Role of PKC iota in Pancreatic Carcinogenesis

描述（由申请方提供）：胰腺导管腺癌（PDAC）是一种侵袭性、高致死性疾病，其特征为高水平的染色体不稳定性，包括频繁的3q染色体增益。PDAC对常规化疗具有高度抗性;因此，迫切需要确定胰腺癌化疗的新分子靶点。致癌性K-ras及其下游效应通路是启动和维持胰腺导管上皮转化所必需的。我们已经确定了一个必要的作用，PKC（在致癌K-ras信号在体外和体内。蛋白激酶C（PKC）在肺癌和结肠癌细胞的转化生长、侵袭和迁移中起关键作用。基于以下观察结果，PKC被表征为NSCLC中的癌基因：1）PKC（在大多数原发性NSCLC肿瘤中过度表达，2）PKC（表达水平预测NSCLC患者的生存率较差，3）PKC（位于3q 26）在NSCLC中经常扩增，扩增驱动PKC（表达和4）PKC（功能阻断NSCLC细胞系中的转化生长。基于肺癌、结肠癌和胰腺癌中致癌信号转导途径的相似性，我们假设PKC（也在胰腺癌细胞转化中起必要的作用。具体而言，我们假设PKC β是PDAC细胞转化所必需的，并且PKC β的遗传或药理学抑制将通过抑制PKC β介导的致癌信号传导来阻断胰腺癌细胞系的转化表型。此外，我们假设在胰腺癌细胞系和肿瘤中经常观察到的染色体3q的获得导致基因拷贝数的增加和PKC的过度表达（在胰腺肿瘤中）。最后，我们假设胰腺肿瘤中PKC β的表达水平与胰腺癌患者的生存率相关。三个相互关联的具体目标将检验这些假设。在具体目标1中，我们将检验以下假设：通过遗传和非遗传性抑制PKC功能，PKC是胰腺癌细胞转化表型所必需的。在具体目标2中，我们将检验PKC在介导PDAC细胞转化表型的促癌信号通路中起必要作用的假设。在具体目标3，我们将评估的可能性，类似于其在非小细胞肺癌中的作用，蛋白激酶C（是一种癌基因在胰腺癌。这些目标的成功完成将显著提高我们对PKC β在胰腺癌细胞转化中作用的认识，并可能证明PKC β是治疗胰腺癌的潜在分子靶点。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly lethal disease marked by a high level of chromosomal instability, including frequent chromosomal gains at 3q. PDAC is highly resistant to conventional chemotherapies; therefore, there is a dire need to identify new molecular targets for pancreatic cancer chemotherapy. Oncogenic K-ras and its downstream effector pathways are required for initiation and maintenance of transformation of pancreatic ductal epithelium. We have identified a requisite role for PKC( in oncogenic K-ras signaling in vitro and in vivo. PKC( plays a critical role in the transformed growth, invasion and migration of lung and colon cancer cells. PKC( is characterized as an oncogene in NSCLC based on the following observations: 1) PKC( is over-expressed in a majority of primary NSCLC tumors, 2) PKC( expression levels predict poor survival in NSCLC patients, 3) PKC( (located at 3q26) is frequently amplified in NSCLC and amplification drives PKC( expression and 4) disruption of PKC( function blocks transformed growth in NSCLC cell lines. Based on the similarities in oncogenic signal transduction pathways in lung, colon and pancreatic cancers, we hypothesize that PKC( also plays a requisite role in pancreatic cancer cell transformation. Specifically, we hypothesize that PKC( is required for PDAC cellular transformation and that either genetic or pharmacological inhibition of PKC( will block the transformed phenotype of pancreatic cancer cell lines by inhibiting PKC(-mediated oncogenic signaling. In addition, we hypothesize that the gain of chromosome 3q frequently observed in pancreatic cancer cell lines and tumors results in an increase in gene copy number and over-expression of PKC( in pancreatic tumors. Finally, we hypothesize that the level of expression of PKC( in pancreatic tumors will correlate with poor survival in pancreatic cancer patients. Three interrelated specific aims will test these hypotheses. In Specific Aim 1, we will test the hypothesis that PKC( is required for the transformed phenotype of pancreatic cancer cells by genetically and pharmacologically inhibiting PKC( function. In Specific Aim 2, we will test the hypothesis that PKC( plays a requisite role in the pro-carcinogenic signaling pathways that mediate the transformed phenotype of PDAC cells. In Specific Aim 3, we will evaluate the possibility that, similar to its role in non-small cell lung cancer, PKC( is an oncogene in pancreatic cancer. The successful completion of these aims will significantly enhance our knowledge of the role of PKC( in pancreatic cancer cell transformation, and will likely demonstrate that PKC( is a potential molecular target for the treatment of pancreatic cancer.