Signaling pathways during hepatocarcinogenesis
肝癌发生过程中的信号通路
基本信息
- 批准号:10570081
- 负责人:
- 金额:$ 35.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AblationCTNNB1 geneCellular Metabolic ProcessDataData SetDevelopmentDiseaseEventFOXO1A geneFRAP1 geneGeneticGenetic studyGlutamate-Ammonia LigaseHepatocarcinogenesisHeterogeneityHumanIn VitroKnockout MiceLiver neoplasmsMCL1 geneMYC geneMalignant NeoplasmsMalignant neoplasm of liverMediatingModelingMultiprotein ComplexesMusMutationOncogenesOncogenicPI3K/AKTPathogenesisPathway interactionsPhenotypePhosphotransferasesPrimary carcinoma of the liver cellsProto-Oncogene Proteins c-aktRoleSamplingSampling StudiesSignal PathwaySignal TransductionTSC1/2 geneTestingThe Cancer Genome AtlasTumor Suppressor GenesTumor Suppressor Proteinsbasebeta cateninc-myc Genescell growthexperimental studygenetic approachin vivoinnovationinsightliver cancer modelmouse geneticsnovelprecision medicinepreventtherapeutic developmenttherapeutic targettreatment strategytumor
项目摘要
ABSTRACT
Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Signaling pathways
which promote HCC pathogenesis remain poorly defined. Activation of PI3K/AKT/mTOR signaling cascade has
been demonstrated in multiple tumor types, including HCC. mTOR regulates cell growth and metabolism via the
formation of two multiprotein complexes: mTORC1 and mTORC2. While mTORC1 has been extensively studied
in HCC, the functional contribution of mTORC2 during hepatocarcinogenesis is not well understood. mTORC2
functions by modulating AGC kinases, especially AKT kinases. AKT functions to regulate multiple pathways,
including FOXOs and TSC1/2 tumor suppressor genes. Our previous studies have shown that coexpression of
activated forms of AKT and Ras could cooperate to rapidly induce liver tumor development in mice. Recently,
we discovered that concomitant activation of Ras and loss of Tsc2 induced HCC formation in mice over long
latency. The results suggest additional signaling function downstream of AKT in HCC pathogenesis. FOXO1 is
a major downstream target of AKT, and its expression is strongly downregulated in human HCC samples.
However, whether loss of FOXO1 is able to promote HCC development, and how it interacts with TSC/mTORC1
to transduce signal downstream of mTORC2/AKT during HCC pathogenesis remains to be determined. Based
on these preliminary data, we hypothesize that TSC/mTORC1 and FOXO1 cascades have distinct roles in
mediating mTORC2/AKT signaling in HCC pathogenesis. To test these hypotheses, we propose the following
three aims. In Aim 1, we will investigate the genetic crosstalk between FOXO1 and TSC tumor suppressors in
HCC. In Aim 2, we will define the functional roles of Tsc/mTORC1 and FoxO1 signaling cascades downstream
of mTORC2/Akt1 in c-Myc driven HCC. And in Aim 3, we plan to elucidate the signaling pathways downstream
of mTORC2/Akt during c-Met/β-catenin HCC pathogenesis. In summary, in this application, we will apply
innovative mouse genetic approaches in combination with in vitro experiments as well as human HCC sample
studies to delineate mTORC2/AKT, TSC/mTORC1 and FOXO1 signaling cascades during hepatic
carcinogenesis. The results will not only provide novel mechanistic insight into how deregulated signaling
pathways contribute to oncogene driven HCC development, but also will help pave the way for precision medicine
for HCC treatment.
摘要
项目成果
期刊论文数量(0)
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Xin Chen其他文献
Xin Chen的其他文献
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{{ truncateString('Xin Chen', 18)}}的其他基金
Investigating multifactorial beta-catenin activation in hepatocellular cancers
研究肝细胞癌中的多因素 β-连环蛋白激活
- 批准号:
10541171 - 财政年份:2022
- 资助金额:
$ 35.05万 - 项目类别:
Investigating multifactorial beta-catenin activation in hepatocellular cancers
研究肝细胞癌中的多因素 β-连环蛋白激活
- 批准号:
10574374 - 财政年份:2022
- 资助金额:
$ 35.05万 - 项目类别:
Investigating multifactorial beta-catenin activation in hepatocellular cancers
研究肝细胞癌中的多因素 β-连环蛋白激活
- 批准号:
10326862 - 财政年份:2021
- 资助金额:
$ 35.05万 - 项目类别:
Cabozentinib based combination therapy for the treatment of hepatocellular carcinoma
基于卡博替尼的联合疗法治疗肝细胞癌
- 批准号:
10117217 - 财政年份:2020
- 资助金额:
$ 35.05万 - 项目类别:
Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma
癌症相关成纤维细胞在胆管癌中的作用
- 批准号:
10166796 - 财政年份:2018
- 资助金额:
$ 35.05万 - 项目类别:
Role of Cancer-Associated Fibroblasts in Cholangiocarcinoma
癌症相关成纤维细胞在胆管癌中的作用
- 批准号:
10414782 - 财政年份:2018
- 资助金额:
$ 35.05万 - 项目类别:
Inducible systems for studying liver tumor mainenance in vivo
用于研究肝脏肿瘤体内维持的诱导系统
- 批准号:
9457376 - 财政年份:2017
- 资助金额:
$ 35.05万 - 项目类别:
Yap and beta-catenin interactions in liver: Implications in Pathophysiology
Yap 和 β-连环蛋白在肝脏中的相互作用:对病理生理学的影响
- 批准号:
9901472 - 财政年份:2016
- 资助金额:
$ 35.05万 - 项目类别: