Role of PKC iota in Pancreatic Carcinogenesis

PKC iota 在胰腺癌发生中的作用

• 批准号: 7474568
• 负责人: Nicole R Murray
• 金额: $ 18.36万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474568
• 关键词: 3q26; Adenocarcinoma Cell; Cancer Patient; Cancer cell line; Cell Line; Chemotherapy-Oncologic Procedure; Chromosomal Gain; Chromosomal Instability; Chromosomes; Clinical; Colon; Colon Carcinoma; Disease; Disruption; Ductal Epithelium; Epidermal Growth Factor Receptor; Gene Amplification; Gene Dosage; Genes; Genetic; Genus Cola; Growth; In Vitro; Knowledge; Lung; Maintenance; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Molecular Target; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Phenotype; Play; Resistance; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Tumor Cell Line; base; cancer cell; cancer type; carcinogenesis; cell transformation; chemotherapy; chromosome 3q gain; in vivo; metaplastic cell transformation; migration; pancreatic neoplasm; protein kinase C iota; tumor

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.

描述(申请人提供)：胰腺导管腺癌(PDAC)是一种侵袭性的、高度致命的疾病，其特点是高度的染色体不稳定，包括3Q染色体的频繁获得。PDAC对常规化疗具有高度耐药性，因此迫切需要为胰腺癌化疗寻找新的分子靶点。致癌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PKC(在体外和体内的致癌K-ras信号转导中)的一个必要的作用。PKC(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。PKC(定位于3q26)在NSCLC中频繁扩增，并驱动PKC(表达)驱动PKC(表达)功能受阻于NSCLC细胞系的生长。基于肺癌、结肠癌和胰腺癌中致癌信号转导途径的相似性，我们推测PKC在胰腺癌细胞转化中也起着必要的作用。具体来说，我们假设PKC(是PDAC细胞转化所必需的)，并且PKC()的遗传或药物抑制将通过抑制PKC(介导的致癌信号)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的获得导致胰腺肿瘤中PKC基因拷贝数的增加和过度表达。最后，我们假设胰腺肿瘤中PKC()的表达水平将与胰腺癌患者的低生存率相关。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，我们将验证这样一个假设，即通过从基因和药物上抑制PKC(功能)，PKC(是胰腺癌细胞转化表型所必需的)。在特定的目标2中，我们将检验PKC在介导PDAC细胞转化表型的致癌信号通路中发挥必要作用的假设。在具体目标3中，我们将评估PKC(与其在非小细胞肺癌中的作用类似)在胰腺癌中是癌基因的可能性。这些目标的成功实现将大大提高我们对PKC(在胰腺癌细胞转化中的作用)的认识，并可能证明PKC()是治疗胰腺癌的潜在分子靶点。