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.

摘要 肝细胞癌（HCC）是一种致命的恶性肿瘤，治疗选择有限。信号通路 促进HCC发病机制的机制仍不清楚。PI 3 K/AKT/mTOR信号级联的激活具有 在多种肿瘤类型中得到证实，包括HCC。mTOR调节细胞生长和代谢，通过 两种多蛋白复合物的形成：mTORC 1和mTORC 2。虽然mTORC 1已经被广泛研究， 在HCC中，mTORC 2在肝癌发生过程中的功能作用还不清楚。mTORC2 通过调节AGC激酶，特别是AKT激酶发挥作用。AKT的功能是调节多种途径， 包括FOXO和TSC 1/2肿瘤抑制基因。我们以前的研究表明， 活化形式的AKT和Ras可以协同作用以快速诱导小鼠中的肝肿瘤发展。最近， 我们发现Ras的激活和Tsc 2的缺失长期诱导小鼠肝癌的形成， 延迟。结果表明，在HCC发病机制中，AKT下游具有额外的信号传导功能。FOXO 1是 AKT的主要下游靶点，并且其表达在人HCC样品中强烈下调。 然而，FOXO 1的缺失是否能够促进HCC的发展，以及它如何与TSC/mTORC 1相互作用， 在HCC发病过程中mTORC 2/AKT下游信号转导通路的作用仍有待确定。基于 根据这些初步数据，我们假设TSC/mTORC 1和FOXO 1级联在 在HCC发病机制中介导mTORC 2/AKT信号传导。为了验证这些假设，我们提出以下建议： 三个目标。在目标1中，我们将研究FOXO 1和TSC肿瘤抑制因子之间的遗传串扰， HCC。在目标2中，我们将定义Tsc/mTORC 1和FoxO 1信号级联下游的功能作用。 mTORC 2/Akt 1在c-Myc驱动的HCC中的表达。在目标3中，我们计划阐明下游的信号通路， mTORC 2/Akt在c-Met/β-catenin HCC发病中的作用。总之，在本申请中，我们将申请 创新小鼠遗传学方法与体外实验以及人类HCC样品相结合 描述肝细胞凋亡过程中mTORC 2/AKT、TSC/mTORC 1和FOXO 1信号级联的研究 致癌作用这些结果不仅将提供新的机制洞察如何解除管制的信号 这些通路有助于癌基因驱动的HCC发展，但也将有助于为精准医学铺平道路 用于HCC治疗。