A novel mediator of obesity associated hepatocellular carcinoma (HCC)

肥胖相关肝细胞癌 (HCC) 的新型介质

• 批准号: 8676043
• 负责人: DEVANAND SARKAR
• 金额: $ 19.9万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676043
• 关键词: Albumins; Animals; Awareness; Blood Transfusion; Cholesterol; Chronic viral hepatitis; Coupled; Development; Diet; Diet Monitoring; Disease; Enhancers; Enzymes; Evaluation; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Generations; Genetic Transcription; HBV Vaccination; Health; Hepatitis B; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; Homologous Gene; Human; Hygiene; Incidence; Individual; Lead; Lipids; Liver; Liver diseases; Liver neoplasms; Malignant Epithelial Cell; Malignant Neoplasms; Mediator of activation protein; Micrococcal Nuclease; Modeling; Molecular; Monitor; Mus; NF-kappa B; NIH Program Announcements; Obesity; Overweight; Palmitates; Patients; Pharmaceutical Preparations; Play; Primary carcinoma of the liver cells; Process; Proteins; Proteome; RNA Interference; RNA Splicing; Research; Risk; Role; Running; Signal Transduction; Sodium; Steatohepatitis; Therapeutic; Transgenic Mice; Translations; Triglycerides; advanced disease; angiogenesis; cancer risk; effective therapy; feeding; gain of function; inhibitor/antagonist; lipid biosynthesis; loss of function; mortality; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; nuclease; overexpression; promoter; public health relevance; response

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality running parallel to its incidence. HCC is one of the rare cancers the incidence of which is increasing in the USA and one major cause of this rising incidence is non-alcoholic fatty liver disease (NAFLD) as a consequence of obesity, a huge health burden. Overweight individuals showed a 17% increase in risk of developing HCC while obese patients had an 89% increase in risk. Obesity leads to NAFLD that includes accumulation of fat in the form of neutral lipid droplets in the hepatocytes (hepatic steatosis) with subsequent non-alcoholic steatohepatitis (NASH). Uncontrolled NAFLD eventually causes the development of HCC. As yet the underlying molecular mechanism of obesity-induced HCC is not clear and identification of novel molecules regulating this process is mandatory to develop novel, targeted therapies. We previously identified that Staphylococcal nuclease domain containing-1 (SND1) is overexpressed in HCC and promotes hepatocarcinogenesis and angiogenesis. We have also demonstrated that SND1 activates NF-kB and TGF? signaling. We now document an intriguing observation that SND1 is significantly overexpressed in human NASH patients. Additionally marked SND1 overexpression is detected in livers of mice fed with high fat and cholesterol containing Western diet (HFD), compared to chow diet, as well as in the liver tumors developed in these mice. We document that SND1 is induced in human HCC cells upon sodium palmitate treatment and SND1 itself promotes de novo lipogenesis thereby contributing to increases in triglyceride (TG) and cholesterol synthesis. The long-term objective of the present proposal is to identify novel regulators of HCC to develop targeted and effective therapies. The immediate objective of the proposal is to probe in detail the mechanism by which SND1 promotes obesity-induced hepatocarcinogenesis. We hypothesize that fatty acid (e.g., palmitate) in the diet induces SND1 which contributes to the steatohepatitic and fibrotic processes by activating NF-kB and TGF? signaling. Additionally, SND1 itself induces de novo lipogenesis further accentuating the process. Thus SND1 might play a key role in NASH-induced HCC. We will confirm our hypothesis using a novel mouse model with hepatocyte-specific overexpression of SND1 (Alb/SND1). Alb/SND1 mice will be fed chow diet or high fat diet (HFD) and monitored for steatohepatitis and HCC. We anticipate that Alb/SND1 mouse will be a valuable model to help establish the role of SND1 in obesity- associated HCC. SND1 is an enzyme (nuclease) and structurally it is unique in human proteome with no homolog. Successful completion of our proposed studies will pave the way for developing potential specific inhibitors of SND1 as therapeutic for NASH and HCC.

描述（由申请人提供）：肝细胞癌（HCC）是一种高度致命的疾病，死亡率与其发病率平行。 HCC是美国罕见的癌症之一，在美国的发生率正在升高，导致这种升高的一个主要原因是由于肥胖而导致的非酒精性脂肪肝病（NAFLD），这是一个巨大的健康负担。超重患者出现HCC的风险增加了17％，而肥胖患者的风险增加了89％。肥胖会导致NAFLD，其中包括肝细胞中中性脂肪滴的形式积累的脂肪（肝脂肪变性），随后非酒精性脂肪性肝炎（NASH）。不受控制的NAFLD最终导致HCC的发展。到目前为止，肥胖诱导的HCC的潜在分子机制尚不清楚，并且必须鉴定出调节此过程的新分子以开发新型的，有针对性的疗法。我们先前确定含有1-1的葡萄球菌核酸酶结构域（SND1）在HCC中过表达，并促进肝癌发生和血管生成。我们还证明了SND1激活NF-KB和TGF？信号。现在，我们记录了一个有趣的观察结果，即SND1在人类NASH患者中显着过表达。此外，与食物饮食以及这些小鼠中发育的肝肿瘤相比，在用高脂肪和含有西方饮食的高脂肪和胆固醇（HFD）的小鼠的肝脏中检测到SND1过表达。我们记录了棕榈酸钠处理后人类HCC细胞诱导的SND1，SND1本身促进了从头脂肪生成，从而有助于甘油三酸酯（TG）和胆固醇合成的增加。本提案的长期目标是确定HCC的新型调节剂，以开发针对性和有效的疗法。该提案的直接目的是详细探究SND1促进肥胖引起的肝癌发生的机制。我们假设饮食中的脂肪酸（例如棕榈酸酯）通过激活NF-KB和TGF而诱导SND1，从而促进脂肪性和纤维化过程？信号。此外，SND1本身会诱导从头脂肪生成进一步加强该过程。因此，SND1可能在NASH诱导的HCC中起关键作用。我们将使用具有SND1的肝细胞特异性过表达（ALB/SND1）的新型小鼠模型来证实我们的假设。 Alb/SND1小鼠将喂食Chow饮食或高脂饮食（HFD），并监测脂肪性肝炎和HCC。我们预计ALB/SND1小鼠将是一个有价值的模型，以帮助确定SND1在肥胖相关的HCC中的作用。 SND1是一种酶（核酸酶），从结构上讲，它在没有同源物的人类蛋白质组中是独一无二的。成功完成我们建议的研究将为开发SND1的潜在特异性抑制剂作为NASH和HCC的治疗方法铺平道路。