Intra- and inter-cellular signals that drive hepato-oncogenesis

驱动肝肿瘤发生的细胞内和细胞间信号

• 批准号: 9887833
• 负责人: Gen-Sheng Feng
• 金额: $ 42.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9887833
• 关键词: Animal Model; Automobile Driving; BAY 54-9085; Cancer Patient; Cells; Cessation of life; Chemicals; Clinical; Complement; Conflict (Psychology); Data; Diethylnitrosamine; Disease; Environment; Environmental Risk Factor; Epidermal Growth Factor Receptor; Excision; Goals; Hepatic; Hepatocarcinogenesis; Hepatocyte; Human; Immunotherapy; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Molecular; Mus; NF-kappa B; Oncogenes; Oncogenic; Oncoproteins; Oxidative Stress; PIK3CA gene; Paper; Pathogenicity; Pathway interactions; Patients; Pharmacologic Substance; Pharmacy (field); Phenotype; Play; Primary carcinoma of the liver cells; Process; Proteins; Publishing; Research; Role; Sampling; Signal Pathway; Signal Transduction; Sister; TP53 gene; Testing; Therapeutic; Transfection; Treatment Efficacy; Tumor Suppressor Proteins; base; beta catenin; cancer type; chemical carcinogen; design; experimental study; genetic analysis; inhibitor/antagonist; interdisciplinary approach; liver inflammation; liver injury; methionylmethionine; mouse model; novel; novel therapeutics; single-cell RNA sequencing; theories; tumor; tumorigenesis; tumorigenic

Liver cancer, mainly hepatocellular carcinoma (HCC), has become a most deadly malignant disease worldwide. So far, pharmaceutic inhibition of major oncogenic pathways has achieved little therapeutic benefit to liver cancer patients. We believe this is due to under- appreciation of the complexity in mechanisms of hepato-oncogenesis. In recent experiments, we and others have identified paradoxically anti-oncogenic effects of classical oncogenic molecules, such as c-Met, EGFR, β-catenin, Ikkβ, Jnk, and Shp2, in the liver. Ablating these molecules in hepatocytes enhanced HCC induced by chemical carcinogen DEN. To test a theory that loss of the oncogenic molecules generates an oncogenic microenvironment that promotes DEN-induced HCC, we have established another mouse HCC model, by transfection of oncogenic β-catenin (CAT), c-Met (MET) and PIK3CA (PIK), oncoproteins frequently detected in human HCCs. As expected, MET/CAT-driven HCC was aggravated in β-catenin-deficient liver, due to tumor-promoting factors induced by β-catenin removal. In contrast, Shp2 deletion dramatically suppressed HCC driven by MET/CAT or MET/PIK, despite a similar pro-tumorigenic environment in Shp2-deficient liver. Based on these novel unanticipated data, we propose a new hypothesis that although removal of Shp2 or β-catenin generates cell-extrinsic tumorigenic factors in the hepatic environment, the endogenous Shp2 is indispensable for oncogenic signaling in hepatocytes. To test this hypothesis, we propose three specific aims on this project. Aim 1 is to determine the cell-intrinsic role of Shp2 in hepato-oncogenic signaling. Aim 2 is to determine the cell-autonomous effect of β-catenin in liver tumorigenesis. Aim 3 is to search and identify cell-extrinsic factors induced by loss of the oncoproteins in hepatocytes. The results are expected to be instrumental for design of novel therapeutic strategies for liver cancer by inhibiting both cell-intrinsic oncogenic signals and the secondary environmental factors.

肝癌，主要是肝细胞癌（HCC），已成为最致命的癌症 世界范围内的恶性疾病。到目前为止，主要致癌途径的药物抑制 对肝癌患者几乎没有治疗效果。我们认为这是由于- 认识肝癌发生机制的复杂性。在最近的实验中， 我们和其他人已经发现了经典致癌基因的矛盾的抗癌作用， 在肝脏中，细胞因子可以抑制c-Met、EGFR、β-连环蛋白、Ikkβ、Jnk和Shp 2等分子的表达。将这些 分子增强化学致癌物DEN诱导的HCC。测试一个 致癌分子的丢失产生致癌微环境， 促进DEN诱导的HCC，我们建立了另一种小鼠HCC模型， 致癌β-连环蛋白（CAT）、c-Met（MET）和PIK 3CA（PIK）癌蛋白的转染 在人类肝癌中经常检测到。正如预期的那样，MET/CAT驱动的HCC在 β-连环蛋白缺乏的肝脏，由于β-连环蛋白去除诱导的促肿瘤因子。在 相反，Shp 2缺失显著抑制由MET/CAT或MET/PIK驱动的HCC， 尽管在Shp 2缺陷的肝脏中存在类似的促肿瘤发生环境。根据这些小说 出乎意料的数据，我们提出了一个新的假设，即尽管去除了Shp 2或β-连环蛋白 在肝脏环境中产生细胞外源性致瘤因子，内源性Shp 2 是肝细胞中致癌信号传导不可或缺的。为了验证这一假设，我们建议 这个项目的三个具体目标。目的1是确定Shp 2在细胞内的作用， 肝致癌信号。目的2是确定β-连环蛋白在细胞中的细胞自主作用 肝肿瘤发生目的3：寻找和鉴定细胞外因子， 肝细胞中的癌蛋白。研究结果可为设计新颖的 通过抑制细胞内在致癌信号和 二是环境因素。