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.

描述（由应用程序提供）：此应用集中于研究参与肺癌早期事件的新机制。环境致癌物是肺癌的主要结构药物，因为它们诱导遗传和表观遗传学改变，最终导致肺上皮细胞的恶性转化。 KRAS中的致癌突变是非小细胞肺癌（NSCLC）的常见改变，通过肺癌（如多环芳烃（PAHS）和许多其他环境癌剂）诱导高频诱导。已经确定，蛋白激酶C epsilon（PKC）是一种有丝分裂，促卵巢和肿瘤激酶的蛋白质激酶，在上皮癌中被上调，包括 NSCLC。我们实验室的研究表明，PKC是NSCLC细胞的肿瘤形成，侵入性和转移的重要介体。最近，我们开发了一种小鼠模型，用于在PKC缺陷背景（LSL-K-Rasg12d;PKC-/ - ）中的KRAS诱导性肺特异性表达，发现PKC基因（PRKCE）的遗传消融显着影响肿瘤形成的肿瘤形成。这表明KRAS肺肿瘤发生的倡议需要PKC。此外，在KRAS突变的人类肺腺癌中的Silico数据库分析中，发现高PKC表达与较短的总体患者生存之间存在显着关联。总的来说，这使我们假设PKC是肺癌作用的必要介体。在特定的目标1中，我们将检查PKCKO小鼠（在A/J遗传背景中）是否对已知会诱导KRAS突变的肺癌的作用有抵抗力，包括PAH Benzo [A] pyrene（B [A] P）和氨基甲酸酯。我们将检查PKC的药物抑制剂（V1-2）是否抑制了形成将进行机械研究，以评估致癌物是否上调肺部上皮细胞。在特定的目标2中，我们将使用遗传和药物方法来确定PKC是否介导了KRAS-和致癌物诱导的肿瘤发生所需的肺癌祖细胞（支气管肺泡干细胞或BASC）的扩张。明确地在启动中确立了PKC的作用，我们将在细胞模型中使用功能增益方法，并生成该激酶的诱导性肺特异性转基因小鼠系，以确定这是否导致形成前身体或恶性肿瘤的肺部病变。最后，在特定目标3中，我们将阐述肺癌中KRAS和PKC之间功能相互作用的机械基础，重点是a）分析Ras级联的元素，b）鉴定PKC创世记和转录网络在该激酶中对KRAS肿瘤的上下文中的pker the the Insperial consement consement consement the seplial consement the pk cy the seplial the pkc ress的转录网络的鉴定，以及PK）。（EMT），这是获得肺癌细胞浸润能力所需的过程。我们的研究应提供对环境致癌物分子作用的新型机械见解，并揭示了肺癌发生早期事件的重要方面，从而影响了我们对肺癌病因的理解。