Tumor-promoting liver injuries and mechanisms

促肿瘤肝损伤及其机制

基本信息

批准号：
10332735
负责人：
Gen-Sheng Feng
金额：
$ 49.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-20 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10332735
关键词：
Address Animals Automobile Driving Cancer Etiology Carcinogenesis Mechanism Cells Clinical Treatment Complement Conflict (Psychology)Country Data Defect Development Diethylnitrosamine Disease Drug Targeting Environmental Risk Factor Event Excision Gene Mutation Goals Hepatocarcinogenesis Hepatocyte Human Incidence Inflammatory Response Knock-out Lead Liver Liver diseases Malignant - descriptor Malignant neoplasm of liver Modeling Molecular Molecular Analysis Mus Mutant Strains Mice Mutation NFKB Signaling Pathway Oncogenic Oncoproteins Outcome Pathogenicity Pathway interactions Patients Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Process Recurrence Reporting Role Signal Transduction Signaling Molecule Testing Therapeutic Time Work base beta catenin carcinogenicity chemical carcinogen design experimental study liver cancer model liver cancer patient liver cell proliferation liver injury mortality mouse model mutant nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics success theories therapeutically effective tumor tumor initiation tumor progression tumorigenesis tumorigenic

Address Animals Automobile Driving Cancer Etiology Carcinogenesis Mechanism Cells Clinical Treatment Complement Conflict (Psychology)Country Data Defect Development Diethylnitrosamine Disease Drug Targeting Environmental Risk Factor Event Excision Gene Mutation Goals Hepatocarcinogenesis Hepatocyte Human Incidence Inflammatory Response Knock-out Lead Liver Liver diseases Malignant - descriptor Malignant neoplasm of liver Modeling Molecular Molecular Analysis Mus Mutant Strains Mice Mutation NFKB Signaling Pathway Oncogenic Oncoproteins Outcome Pathogenicity Pathway interactions Patients Primary Malignant Neoplasm of Liver Primary carcinoma of the liver cells Process Recurrence Reporting Role Signal Transduction Signaling Molecule Testing Therapeutic Time Work base beta catenin carcinogenicity chemical carcinogen design experimental study liver cancer model liver cancer patient liver cell proliferation liver injury mortality mouse model mutant nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics success theories therapeutically effective tumor tumor initiation tumor progression tumorigenesis tumorigenic

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项目摘要

The goal of this project is to decipher how various liver injuries and disorders can accelerate and exacerbate development of hepatocellular carcinoma (HCC), one leading cause of cancer-related mortality worldwide. The immediate focus is on elucidating the tumorigenic liver damages generated ironically by loss of pro-oncogenic molecules in hepatocytes. In recent experiments, we found that deletion of Shp2/Ptpn11, previously known to be pro-oncogenic, aggravated HCC development induced by diethylnitrosamine (DEN) or by Pten deficiency and NASH. Consistently, several other groups reported that targeted removal of oncoproteins, such as c-Met, Ikkb, and b-catenin, from hepatocytes indeed aggravated HCC induced by DEN or other oncogenic drivers. However, the underlying mechanisms for the anti-oncogenic effect of these oncoproteins are unclear. Our hypothesis is that loss of the pro-oncogenic molecules generates a variety of tumor-promoting factors in the liver microenvironment, resulting in exacerbated tumorigenesis. Of note, these mouse tumor models closely recapitulate many aspects of the pathogenic process in liver cancer patients. Therefore, we believe that common mechanisms or oncogenic liver disorders are shared between the mouse models and human patients in tumor initiation and progression. On this project, we will pursue a comprehensive analysis of the molecular and cellular events that drive hepato-carcinogenesis using several mouse models. We propose the following three Specific Aims: 1) to search and identify tumorigenic factors in livers deficient for c-Met, Ikkb, Shp2 or b-catenin; 2) to determine the mutation profiles and HCC initiation in these mutants; and 3) to characterize DEN-induced and spontaneous tumorigenesis in liver deficient for both Shp2 and Ikkb. Success of this project will decipher common and distinctive mechanisms that drive liver tumorigenesis, and will facilitate design of novel and effective therapeutic strategies for liver cancer.

该项目的目的是破译各种肝脏损伤和疾病如何肝细胞癌（HCC）加速和加剧的发展，这是一个主要原因全球与癌症有关的死亡率。直接的重点是阐明肿瘤性肝细胞中促促性分子的丧失造成讽刺性的肝脏损害。最近实验，我们发现SHP2/PTPN11的缺失，以前已知是亲构的，二乙基硝基胺（DEN）引起的加重HCC发育或PTEN缺乏症和纳什。一致地，其他几个小组报告说，针对去除癌蛋白，此类作为C-MET，IKKB和B-catenin，来自DEN或其他致癌驱动器。但是，抗结合作用的基本机制这些癌蛋白尚不清楚。我们的假设是促进分子的丧失在肝微环境中产生多种肿瘤促进因素，导致加剧的肿瘤发生。值得注意的是，这些小鼠肿瘤模型紧密概括了许多肝癌患者的致病过程方面。因此，我们认为这很普遍小鼠模型与人之间共享机制或致癌性肝疾病肿瘤开始和进展的患者。在这个项目上，我们将追求一个全面的分析分子和细胞事件，这些事件使用几个鼠标模型。我们提出以下三个具体目标：1）搜索和识别缺乏C-MET，IKKB，SHP2或B-catenin的肝脏的致瘤因子； 2）确定这些突变体中的突变谱和HCC启动； 3）表征den诱导的和 SHP2和IKKB缺乏肝脏的自发性肿瘤发生。这个项目的成功将破译的常见和独特的机制，这些机制驱动肝肿瘤发生，并将促进针对肝癌的新型有效治疗策略的设计。