Tumor-promoting liver injuries and mechanisms

促肿瘤肝损伤及其机制

基本信息

批准号：
9887578
负责人：
Gen-Sheng Feng
金额：
$ 50.15万
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/9887578
关键词：
Address Animals Automobile Driving Cancer Etiology Cancer Patient 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 Treatment Efficacy Work base beta catenin carcinogenicity chemical carcinogen design experimental study liver cell proliferation liver injury mortality mouse model mutant nonalcoholic steatohepatitis novel novel therapeutics success theories tumor tumor initiation tumor progression tumorigenesis tumorigenic

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.

该项目的目标是破译各种肝损伤和疾病如何影响加速和加剧肝细胞癌 (HCC) 的发展，这是主要原因之一全球癌症相关死亡率。当前的焦点是阐明致瘤性具有讽刺意义的是，肝损伤是由于肝细胞中促癌分子的丢失而产生的。近来实验中，我们发现先前已知具有促癌作用的Shp2/Ptpn11的缺失，二乙基亚硝胺 (DEN) 或 Pten 缺乏引起的 HCC 进展加剧，以及纳什。一致地，其他几个小组报告说，有针对性地去除癌蛋白，例如来自肝细胞的 c-Met、Ikkb 和 b-catenin 确实会加重 DEN 或诱导的 HCC 其他致癌驱动因素。然而，抗癌作用的潜在机制这些癌蛋白尚不清楚。我们的假设是促癌分子的丢失在肝脏微环境中产生多种促肿瘤因子，导致加剧了肿瘤的发生。值得注意的是，这些小鼠肿瘤模型密切再现了许多肝癌患者致病过程的各个方面。因此，我们认为共同小鼠模型和人类共有致癌机制或致癌性肝病肿瘤发生和进展的患者。在这个项目中，我们将追求全面的使用多种方法分析驱动肝癌发生的分子和细胞事件鼠标模型。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-连环蛋白的肝脏中的致瘤因子； 2）确定这些突变体的突变谱和 HCC 起始； 3) 表征 DEN 引起的和 Shp2 和 Ikkb 缺乏的肝脏中自发性肿瘤发生。该项目的成功将破译驱动肝脏肿瘤发生的常见和独特机制，并将促进设计新颖有效的肝癌治疗策略。