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

与妇科癌症增殖和进展相关的信号交易分析

基本信息

批准号：
11671629
负责人：
KATO Kiyoko
金额：
$ 2.5万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671629/
关键词：
Ovarian Cancer HGF Ras MAPK PI3K invasiveness differentiation Apoptosis 分化アポトーシス P13K

项目摘要

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.

1)肝细胞生长因子（Hepatocyte growth factor，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种生物学作用。腹膜转移是卵巢癌进展的关键，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（促分裂原活化肽）激酶级联反应。此外，Ras显性阴性腺病毒感染卵巢癌减少了HGF诱导的运动和侵袭活动。此外，Ras下游的MEK和PI 3-Kinase通路均参与了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本研究探讨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可能通过激活CAMP-PKA信号转导途径促进上皮细胞向上皮细胞系的分化。(2)ER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激活ER是通过Ras-MAPK直接激活ER-AF 1和抑制PR表达介导的，与ER激活竞争。3）激活的K-Ras突变体刺激细胞凋亡诱导。与此相反，激活的H-Ras在凋亡信号的存在下急剧抑制细胞的凋亡。从目前的结果，我们定义Ras蛋白作为子宫内膜细胞分化，增殖和凋亡的关键调节因子。