title: 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 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 PGE2production 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 PGE2in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2and 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.
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
authors.forename: Tze Mun
authors.initials: TM
authors.lastname: Loo
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kamachi
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.|LSI Medience Corporation, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Yoshimoto
authors.affiliation: Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kanda
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.|Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kumagai
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.|CREST, Japan Science and Technology Agency (JST), Saitama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Kyoto, Japan.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Konoe-cho Yoshida, Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Konoe-cho Yoshida, Kyoto, Japan.|Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.|AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.|Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.|Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.|Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.|AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.|Department of Molecular Microbiology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Hara
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan. ohtani.naoko@med.osaka-cu.ac.jp.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohtani
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000382:microbiology; D013682:Teichoic Acids / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D013682:Teichoic Acids; C009900:lipoteichoic acid; D015232:Dinoprostone