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

1)信号转导与卵巢癌进展相关。肝细胞生长因子（HGF）是一种多功能生长因子，对上皮细胞具有增殖、侵袭和形态发生等多营养生物学作用。腹膜播散对卵巢癌的进展至关重要，我们的研究表明HGF诱导卵巢癌细胞的迁移和侵袭。我们还证明了HGF刺激其受体的自磷酸化，随后是Ras-MAP（丝裂原活化肽）激酶级联反应。此外，Ras显性阴性腺病毒感染卵巢癌可降低hgf诱导的动性和侵袭性活性。此外，Ras下游的MEK和pi3激酶通路都参与了hgf刺激的卵巢癌细胞侵袭。2)子宫内膜细胞生长分化相关的信号转导。在本研究中，我们探讨了ras介导的信号转导系统在子宫内膜细胞分化、增殖和凋亡中的作用。(1)活化的K-Ras有可能通过刺激CAMP-PKA信号转导促进上皮细胞谱系的分化。(2)内质网的转录激活对于K-Ras介导的细胞生长促进和由此产生的细胞转化至关重要。Ras对ER的激活是通过Ras- mapk直接激活ER- af1和抑制PR表达介导的，PR表达与ER激活竞争。3)活化的K-Ras突变体刺激细胞凋亡诱导。相反，激活的H-Ras在存在凋亡信号的情况下显著抑制细胞凋亡。根据目前的结果，我们将Ras蛋白定义为子宫内膜细胞分化、增殖和凋亡的关键调节因子。

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.