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

基本信息

  • 批准号:
    9887833
  • 负责人:
  • 金额:
    $ 42.1万
  • 依托单位:
  • 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:
    2020-02-10 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

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-catenin缺乏的肝脏,由于β-catenin去除诱导的肿瘤促进因子。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 意外的数据,我们提出了一个新的假设,虽然去除Shp 2或β-catenin 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。

项目成果

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Gen-Sheng Feng其他文献

Gen-Sheng Feng的其他文献

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{{ truncateString('Gen-Sheng Feng', 18)}}的其他基金

A new mechanism of hepatocyte proliferation under stress
应激下肝细胞增殖的新机制
  • 批准号:
    10186136
  • 财政年份:
    2021
  • 资助金额:
    $ 42.1万
  • 项目类别:
A new mechanism of hepatocyte proliferation under stress
应激下肝细胞增殖的新机制
  • 批准号:
    10577880
  • 财政年份:
    2021
  • 资助金额:
    $ 42.1万
  • 项目类别:
A new mechanism of hepatocyte proliferation under stress
应激下肝细胞增殖的新机制
  • 批准号:
    10358625
  • 财政年份:
    2021
  • 资助金额:
    $ 42.1万
  • 项目类别:
Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy
项目 4:在 HCC 预防和治疗中探究和利用与年龄相关的 IFN 信号传导和先天免疫
  • 批准号:
    10698110
  • 财政年份:
    2021
  • 资助金额:
    $ 42.1万
  • 项目类别:
Project 4: Interrogating and harnessing age-related IFN signaling and innate immunity in HCC prevention and therapy
项目 4:在 HCC 预防和治疗中探究和利用与年龄相关的 IFN 信号传导和先天免疫
  • 批准号:
    10270689
  • 财政年份:
    2021
  • 资助金额:
    $ 42.1万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 42.1万
  • 项目类别:
Tumor-promoting liver injuries and mechanisms
促肿瘤肝损伤及其机制
  • 批准号:
    9887578
  • 财政年份:
    2020
  • 资助金额:
    $ 42.1万
  • 项目类别:
Tumor-promoting liver injuries and mechanisms
促肿瘤肝损伤及其机制
  • 批准号:
    10560586
  • 财政年份:
    2020
  • 资助金额:
    $ 42.1万
  • 项目类别:
Tumor-promoting liver injuries and mechanisms
促肿瘤肝损伤及其机制
  • 批准号:
    10332735
  • 财政年份:
    2020
  • 资助金额:
    $ 42.1万
  • 项目类别:
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:
    10557925
  • 财政年份:
    2020
  • 资助金额:
    $ 42.1万
  • 项目类别:

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  • 批准号:
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