Analysis of signal transaction associated with proliferation and progression in gynecologic cancer

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1) Signal transduction associated with ovarian cancer progression.Hepatocyte growth factor (HGF) is a multifunctional growth which has pleiotrophic biological effects on epithelial cells such as proliferation, invasiveness and morphogenesis. Peritoneal dissemination is critical for the progression of ovarian cancer, and our study revealed that HGF induces migration and invasion of ovarian cancer cells. We also demonstrated that HGF stimulates autophosphorylation of its receptor, followed of the Ras-MAP(mitogen-activated peptide) kinase cascade. Moreover, infection of ovarian cancer with Ras dominant-negative adenovirus reduced the HGF-induced motogenic and invasive activities. Additionally, both MEK and PI3-Kinase pathways downstream of Ras were involved in HGF-stimulated ovarian cancer cell invasiveness.2) Signal transduction associated with cell growth and differentiation in endometrial cell.In the present study, we addressed the role of Ras-mediated signal transduction systems in endometrial cell differentiation, proliferation and apoptosis.(1) Activated K-Ras has a potential to promote the differentiation to epithelial cell lineage by stimulating the CAMP-PKA signal transduction.(2) Tanscriptional activation by ER is critical for the K-Ras mediated cell growth promotion and the resultant cell transformation. ER activation by Ras is mediated by the direct activation of ER-AF1 through Ras-MAPK and suppression of PR expression, that competes with ER activation.3) An activated K-Ras mutant stimulated apoptosis induction. In contrast, An activated H-Ras sharply suppressed apoptosis of the cells in the presence of apoptotic signals. From the present results, we define Ras proteins as a critical regulator of endometrial cell differentiation, proliferation and apoptosis.