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
- 来源:
- 关键词:Animal ModelAutomobile DrivingBAY 54-9085Cancer PatientCellsCessation of lifeChemicalsClinicalComplementConflict (Psychology)DataDiethylnitrosamineDiseaseEnvironmentEnvironmental Risk FactorEpidermal Growth Factor ReceptorExcisionGoalsHepaticHepatocarcinogenesisHepatocyteHumanImmunotherapyLiverMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of liverModelingMolecularMusNF-kappa BOncogenesOncogenicOncoproteinsOxidative StressPIK3CA genePaperPathogenicityPathway interactionsPatientsPharmacologic SubstancePharmacy (field)PhenotypePlayPrimary carcinoma of the liver cellsProcessProteinsPublishingResearchRoleSamplingSignal PathwaySignal TransductionSisterTP53 geneTestingTherapeuticTransfectionTreatment EfficacyTumor Suppressor Proteinsbasebeta catenincancer typechemical carcinogendesignexperimental studygenetic analysisinhibitor/antagonistinterdisciplinary approachliver inflammationliver injurymethionylmethioninemouse modelnovelnovel therapeuticssingle-cell RNA sequencingtheoriestumortumorigenesistumorigenic
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
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
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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