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Role of E-cadherin in the serous borderline ovarian tumor and low-grade serous ovarian carcinoma cell invasion

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Title: Role of E-cadherin in the serous borderline ovarian tumor and low-grade serous ovarian carcinoma cell invasion
Author: Cheng, Jung-Chien
Degree Doctor of Philosophy - PhD
Program Reproductive and Developmental Sciences
Copyright Date: 2012
Publicly Available in cIRcle 2012-12-05
Abstract: E-cadherin is a membrane glycoprotein located at cell adherens junctions. A switch from E-cadherin to N-cadherin expression has been considered a hallmark of the epithelial-mesenchymal transition (EMT), which is primarily due to the up-regulation of the transcription factors Snail, Slug, Twist and ZEB1. Epithelial ovarian cancer cells with low E-cadherin expression are more invasive, and the absence of E-cadherin expression in ovarian cancer is associated with poor prognosis and survival. Serous borderline ovarian tumors (SBOT) are slow-growing, non-invasive ovarian epithelial neoplasms. SBOT are considered distinct entities that give rise to invasive low-grade serous carcinomas (LGSC), which have a relatively poor prognosis and are unrelated to high-grade serous carcinomas (HGSC). The mechanisms underlying the progression of non-invasive SBOT to invasive LGSC are not understood. We have established short-term cultures of SBOT cells from tumor biopsies and have shown that inactivation of p53, Rb and/or PP2A by the SV40 large T (LT) and small T (ST) antigens allows SBOT cells to acquire characteristics associated with neoplastic progression, including increased cell motility, invasion and EMT. However, the overexpression of N-cadherin does not induce cell invasion in SBOT cells. In this study, using loss- and gain-of-function approaches, we show that p53 acts as a tumor suppressor in the regulation of SBOT and LGSC cell invasion by regulating E-cadherin expression through PI3K/Akt-mediated transcriptional and epigenetic machineries. In high-grade ovarian cancer cultures, it has been shown that epidermal growth factor (EGF) and transforming growth factor-beta (TGF-β) induce cell invasion by activating the EMT. However, the effects of EGF and TGF-β on SBOT and LGSC cell invasion remain unknown. We show that EGF induces SBOT cell invasion by activating the EMT. In addition, our results suggest that there are EMT-independent mechanisms that mediate EGF-induced LGSC cell invasion. Interestingly, we show a dual function for TGF-β in which it induces invasion in SBOT cells by activating the EMT and promotes apoptosis in LGSC cells. Overall, this study demonstrates that the loss of E-cadherin expression in SBOT may play an important role in the transition to invasive LGSC.
URI: http://hdl.handle.net/2429/43651
Scholarly Level: Graduate

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