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 全世界的恶性疾病。迄今为止，主要致癌途径的药物抑制 对肝癌患者的治疗效果甚微。我们认为这是由于不足 了解肝肿瘤发生机制的复杂性。在最近的实验中， 我们和其他人已经确定了经典致癌物质的矛盾的抗癌作用 肝脏中的分子，例如 c-Met、EGFR、β-连环蛋白、Ikkβ、Jnk 和 Shp2。消融这些 肝细胞中的分子增强了化学致癌剂 DEN 诱导的 HCC。测试一个 致癌分子丢失会产生致癌微环境的理论 促进 DEN 诱导的 HCC，我们建立了另一种小鼠 HCC 模型，通过 致癌 β-连环蛋白 (CAT)、c-Met (MET) 和 PIK3CA (PIK)、癌蛋白的转染 经常在人类 HCC 中检测到。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-连环蛋白去除引起的肿瘤促进因子。在 相比之下，Shp2 缺失显着抑制了 MET/CAT 或 MET/PIK 驱动的 HCC， 尽管在Shp2缺陷的肝脏中存在类似的促肿瘤环境。根据这些小说 由于未预料到的数据，我们提出了一个新的假设，即虽然去除了 Shp2 或 β-catenin 在肝脏环境中产生细胞外源性致瘤因子，即内源性Shp2 对于肝细胞中的致癌信号传导是必不可少的。为了检验这个假设，我们提出 该项目的三个具体目标。目标 1 是确定 Shp2 在细胞内的内在作用 肝致癌信号传导。目标 2 是确定 β-catenin 在 肝脏肿瘤发生。目标 3 是寻找和鉴定因细胞外源性基因缺失而引起的细胞外在因素。 肝细胞中的癌蛋白。研究结果预计将有助于新颖的设计 通过抑制细胞内在致癌信号和 次要环境因素。