Role of Protein Kinase C in Colon Carcinogenesis

蛋白激酶 C 在结肠癌发生中的作用

• 批准号: 7122483
• 负责人: Alan P. Fields
• 金额: $ 42.53万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-02 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122483
• 关键词: athymic mouse; biological signal transduction; carcinogenesis; cell growth regulation; cell line; cell proliferation; clinical research; colon neoplasms; gastrointestinal epithelium; gene expression; gene interaction; genetic regulation; genetically modified animals; isozymes; metastasis; molecular oncology; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic cell; oncogenes; protein kinase C; protein protein interaction; protein structure function; transforming growth factors

DESCRIPTION (provided by applicant): Colon cancer is the second leading cause of cancer death in the United States. It arises by a multi-step process involving progressive changes in signaling pathways that regulate epithelial cell proliferation, differentiation and survival. PKCbetaII induces hyperproliferation in the colon, and is required for early steps in colon carcinogenesis in vivo. PKCbetaII induces resistance to the growth inhibitory effects of TGFbeta in rat intestinal epithelial (RIE) cells through activation of a novel PKCbetaII->Cox-2->TGFbetaRII signaling axis. PKCbetaII also induces an invasive phenotype in RIE cells through activation of a PKCbetaII->Ras/Mek->PKCI/Rac1 signaling pathway. The overall hypothesis to be tested in this proposal is that PKCbetaII is required for the transformed phenotype in human colon cancer cells. Aim 1 will test the hypothesis that PKCbetaII confers TGFbeta resistance on human colon cancer cells by activating the PKCbetaII->Cox-->?TGFbetaRII signaling axis. Aim 2 will test the hypothesis that PKCbetaII is important for anchorage-independent growth and invasion of human colon cancer cells in vitro, and for tumorigenicity and metastasis in vivo. PKCbetaII expression will also be assessed in human colon cancers and compared with clinical outcome. Aim 3 will test the hypothesis that PKCII is required for K-Ras-mediated colon carcinogenesis in vivo using two complementary transgenic K-Ras mouse models crossed to PKCbeta KO mice. Aim 4 will test the hypothesis that PKCbetaII and PKC/I collaborate to promote colon carcinogenesis in vivo. The role of PKC/I in PKCbetaII-mediated colon carcinogenesis will be assessed in transgenic PKCbetaII mice crossed to transgenic mice expressing kinase-deficient PKC/I. Synergism between PKCbetaII and PKC/I in colon cancer progression, invasion and metastasis will be assessed in transgenic PKCbetaII mice crossed to mice expressing constitutively-active PKC/I. These studies will determine the role of PKCbetaII in human colon cancer cell transformation, the signaling mechanisms by which PKCbeta/II contributes to cellular transformation, and the relationship between PKCbetaII, PKC? and oncogenic K-Ras in promoting colon carcinogenesis in vivo. They will also assess PKCbetaII as a potential therapeutic target and prognostic marker in colon cancer, and develop new genetic models of colon cancer that may be suitable for studying all stages of colon carcinogenesis from initiation to invasive carcinoma in vivo.

描述（由申请人提供）：结肠癌是美国癌症死亡的第二大原因。它是由一个多步骤过程产生的，涉及调节上皮细胞增殖、分化和存活的信号通路的渐进变化。 PKCbetaII 诱导结肠过度增殖，并且是体内结肠癌发生早期步骤所必需的。 PKCbetaII 通过激活新型 PKCbetaII->Cox-2->TGFbetaRII 信号轴，诱导大鼠肠上皮 (RIE) 细胞对 TGFbeta 的生长抑制作用产生抵抗。 PKCbetaII 还通过激活 PKCbetaII->Ras/Mek->PKCI/Rac1 信号通路在 RIE 细胞中诱导侵袭表型。本提案要测试的总体假设是，人结肠癌细胞的转化表型需要 PKCbetaII。目标 1 将检验以下假设：PKCbetaII 通过激活 PKCbetaII->Cox-->TGFbetaRII 信号轴赋予人类结肠癌细胞 TGFbeta 抗性。目标 2 将检验以下假设：PKCbetaII 对于人类结肠癌细胞的体外贴壁依赖性生长和侵袭以及体内的致瘤性和转移非常重要。还将评估人类结肠癌中的 PKCbetaII 表达并与临床结果进行比较。目标 3 将使用与 PKCbeta KO 小鼠杂交的两个互补的转基因 K-Ras 小鼠模型来测试以下假设：PKCII 是 K-Ras 介导的体内结肠癌发生所必需的。目标 4 将检验 PKCbetaII 和 PKC/I 协同促进体内结肠癌发生的假设。将在与表达激酶缺陷型 PKC/I 的转基因小鼠杂交的转基因 PKCbetaII 小鼠中评估 PKC/I 在 PKCbetaII 介导的结肠癌发生中的作用。将在与表达组成型活性 PKC/I 的小鼠杂交的转基因 PKCbetaII 小鼠中评估 PKCbetaII 和 PKC/I 在结肠癌进展、侵袭和转移中的协同作用。这些研究将确定 PKCbetaII 在人结肠癌细胞转化中的作用、PKCbeta/II 促进细胞转化的信号机制以及 PKCbetaII 和 PKC? 之间的关系。和致癌K-Ras在体内促进结肠癌发生。他们还将评估 PKCbetaII 作为结肠癌的潜在治疗靶点和预后标志物，并开发新的结肠癌遗传模型，该模型可能适合研究体内结肠癌从起始到浸润性癌的所有阶段。