炎症微环境通过下调PP2Ac抑制胰腺癌细胞Par/aPKC极性复合体形成并诱导EMT的机制研究

项目名称： 炎症微环境通过下调PP2Ac抑制胰腺癌细胞Par/aPKC极性复合体形成并诱导EMT的机制研究

项目编号： No.81472296

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： 李伟

作者单位： 苏州大学

项目金额： 70万元

中文摘要： 胰腺癌易转移。炎症是胰腺癌高危因素，可诱导癌细胞发生EMT（上皮-间质转化），促进转移。细胞极性丧失是EMT的特征之一。课题组在前一NSCF资助下研究发现：①炎症通过下调PP2Ac（蛋白磷酸酶2A催化亚基），促进胰腺癌细胞转移；②抑制PP2Ac，可削弱细胞极性并诱导EMT。Par/aPKC复合体是调控细胞极性的关键，最近发现PP2A是其调控因子。我们推测炎症微环境抑制胰腺癌细胞PP2Ac后，很可能通过影响Par/aPKC复合体的形成而削弱细胞极性，进而诱导EMT并促进转移。依靠前期建立的多种动物模型，结合分子生物学手段和临床样本检测，本项目将研究：①Par/aPKC复合体对胰腺癌演进过程的影响；②炎症/PP2Ac信号通路，对胰腺癌细胞EMT和转移的调控作用，以及这种调控是否由Par/aPKC复合体依赖性机制介导。本研究有助于阐明炎症微环境促胰腺癌转移的分子机制，有望为胰腺癌治疗找到新靶点。

中文关键词： C11_胰肿瘤；炎症微环境；蛋白磷酸酶2A催化亚基；Par/aPKC极性复合体；上皮间质转化

英文摘要： Pancreatic cancer has the proclivity of early metastasis. Inflammatory tumor microenvironment correlates with the development and progression of pancreatic cancer. Inflammation promotes metastasis by inducing epithelial-mesenchymal transition (EMT), in which epithelial cells lose polarity, break down cell-cell and cell-extracellular matrix connections, and acquire the metastatic capacity. With the support of our previous NSFC grant, we have demonstrated that inflammation promoted metastasis through downregulation of PP2Ac (protein phosphatase 2A catalytic subunit). Inhibition of PP2Ac disrupted cell polarity and induced EMT. Par/aPKC complex is a key regulator of cell polarity. Because the function of PP2A is highly conserved in Drosophila, in which PP2A is an essential regulator of Par/aPKC complex; we propose that inflammatory tumor microenvironment induces EMT and metastasis in pancreatic cancer cells by suppressing PP2Ac, resulting the inhibition of the Par/aPKC complex formation. By using several well-established animal models, various contemporary molecular biology techniques, and human pancreatic cancer specimens, we will investigate the critical role and function of the Par/aPKC complex in the progression of pancreatic cancer in vitro and in vivo. We will also delineate the signal pathway underlying the PP2Ac-Par/aPKC axis in inflammation-mediated EMT. Our study will not only establish a new paradigm that significantly affects our views on how chronic inflammation leads to the disruption of cell polarity in EMT and metastasis, but will also lay groundwork for developing new therapeutic strategies against the deadly pancreatic cancer.

英文关键词： Pancreatic cancer;Inflammatory microenvironment;PP2Ac;Par/aPKC polarity complex;EMT