. In addition, the association between LRIG1 and PTEN expression was examined in 48 samples from patients with ESCC. LRIG1 overexpression was demonstrated to downregulate PTEN expression in ESCC cell lines, and promote their proliferation and inhibit apoptosis. In addition, LRIG1-mediated suppression of PTEN expression was inhibited by the U0126 inhibitor, which suggests that LRIG1 may inhibit the activation of PTEN signaling molecules by triggering the mitogen-activated protein kinase (MAPK)/MAPK kinase 1 (MEK) signaling pathway. In conclusion, the present study demonstrated that overexpression of LRIG1 significantly and adversely affected the survival of ESCC cells, and that the MAPK/MEK signaling pathway may be responsible for the repression of PTEN expression and function. PMID:27698691

  13. Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes.

    NARCIS (Netherlands)

    Menko, F.H.; Kneepkens, C.M.; Leeuw, N. de; Peeters, E.A.; Maldergem, L Van; Kamsteeg, E.J.; Davidson, R.; Rozendaal, L.; Lasham, C.A.; Peeters-Scholte, C.M.; Jansweijer, M.C.E.; Hilhorst-Hofstee, Y.; Gille, J.J.P.; Heins, Y.M.; Nieuwint, A.W.; Sistermans, E.A.

    2008-01-01

    Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic effe

  14. Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction.

    Science.gov (United States)

    Chen, Wei-Jan; Pang, Jong-Hwei S; Lin, Kwang-Huei; Lee, Dany-Young; Hsu, Lung-An; Kuo, Chi-Tai

    2010-01-01

    Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury.

  15. Deletion of PTEN Produces Deficits in Conditioned Fear and Increas