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: 10330463
• 负责人: Gen-Sheng Feng
• 金额: $ 43.38万
• 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/10330463
• 关键词: Animal Model; Automobile Driving; BAY 54-9085; 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; Tumor Suppressor Proteins; base; beta catenin; cancer type; chemical carcinogen; design; experimental study; genetic analysis; inhibitor; interdisciplinary approach; liver cancer model; liver cancer patient; liver inflammation; liver injury; methionylmethionine; mouse model; novel; novel therapeutic intervention; single-cell RNA sequencing; theories; therapeutically effective; 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 全球恶性疾病。到目前为止，药物对主要致癌途径的抑制作用 它几乎没有对肝癌患者获得的治疗益处。我们认为这是由于不足 欣赏肝结合发生机制的复杂性。在最近的实验中， 我们和其他人已经确定了经典致癌性的矛盾的抗疾病作用 肝脏中的分子，例如C-MET，EGFR，β-catenin，Ikkβ，JNK和SHP2。减轻这些 化学致癌物诱导的肝细胞中的分子增强了HCC。测试 理论认为，致癌分子的丧失会产生一种致癌的微环境，即 促进DEN引起的HCC，我们建立了另一个鼠标HCC模型， 致癌β-catenin（CAT），C-MET（MET）和PIK3CA（PIK），癌蛋白的转染 经常在人类HCC中检测到。不出所料，MET/CAT驱动的HCC聚集在 由于去除β-catenin诱导的肿瘤促进因子，β-catenin缺乏肝脏。在 对比，SHP2删除大大抑制了由MET/CAT或MET/PIK驱动的HCC， 尽管在SHP2缺陷肝脏中也有类似的促肿瘤环境。基于这些小说 意外数据，我们提出了一个新的假设，即尽管去除SHP2或β-catenin 在肝脏环境中产生细胞 - 肢体肿瘤因子，内源性SHP2 对于肝细胞中的致癌信号传导是必不可少的。为了检验这一假设，我们提出了 该项目的三个具体目标。 AIM 1是确定SHP2的细胞中性作用 肝癌信号传导。目标2是确定β-catenin在 肝肿瘤发生。 AIM 3是搜索和识别因丢失而引起的细胞超支因子 肝细胞中的癌蛋白。预计结果将有助于新颖的设计 肝癌的治疗策略是通过抑制细胞中性致癌信号和 次要环境因素。