Signaling pathways during hepatocarcinogenesis

肝癌发生过程中的信号通路

• 批准号: 9906655
• 负责人: Xin Chen
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9906655
• 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; 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 肝细胞癌是一种致命的恶性肿瘤，治疗选择有限。信号通路 哪些因素促进了肝细胞癌的发病机制目前尚不清楚。PI3K/AKT/mTOR信号级联激活HAS 已在多种肿瘤类型中得到证实，包括肝细胞癌。MTOR通过调节细胞生长和新陈代谢 形成两个多蛋白复合体：mTORC1和mTORC2。虽然对mTORC1进行了广泛的研究 在肝细胞癌中，mTORC2在肝癌发生过程中的功能作用尚不清楚。MTORC2 通过调节AGC激酶，特别是AKT激酶发挥作用。AKT具有调节多条通路的功能， 包括FOXO和TSC1/2抑癌基因。我们之前的研究表明，共表达的 活化形式的AKT和RAS可以协同作用，快速诱导小鼠肝肿瘤的发生。最近， 我们发现，RAS的激活和TSC2的缺失共同诱导了小鼠肝癌的形成 延迟。这些结果提示AKT下游在肝细胞癌的发病机制中具有额外的信号功能。Foxo1是 AKT的一个主要下游靶点，其表达在人肝细胞癌样本中强烈下调。 然而，FOXO1的缺失是否能够促进肝癌的发展，以及它与TSC/mTORC1的相互作用 MTORC2/AKT下游信号在肝细胞癌发病机制中的作用尚不清楚。基座 根据这些初步数据，我们假设TSC/mTORC1和FOXO1级联在 介导mTORC2/AKT信号在肝细胞癌发病机制中的作用为了检验这些假设，我们提出了以下建议 三个目标。在目标1中，我们将研究FOXO1和TSC肿瘤抑制基因之间的遗传串扰。 肝细胞癌。在目标2中，我们将定义TSC/mTORC1和FoxO1信号级联下游的功能角色 C-Myc驱动的肝细胞癌中mTORC2/Akt1的表达。在目标3中，我们计划阐明下游的信号通路 C-Met/β-catenin肝癌发病机制中mTORC2/Akt的表达总之，在此应用程序中，我们将应用 结合体外实验和人类肝癌样本的创新小鼠遗传方法 肝脏mTORC2/AKT、TSC/mTORC1和FOXO1信号转导通路的研究 致癌。这一结果不仅将为如何放松信号管制提供新的机制洞察力 途径有助于癌基因驱动的肝癌发展，但也将有助于为精确医学铺平道路 用于治疗肝细胞癌。