探索非典型蛋白激酶C异构体对胰腺癌细胞的生长及程序性死亡的影响

项目名称： 探索非典型蛋白激酶C异构体对胰腺癌细胞的生长及程序性死亡的影响

项目编号： No.81472555

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 朱彤波

作者单位： 四川大学

项目金额： 73万元

中文摘要： 胰腺癌在我国的发病率呈逐年上升趋势，已成为危胁人民健康的重大隐患。由于其早诊困难，预后性差，加之缺乏有效的治疗手段，导致胰腺癌的治愈率低，五年存活率不到1%。已有研究证明，超过90%的胰腺导管腺癌细胞中均含有K-RAS的基因突变。但有关K-RAS在胰腺癌的发生、发展，以及K-RAS对胰腺癌细胞内其它信号分子所起的作用，还未被完全阐明。最新研究显示，蛋白激酶Ｃ家族中的两种非典型PKC异构体，PKCζ 和 ι，对于胰腺病变的产生、胰腺导管上皮化生、以及胰腺上皮内瘤样病变、直至发展为转移性胰腺癌，均有重要促进作用。但抑制这两种PKC异构体是否会影响胰腺癌细胞的生长、甚至诱发细胞凋亡，还未有相关报道。本研究希望通过揭示下调PKCζ和ι在细胞中的表达对胰腺癌细胞的生长和细胞凋亡的影响、以及与之相关的分子机理，为开发新型的治疗胰腺癌的靶向药物提供线索，并为进一步揭示胰腺癌的病理机制提供依据。

中文关键词： 胰腺导管腺癌；K-RAS；非典型蛋白激酶C异构体；PKC；iota；&；zeta；细胞凋亡

英文摘要： Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with fewer than 1% patients surviving more than 5 years due to its poor prognosis and lack of effective targeted therapies. It is becoming an increasing problem in modern industrialized China, accompanied by deteriorating environment and people adopting a more stressful lifestyle. While mutant K-RAS was identified in >90% PDAC lesions, the exact roles that mutant K-RAS played and its cooperation with other signaling pathways in initiation and progression of PDAC have not been fully understood. Recent studies revealed that two atypical protein kinase C (PKC) isoforms, PKCζ and ι are crucial mediators in PDAC formation, capable of promoting pancreatic acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) that progress to metastatic PDAC. However, the effects of these two PKC isoforms, when downregulated, on the growth, proliferation and apoptosis of PDAC have not been examined. In this study, we propose to demonstrate that the suppression of PKCζ or/and ι leads to growth inhibition and apoptosis in pancreatic cancer cell lines harboring mutant K-RAS. Further disclosure of the underlying mechanism will shed light on the discovery of novel therapeutical drugs for pancreatic cancer.

英文关键词： pancreatic ductal adenocarcinoma;K-RAS;atypical protein kinase C isoforms;PKCζ&ι;apoptosis