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.

抽象的 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 发病机制的因素仍不清楚。 PI3K/AKT/mTOR 信号级联的激活 已在包括 HCC 在内的多种肿瘤类型中得到证实。 mTOR 通过以下途径调节细胞生长和代谢 形成两种多蛋白复合物：mTORC1 和 mTORC2。虽然 mTORC1 已被广泛研究 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 激酶发挥作用。 AKT 具有调节多种途径的功能， 包括 FOXO 和 TSC1/2 肿瘤抑制基因。我们之前的研究表明，共表达 AKT 和 Ras 的激活形式可以协同作用，快速诱导小鼠肝脏肿瘤的发展。最近， 我们发现 Ras 的同时激活和 Tsc2 的缺失会在长期内诱导小鼠 HCC 形成 延迟。结果表明 AKT 下游在 HCC 发病机制中具有额外的信号传导功能。 FOXO1 是 AKT 的主要下游靶标，其表达在人类 HCC 样本中强烈下调。 然而，FOXO1 的缺失是否能够促进 HCC 的发展，以及它如何与 TSC/mTORC1 相互作用 HCC 发病机制中 mTORC2/AKT 下游信号的转导仍有待确定。基于 根据这些初步数据，我们假设 TSC/mTORC1 和 FOXO1 级联在 介导 HCC 发病机制中的 mTORC2/AKT 信号传导。为了检验这些假设，我们提出以下建议 三个目标。在目标 1 中，我们将研究 FOXO1 和 TSC 肿瘤抑制因子之间的遗传串扰 肝癌。在目标 2 中，我们将定义 Tsc/mTORC1 和 FoxO1 信号级联下游的功能作用 mTORC2/Akt1 在 c-Myc 驱动的 HCC 中的作用。在目标 3 中，我们计划阐明下游信号通路 mTORC2/Akt 在 c-Met/β-catenin HCC 发病机制中的作用。总之，在这个应用程序中，我们将应用 创新的小鼠遗传方法与体外实验以及人类 HCC 样本相结合 描绘肝脏过程中 mTORC2/AKT、TSC/mTORC1 和 FOXO1 信号级联的研究 致癌作用。研究结果不仅将为了解信号传导如何解除管制提供新的机制见解 途径有助于癌基因驱动的 HCC 发展，同时也有助于为精准医疗铺平道路 用于 HCC 治疗。