The role of adiponectin in hepatocelluar carcinoma

描述(由申请人提供)： 与其他一些常见形式的癌症相比，肝细胞癌因肥胖而导致的相对风险增加最高。最近的研究证实，肥胖是一种内分泌紊乱，其内分泌作用是由脂肪细胞因子介导的。脂联素，一种被认为具有治疗潜力的脂肪细胞因子，与肥胖成反比。重要的是，血清脂联素水平较低与子宫内膜癌、乳腺癌、胃癌、结直肠癌等癌症的高风险相关。我的初步研究表明，脂联素抑制肝癌细胞的增殖，诱导细胞凋亡，并激活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。这项建议将验证脂联素通过增加AMPK和LKB1-TSC2-mTOR通路之间的串扰来抑制肝细胞癌细胞的生长和转移潜能的假说。目的：(1)研究脂联素对肝细胞癌转移的抑制作用。2)阐明脂联素作用的潜在信号转导机制。3)探讨脂联素对人肝癌裸鼠移植瘤的抑制作用。研究设计：脂联素对肝癌细胞系HepG2转移潜能的抑制作用将通过不同的生长、侵袭、迁移和失巢凋亡试验来分析。参与脂联素生物学功能的信号转导通路涉及AMPK的激活。该途径的上游和下游成分将通过激酶分析、Western blotting、RT-PCR分析来阐明。使用siRNA沉默的选择性抑制将被用来定义脂联素受体的功能。采用裸鼠移植人肝癌细胞建立异种移植瘤模型，研究脂联素在体内的保护作用。与公众相关：肥胖是美国的一个主要健康问题，也是肝细胞癌的重要风险因素，其内分泌效应是由脂肪细胞因子介导的。这些研究旨在建立脂联素作为一种新的肝细胞癌负调控因子，并系统地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.