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

项目成果

期刊论文数量(0)
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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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    25330237
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    2013
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