Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity

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 senescenceassociated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesityinduced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E 2 (PGE 2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE 2 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 PGE 2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE 2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC.

Environmental Factors, Gut Microbiota, and Colorectal Cancer Prevention

“…21, 22 More recent evidence indicates that this effect requires cooperative induction of another Gram-positive gut microbial component, lipoteichoic acid, which upregulates the expression of prostaglandin-endoperoxide synthase 2 [also known as cyclooxygenase-2 (COX-2)] in deoxycholic acid-induced senescent hepatic stellate cells to promote cancer development in obese mice. 23 As a critical enzyme in inflammation, prostaglandin-endoperoxide synthase 2 mediates production of prostaglandin E 2 that suppresses antitumor immunity. 23 Given the potential role of prostaglandin E 2 and secondary bile acid in promoting colorectal cancer, further studies are needed to investigate whether microbial imbalance-induced metabolic change also mediates obesity-related tumor promotion in the colon.…”

“…23 As a critical enzyme in inflammation, prostaglandin-endoperoxide synthase 2 mediates production of prostaglandin E 2 that suppresses antitumor immunity. 23 Given the potential role of prostaglandin E 2 and secondary bile acid in promoting colorectal cancer, further studies are needed to investigate whether microbial imbalance-induced metabolic change also mediates obesity-related tumor promotion in the colon.…”

Future cancer research priorities in the USA: a Lancet Oncology Commission

“…Gut microbiota-induced metabolites promote obesity-linked immune escape in hepatic tumorigenesis. 30 Circadian disruption is also associated with an increased incidence of obesity, diabetes, and cancer. Circadian dysregulation of farnesoid X receptor (FXR) promoted fatty acid-induced hepatocellular carcinoma in mice, 31 providing biological plausibility for the chemopreventive benefit of an FXR ligand in patients with non-cirrhotic, non-alcoholic steatohepatitis.…”

Diet, Gut Microbiota, and Colorectal Cancer Prevention: a Review of Potential Mechanisms and Promising Targets for Future Research

“…171, 172 Besides deoxycholic acid, another gut microbial component, lipoteichoic acid, may also contribute to obesity-induced liver cancer by enhancing senescence-associated secretory phenotype and upregulating the expression of prostaglandin-endoperoxide synthase 2. 173 As a critical enzyme in inflammation, prostaglandin-endoperoxide synthase 2 mediates production of prostaglandin E 2 , which governs tumor-mediated immune dysfunction and contributes to a shift in the tumor microenvironment from anti-tumor responses to immunosuppressive responses. 174 Given the potential role of prostaglandin E 2 175 and secondary bile acid 176 in promoting CRC, further studies are needed to investigate whether microbial imbalance-induced metabolic change also mediates obesity-related tumor promotion in the colon.…”