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

肠道菌群 六氯环己烷 脂磷壁酸 脱氧胆酸 癌症研究 肿瘤微环境 免疫系统 癌症 生物 医学 免疫学 内科学 免疫 肝细胞癌 内分泌学 胆汁酸 细菌 遗传学 金黄色葡萄球菌
作者
Tze Mun Loo,Fumitaka Kamachi,Yoshihiro Watanabe,Shin Yoshimoto,Hiroaki Kanda,Yutaro Arai,Yaeko Nakajima‐Takagi,Atsushi Iwama,Tomoaki Koga,Yukihiko Sugimoto,Takayuki Ozawa,Masaru Nakamura,Miho Kumagai,Koichi Watashi,Makoto M. Taketo,Tomohiro Aoki,Shuh Narumiya,Masanobu Oshima,Makoto Arita,Eiji Hara,Naoko Ohtani
出处
期刊:Cancer Discovery [American Association for Cancer Research]
卷期号:7 (5): 522-538 被引量:337
标识
DOI:10.1158/2159-8290.cd-16-0932
摘要

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
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