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Protein kinase C and lung carcinogenesis

蛋白激酶C与肺癌发生

基本信息

批准号：
9126982
负责人：
MARCELO G. KAZANIETZ
金额：
$ 39.12万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126982
关键词：
A/J Mouse Ablation Address Air Pollutants Alleles Aromatic Polycyclic Hydrocarbons Benzo(a)pyrene Bioinformatics Breast Cancer Burden Cancer Etiology Carcinogens Case Study Cell model Cells Cessation of life Chemical Actions Codon Nucleotides Computer Simulation DNA Data Databases Development Disease Elements Environmental Carcinogens Epigenetic Process Epithelial Epithelial Cells Etiology Event Exposure to Frequencies Genes Genetic Goals Growth Head and Neck Cancer Health Human Induced Mutation KRAS2 gene Knockout Mice Laboratories Lead Lesion Link Longevity Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Mesenchymal Modeling Molecular Mus Mutate Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nude Mice Oncogenic Patients Phenotype Phosphotransferases Play Premalignant Process Prostate Protein Kinase C RNA Interference Resistance Risk Role Signal Transduction Solid Stem cells Testing Therapeutic Transgenic Mice Up-Regulation Urethane autocrine base cancer cell cancer initiation cancer therapy carcinogenesis cell motility chemical carcinogen environmental chemical expectation gain of function genetic signature in vivo inducible gene expression inhibitor/antagonist insight lung carcinogenesis lung tumorigenesis member mouse model mutant neoplastic novel overexpression prevent protein kinase C epsilon prototype public health relevance response translational medicine tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This application focuses on the study of novel mechanisms involved in early events of lung carcinogenesis. Environmental carcinogens are major causative agents of lung cancer, as they induce genetic and epigenetic alterations that ultimately lead to the malignant transformation of lung epithelial cells. Oncogenic mutations in KRAS, a common alteration in non-small cell lung cancer (NSCLC), are induced in high frequency by lung carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and many other environmental carcinogens. It has been established that protein kinase C epsilon (PKC), a mitogenic, pro-survival, and tumorigenic kinase, is up-regulated in epithelial cancers, including NSCLC. Studies from our laboratory revealed that PKC is an essential mediator of tumor formation, invasiveness, and metastasis of NSCLC cells. More recently, we developed a mouse model for inducible lung-specific expression of KRas in a PKC-deficient background (LSL- K-rasG12D; PKC-/-), and found that genetic ablation of the PKC gene (PRKCE) markedly impairs the formation of tumors driven by the activated KRas allele. This suggests that PKC is required for the initiation of KRas lung tumorigenesis. Moreover, in silico database analysis in KRAS mutated human lung adenocarcinomas revealed a significant association between high PKC expression and short overall patient survival. Altogether, this led us to hypothesize that PKC is a necessary mediator of the actions of lung carcinogens. In Specific Aim 1 we will examine if PKC KO mice (in A/J genetic background) are resistant to the effects of lung carcinogens known to induce mutations in KRas, including the PAH benzo[a]pyrene (B[a]P) and urethane. We will examine if a pharmacological inhibitor of PKC (V1-2) inhibits the formation of lung tumors induced by these carcinogens or by an activated KRas allele. Mechanistic studies will be pursued to assess if carcinogens up-regulate PKCin lung epithelial cells. In Specific Aim 2, we will use genetic and pharmacological approaches to determine if PKC mediates the expansion of lung cancer progenitor cells (bronchioalveolar stem cells or BASCs) required for KRas- and carcinogen-induced tumorigenesis. To unambiguously establish a role for PKC in initiation we will use gain-of-function approaches in cellular models as well as generate an inducible lung-specific transgenic mouse line for this kinase to determine if this leads to the formation of pre-malignant or malignant lung lesions. Finally, in Specific Aim 3 we will dissect the mechanistic basis for the functional interaction between KRas and PKC in lung cancer, focusing on a) the analysis of elements of the Ras cascade, b) the identification of a PKC gene signature and transcriptional networks regulated by this kinase in the context of KRas tumorigenesis, and c) the assessment of a potential role for PKC in epithelial-mesenchymal transition (EMT), a process required for the acquisition of invasive capacity of lung cancer cells. Our studies should provide novel mechanistic insights into the molecular effects of environmental carcinogens as well as reveal important aspects of early events of lung carcinogenesis, thus impacting on our understanding of lung cancer etiology.