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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：
Xin Chen
金额：
$ 35.05万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
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：
https://reporter.nih.gov/project-details/10570081
关键词：
Ablation CTNNB1 gene Cellular Metabolic Process Data Data Set Development Disease Event FOXO1A gene FRAP1 gene Genetic Genetic study Glutamate-Ammonia Ligase Hepatocarcinogenesis Heterogeneity Human In Vitro Knockout Mice Liver neoplasms MCL1 gene MYC gene Malignant Neoplasms Malignant neoplasm of liver Mediating Modeling Multiprotein Complexes Mus Mutation Oncogenes Oncogenic PI3K/AKT Pathogenesis Pathway interactions Phenotype Phosphotransferases Primary carcinoma of the liver cells Proto-Oncogene Proteins c-akt Role Sampling Sampling Studies Signal Pathway Signal Transduction TSC1/2 gene Testing The Cancer Genome Atlas Tumor Suppressor Genes Tumor Suppressor Proteins base beta catenin c-myc Genes cell growth experimental study genetic approach in vivo innovation insight liver cancer model mouse genetics novel precision medicine prevent therapeutic development therapeutic target treatment strategy tumor

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