A novel mediator of obesity associated hepatocellular carcinoma (HCC)

描述（由申请人提供）：肝细胞癌（HCC）是一种高致死率的疾病，其死亡率与其发病率平行。HCC是一种罕见的癌症，其发病率在美国呈上升趋势，其发病率上升的一个主要原因是非酒精性脂肪性肝病（NAFLD），由肥胖引起，这是一个巨大的健康负担。超重个体患HCC的风险增加17%，而肥胖患者患HCC的风险增加89%。肥胖导致非酒精性脂肪性肝炎（NASH），包括肝细胞中性脂滴形式的脂肪积累（肝性脂肪变性）。不受控制的NAFLD最终导致HCC的发展。迄今为止，肥胖诱导的HCC的潜在分子机制尚不清楚，鉴定调节这一过程的新分子是开发新的靶向治疗的必要条件。我们之前发现葡萄球菌核酸酶结构域-1 （SND1）在HCC中过表达，促进肝癌和血管生成。我们也证明了SND1激活NF-kB和TGF？信号。我们现在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，在喂食高脂肪和高胆固醇的西方饮食（HFD）的小鼠肝脏中，以及在这些小鼠的肝脏肿瘤中，检测到显著的SND1过表达。我们的研究表明，棕榈酸钠在人肝癌细胞中诱导SND1，并且SND1本身促进新生脂肪生成，从而促进甘油三酯（TG）和胆固醇合成的增加。本提案的长期目标是确定新的HCC调节因子，以开发靶向和有效的治疗方法。该提案的直接目的是详细探讨SND1促进肥胖诱导的肝癌发生的机制。我们假设饮食中的脂肪酸（如棕榈酸酯）通过激活NF-kB和TGF？信号。此外，SND1本身诱导新生脂肪形成，进一步加剧了这一过程。因此SND1可能在nash诱导的HCC中起关键作用。我们将使用一种具有肝细胞特异性SND1 （Alb/SND1）过表达的新型小鼠模型来证实我们的假设。Alb/SND1小鼠分别饲喂鼠粮或高脂饲料（HFD），并监测脂肪性肝炎和HCC的发生情况。我们预计，Alb/SND1小鼠将是一个有价值的模型，有助于确定SND1在肥胖相关HCC中的作用。SND1是一种结构独特的酶（核酸酶），在人类蛋白质组中没有同源物。我们所提出的研究的成功完成将为开发潜在的SND1特异性抑制剂治疗NASH和HCC铺平道路。

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.