UBC Theses and Dissertations
Roles of epidermal growth factor receptor and its ligands in ovarian cancer Xin, Qiu
The overexpression of epidermal growth factor receptor (EGFR) has been shown in ovarian cancer and is associated with poor prognosis of this malignant disease. Thus, exploring the EGFR-mediated cell signaling in ovarian cancer may deepen our understanding of this disease. The down-regulation of E-cadherin may promote cell proliferation, motility and invasiveness, leading to the cancer progression. We have previously demonstrated that epidermal growth factor (EGF), amphiregulin (AREG) and transforming growth factor-α (TGF-α), all of which bind exclusively to EGFR, down-regulate E-cadherin expression and induce ovarian cancer cell invasion. In this study, we showed that, as was the case for the effect of EGF, the TGF-α- and AREG-induced down-regulation of E-cadherin expression involved both EGFR and HER2. However, in contrast to the cases of EGF and AREG, the transcription factor Snail was not required for the TGF-α-induced down-regulation of E-cadherin expression. This study showed that TGF-α uses common and divergent molecular mediators to regulate E-cadherin expression and cell invasion. Cyclooxygenase-2 (COX-2) has been shown to participate in cancer metastasis by down-regulating E-cadherin expression, and elevated expression of COX-2 has been reported in ovarian cancer. We have previously demonstrated that COX-2-derived prostaglandin E2 (PGE2) promotes cell invasion in human ovarian cancer. In this study, we showed that EGF/EGFR-induced cell invasion was mediated by the elevation of COX-2 expression and PGE2 production in an E-cadherin-independent manner. Aside from the pro-invasive effect, EGF may strongly promote the cell proliferation. Connexin 43 (Cx43) has been shown to regulate cell proliferation, and this gap junction protein can be regulated by EGF. To date, the functional role of EGF in regulating Cx43 expression in human ovarian cancer has never been investigated. Interestingly, we demonstrated that EGF/EGFR up-regulated Cx43 expression through the activation of Akt1. Functionally, Cx43 may act as a negative regulator of EGF/EGFR-induced cell proliferation in human ovarian cancer, in a gap junction-independent manner. Overall, our studies provide important insights into the molecular mechanisms regulating EGF-stimulated human ovarian cancer cell invasion and proliferation.
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