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      The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients

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          Abstract

          Epithelial ovarian cancer is the leading cause of death among female genital malignancies. Reduced expression of the cell adhesion molecule E-cadherin was previously shown to be associated with adverse prognostic features. The role of the E-cadherin repressor Snail in ovarian cancer progression remains to be elucidated. We analysed formalin-fixed and paraffin-embedded specimens of 48 primary ovarian tumours and corresponding metastases for expression of E-cadherin and Snail by immunohistochemistry. We found a significant correlation between E-cadherin expression in primary cancers and their corresponding metastases ( P<0.001). This correlation was found for Snail expression as well ( P<0.001). There was a significant ( P=0.008) association of reduced E-cadherin expression in primary ovarian cancer with shorter overall survival. Similarly, Snail expression in corresponding metastases ( P=0.047) was associated with reduced overall survival of the patients. Additionally, the group of patients showing reduced E-cadherin and increased Snail immunoreactivity in primary tumours and corresponding metastases, respectively, had a significantly higher risk of death ( P=0.002 and 0.022, respectively) when compared to the patient group with the reference expression profile E-cadherin positive and Snail negative. Taken together, the results of our study show that the E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients.

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          Most cited references26

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          Epithelial-mesenchymal transitions in development and pathologies.

          The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. The molecular mechanisms of EMT were primarily studied in epithelial cell lines, leading to the discovery of transduction pathways involved in the loss of epithelial cell polarity and the acquisition of a variety of mesenchymal phenotypic traits. Similar mechanisms have also been uncovered in vivo in different species, showing that EMT is controlled by remarkably well-conserved mechanisms. Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.
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            Worldwide burden of gynaecological cancer: the size of the problem.

            The estimation of cancer burden is valuable to set up priorities for disease control. The comprehensive global cancer statistics from the International Agency for Research on Cancer indicate that gynaecological cancers accounted for 19% of the 5.1 million estimated new cancer cases, 2.9 million cancer deaths and 13 million 5-year prevalent cancer cases among women in the world in 2002. Cervical cancer accounted for 493 000 new cases and 273 000 deaths; uterine body cancer for 199 000 new cases and 50 000 deaths; ovarian cancer for 204 000 new cases and 125 000 deaths; cancers of the vagina, vulva and choriocarcinoma together constituted 45 900 cases. More than 80% of the cervical cancer cases occurred in developing countries and two-thirds of corpus uteri cases occurred in the developed world. Political will and advocacy to invest in healthcare infrastructure and human resources to improve service delivery and accessibility are vital to reduce the current burden in low- and medium-resource countries.
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              Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex.

              The transcription factor Snail has been described as a direct repressor of E-cadherin expression during development and carcinogenesis; however, the specific mechanisms involved in this process remain largely unknown. Here we show that mammalian Snail requires histone deacetylase (HDAC) activity to repress E-cadherin promoter and that treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Snail. Moreover, overexpression of Snail is correlated with deacetylation of histones H3 and H4 at the E-cadherin promoter, and TSA treatment in Snail-expressing cells reverses the acetylation status of histones. Additionally, we demonstrate that Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Most importantly, we demonstrate an interaction between Snail, histone deacetylase 1 (HDAC1) and HDAC2, and the corepressor mSin3A. This interaction is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. Our results establish a direct causal relationship between Snail-dependent repression of E-cadherin and the modification of chromatin at its promoter.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                20 November 2007
                22 January 2008
                29 January 2008
                : 98
                : 2
                : 489-495
                Affiliations
                [1 ]Institute of Pathology, Technical University of Munich Trogerstrasse 18, Munich D-81675, Germany
                [2 ]Department of Obstetrics and Gynecology, Technical University of Munich, Klinikum rechts der Isar Ismaningerstrasse 22, Munich D-81675, Germany
                [3 ]Institute of Medical Statistics and Epidemiology, Technical University of Munich Ismaningerstrasse 22, Munich D-81675, Germany
                [4 ]Institute of Pathology, GSF-National Research Centre for Environment and Health Neuherberg D-85764, Germany
                Author notes
                [* ]Author for correspondence: kf.becker@ 123456lrz.tum.de
                [5]

                Current address: Cancer Research UK Cambridge Research Institute and Department of Oncology, University of Cambridge, Robinson Way, Cambridge, UK.

                Article
                6604115
                10.1038/sj.bjc.6604115
                2361433
                18026186
                c1289129-b67b-44a4-942f-6043cea2b9ad
                Copyright 2008, Cancer Research UK
                History
                : 22 June 2007
                : 15 October 2007
                : 31 October 2007
                Categories
                Genetics and Genomics

                Oncology & Radiotherapy
                epithelial–mesenchymal transition,e-cadherin,snail,ovarian cancer,overall survival

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