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
世界范围内的恶性疾病。到目前为止,药物抑制主要致癌途径
对肝癌患者的治疗效果甚微。我们认为这是由于-
对肝脏肿瘤发生机制的复杂性的认识。在最近的实验中,
我们和其他人发现了经典致癌物质矛盾的抗致癌作用。
C-蛋氨酸、表皮生长因子受体、β-连环蛋白、IKKβ、jnk和shp2等分子在肝脏中的表达。烧蚀这些东西
肝细胞内分子对化学致癌物DEN诱导的肝细胞癌有促进作用。要测试一个
致癌分子的丢失会产生致癌微环境的理论
为了促进DEN诱导的肝癌,我们建立了另一种小鼠肝癌模型,通过
癌基因β-Catenin(CAT)、c-Met(Met)和PIK3CA(Pik)的转导
经常在人类碳氢化合物中检测到。正如预期的那样,MET/CAT驱动的肝细胞癌在
β-连环蛋白缺乏的肝脏,由于去除β-连环蛋白而诱导的促肿瘤因子。在……里面
相反,Shp2缺失可显著抑制MET/CAT或MET/PIK所致的肝细胞癌,
尽管在Shp2缺陷的肝脏中有类似的促肿瘤环境。基于这些小说
出乎意料的数据,我们提出了一个新的假设,尽管移除Shp2或β-连环蛋白
在肝脏环境中产生细胞-外源性致癌因子,内源性Shp2
对于肝细胞中的致癌信号来说是不可或缺的。为了检验这一假设,我们建议
这个项目的三个具体目标。目的1是确定Shp2在细胞中的内在作用。
肝脏致癌信号。目的2是确定β-连环蛋白的细胞自主效应。
肝脏肿瘤的发生。目标3是寻找和识别细胞外在因子,这些外在因子是由缺失的
肝细胞中的癌蛋白。研究结果可望对小说的设计有所帮助。
通过抑制细胞内源性致癌信号和联合治疗肝癌的策略
二次环境因素。
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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