Obesity increases the risk of cancers, including hepatocellular carcinomas (HCCs). 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 (HSCs) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid (DCA) to upregulate the expression of SASP factors and cyclooxygenase-2 (COX-2) through Toll-like receptor (TLR) 2. Interestingly, COX-2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through EP4 receptor, thereby contributing to HCC progression. Moreover, COX-2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with non-cirrhotic, non-alcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.
- Received August 22, 2016.
- Revision received February 13, 2017.
- Accepted February 13, 2017.
- Copyright ©2017, American Association for Cancer Research.