Abstract
Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.Significance: We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. Cancer Discov; 7(5); 522-38. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.
Highlights
Obesity has become a worldwide health problem and is known to increase the risk of diabetes, cardiovascular disease, and several types of cancer [1]
We previously reported that increased enterohepatic circulation of the obesity-induced Gram-positive gut microbial metabolite deoxycholic acid (DCA) facilitates hepatocellular carcinoma (HCC) development by inducing cellular senescence and the senescenceassociated secretory phenotype (SASP) in hepatic stellate cells (HSC) in the tumor microenvironment
We previously reported that neonatal DMBA treatment in high-fat diet (HFD)-fed mice resulted in development of HCC within 30 weeks, and demonstrated that DCA, an obesity-associated gut microbial metabolite, is a critical factor promoting obesityassociated HCC development [4]
Summary
Obesity has become a worldwide health problem and is known to increase the risk of diabetes, cardiovascular disease, and several types of cancer [1]. Hypernutritionrelated systemic alterations are thought to be involved in cancer development [2,3,4], the molecular mechanisms that integrate these events still remain largely unclear. The most common risk factor for hepatocellular carcinoma (HCC) is long-term infection by hepatitis B virus (HBV) or hepatitis C virus obesity-associated nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have recently emerged as important risk factors for liver cancer [6]. Elucidation of the precise molecular mechanisms mediating the development of obesity-induced NASH-a ssociated HCC is urgently needed
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