The role of adiponectin in hepatocelluar carcinoma

描述（由申请人提供）： 与其他一些常见的癌症相比，肝细胞癌显示出最高的相对风险增加，这是肥胖的结果。近年来的研究表明，肥胖是一种内分泌紊乱，其内分泌效应是由脂肪细胞因子介导的。脂联素是一种具有治疗潜力的脂肪细胞因子，与肥胖呈负相关。重要的是，血清脂联素水平较低与癌症如子宫内膜癌、乳腺癌、胃癌、结直肠癌的高风险相关。我的初步研究表明，脂联素抑制肝癌细胞增殖，诱导凋亡，激活AMPK。假设：肝细胞癌进展的一个组成部分是获得侵袭性和转移性。该提案将检验脂联素通过增加AMPK和LKB 1-TSC 2-mTOR通路之间的串扰来抑制肝细胞癌细胞的生长和转移潜力的假设。目的：（1）研究脂联素对肝癌转移的抑制作用。2)阐明脂联素作用的信号转导机制。3)探讨脂联素是否抑制裸鼠肝癌的发生。研究设计：将使用各种生长、侵袭、迁移和失巢凋亡测定来分析脂联素对肝细胞癌细胞系HepG 2的转移潜能的抑制。参与脂联素生物学功能的信号转导途径涉及AMPK活化。这一途径的上游和下游组分将使用激酶测定、蛋白质印迹、RT-PCR分析来阐明。使用siRNA沉默的选择性抑制将用于定义脂联素受体的功能。将使用具有HepG 2细胞的无胸腺裸鼠的肿瘤异种移植物[sic]模型来显示脂联素在体内的保护作用。与公众的相关性：肥胖是美国的一个主要健康问题，是肝细胞癌的一个重要危险因素，其内分泌效应是由脂肪细胞因子介导的。本研究旨在建立脂联素作为一种新的肝细胞癌负调控因子，并系统描述其作用的信号机制。因此，脂联素在肝细胞癌中的保护作用的描述为患者提供了新的预防和治疗选择。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma show the highest relative-risk increase as a consequence of obesity compared to some other common forms of cancer. Recent studies have established that obesity is an endocrine disorder and its endocrine effects are mediated by the adipocytokines. Adiponectin, an adipocytokine proposed to have therapeutic potential, is inversely associated with obesity. Importantly, lower levels of serum adiponectin are associated with high risk of cancers such as endometrial, breast, gastric, colorectal cancer. My preliminary studies show that adiponectin inhibits proliferation, induces apoptosis and activates AMPK in hepatocellular carcinoma cells. Hypothesis: An integral part of the progression of hepatocellular carcinoma is the acquisition of the invasive and metastatic properties. This proposal will examine the hypothesis that adiponectin suppresses the growth and metastatic potential of hepatocellular carcinoma cells by increased crosstalk between AMPK and LKB1-TSC2-mTOR pathway. Objectives: (1) To demonstrate that adiponectin inhibits metastatic properties of hepatocellular carcinoma. 2) To elucidate the potential signal-transduction mechanisms involved in adiponectin action. 3) To examine whether adiponectin inhibits hepatocellular carcinoma tumorigenesis in nude mice. Study design: The inhibition of metastatic potential of hepatocellular carcinoma cell line HepG2 by adiponectin will be analyzed using various growth, invasion, migration and anoikis assays. The signal transduction pathway involved in the biological function of adiponectin involves AMPK activation. Both upstream and downstream components of this pathway will be elucidated using kinase assays, western blotting, RT-PCR analysis. Selective inhibition using siRNA silencing will be used to define the function of adiponectin receptors. Tumor Xenograft [sic] model using athymic nude mice with HepG2 cells will be utilized to show the protective role of adiponectin in vivo. Relevance to public: Obesity, a major health problem in US is a significant risk factor for hepatocellular carcinoma and its endocrine effects are mediated by adipocytokines. The studies proposed here are designed to establish adiponectin as a novel negative regulator of hepatocellular carcinoma and systemically delineate the signaling mechanisms involved in its action. Delineation of the protective role of adiponectin in hepatocellular carcinoma thus presents new preventive and therapeutic options for patients.