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.
There is a paucity of information regarding the molecular mechanism of obesity-associated hepatocellular carcinoma. The present proposal aims at analyzing the role of Staphylococcal nuclease domain containing 1 (SND1) in steatosis of liver and in HCC by characterizing a transgenic mouse with hepatocyte-specific expression of SND1 (Alb/SND1).
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