Signaling pathways during hepatocarcinogenesis

肝癌发生过程中的信号通路

基本信息

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
项目类别：
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

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.

抽象的肝细胞癌 (HCC) 是一种致命的恶性肿瘤，治疗选择有限。促进 HCC 发病机制的 PI3K/AKT/mTOR 信号级联激活尚不清楚。已在多种肿瘤类型中得到证实，包括 HCC，mTOR 通过调节细胞生长和代谢。两种多蛋白复合物的形成：mTORC1 和 mTORC2，而 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。通过调节 AGC 激酶，尤其是 AKT 激酶来调节多种途径，我们之前的研究表明，包括FOXOs和TSC1/2肿瘤抑制基因的共表达。最近，AKT 和 Ras 的激活形式可以合作快速诱导小鼠肝脏肿瘤的发展。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。 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。根据这些初步数据，我们勇敢地认为 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。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。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传导。 mTORC2/Akt 在 c-Met/β-catenin HCC 发病机制中的作用总之，在本申请中，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 信号级联的研究研究结果不仅为了解信号传导失调的机制提供了新的见解。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。