522 | CANCER DISCOVERY MAY 2017 www.aacrjournals.org RESEARCH ARTICLE Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE 2 -Mediated Suppression of Antitumor Immunity Tze Mun Loo 1 , Fumitaka Kamachi 1 , Yoshihiro Watanabe 1 , Shin Yoshimoto 2,3 , Hiroaki Kanda 4 , Yuriko Arai 1,2 , Yaeko Nakajima-Takagi 5 , Atsushi Iwama 5 , Tomoaki Koga 6 , Yukihiko Sugimoto 6 , Takayuki Ozawa 1 , Masaru Nakamura 1 , Miho Kumagai 1 , Koichi Watashi 7,8 , Makoto M. Taketo 9 , Tomohiro Aoki 10 , Shuh Narumiya 10,11,12 , Masanobu Oshima 12,13 , Makoto Arita 14,15,16,17 , Eiji Hara 2,12,18 , and Naoko Ohtani 1,16 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 transloca- tion 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 E 2 (PGE 2 ) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progres- sion. 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. Cancer Discov; 7(5); 522–38. ©2017 AACR. 1 Department of Applied Biological Science, Faculty of Science and Tech- nology, Tokyo University of Science, Chiba, Japan. 2 Division of Cancer Biol- ogy, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. 3 LSI Medience Corporation, Tokyo, Japan. 4 Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. 5 Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan. 6 Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. 7 Department of Virology II, National Insti- tute of Infectious Diseases, Tokyo, Japan. 8 CREST, Japan Science and Technology Agency (JST), Saitama, Japan. 9 Department of Pharmacol- ogy, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Kyoto, Japan. 10 Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Konoe- cho Yoshida, Kyoto, Japan. 11 Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. 12 AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan. 13 Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. 14 Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. 15 Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan. 16 PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan. 17 Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceu- tical Sciences, Keio University, Tokyo, Japan. 18 Department of Molecular Microbiology, Research Institute for Microbial Diseases, Osaka Univer- sity, Osaka, Japan. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Current address for N. Ohtani: Department of Pathophysiology, Osaka City University, Graduate School of Medicine, Osaka, Japan. Corresponding Author: Naoko Ohtani, Department of Pathophysiology, Osaka City University, Graduate School of Medicine, Asahimachi 1-4-3, Abeno-ku, Osaka, 545-8585, Japan. Phone: 81-6-6645-3710; Fax: 81-6- 6645-3712; E-mail: ohtani.naoko@med.osaka-cu.ac.jp doi: 10.1158/2159-8290.CD-16-0932 ©2017 American Association for Cancer Research. on May 20, 2020. © 2017 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst February 15, 2017; DOI: 10.1158/2159-8290.CD-16-0932