Signaling pathways during hepatocarcinogenesis

肝癌发生过程中的信号通路

• 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
• 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

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.

抽象的 肝细胞癌（HCC）是一种致命的恶性肿瘤，治疗方案有限。信号通路 促进HCC发病机理的定义仍然很差。 PI3K/AKT/MTOR信号级联激活的激活 在包括HCC在内的多种肿瘤类型中被证明。 MTOR通过 两种多蛋白络合物的形成：mTORC1和MTORC2。虽然MTORC1已广泛研究 在HCC中，MTORC2在肝癌发生过程中的功能贡献尚不清楚。 mtorc2 通过调节AGC激酶，尤其是Akt激酶来发挥作用。 AKT功能以调节多个途径， 包括FOXOS和TSC1/2抑制肿瘤基因。我们以前的研究表明，共表达 Akt和Ras的活化形式可以协调小鼠迅速诱导肝肿瘤的发展。最近， 我们发现RAS的同时激活和TSC2诱导的HCC形成长期很长 潜伏期。结果表明，AKT在HCC发病机理中下游的其他信号传导函数。 Foxo1是 AKT的主要下游靶标及其表达在人类HCC样品中强烈下调。 但是，FOXO1的损失是否能够促进HCC的发展，以及它如何与TSC/MTORC1相互作用 在HCC发病机理中，MTORC2/AKT下游的信号尚待确定。基于 在这些初步数据上，我们假设TSC/MTORC1和FOXO1级联在 在HCC发病机理中介导MTORC2/AKT信号传导。为了检验这些假设，我们提出以下内容 三个目标。在AIM 1中，我们将研究FOXO1和TSC肿瘤补充剂之间的遗传串扰 HCC。在AIM 2中，我们将定义TSC/MTORC1和FOXO1信号级联的功能作用 C-Myc驱动的HCC中的mtorc2/akt1在AIM 3中，我们计划阐明下游的信号通路 在C-MET/β-catenin HCC发病机理中的MTORC2/AKT的of。总而言之，在此应用程序中，我们将申请 创新的小鼠遗传方法与体外实验以及人类HCC样品结合 在肝脏期间划定MTORC2/AKT，TSC/MTORC1和FOXO1信号级联的研究 致癌作用。结果不仅将提供新的机械洞察力，了解如何放大信号传导 途径有助于Oncogene驱动HCC开发，但也将为精密医学铺平道路 用于HCC治疗。