Gut microbiota promotes obesity-associated liver cancer through pge2-mediated suppression of antitumor immunity

Tze Mun Loo, Fumitaka Kamachi, Yoshihiro Watanabe, Shin Yoshimoto, Hiroaki Kanda, Yuriko 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 & 1 others Naoko Ohtani

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)522-538
Number of pages17
JournalCancer Discovery
Volume7
Issue number5
DOIs
Publication statusPublished - 2017 May 1

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Liver Neoplasms
Hepatocellular Carcinoma
Immunity
Obesity
Dinoprostone
Phenotype
Toll-Like Receptor 2
Hepatic Stellate Cells
Deoxycholic Acid
Tumor Microenvironment
Liver Diseases
Up-Regulation
Gastrointestinal Microbiome
Liver
Neoplasms
lipoteichoic acid

ASJC Scopus subject areas

  • Oncology

Cite this

Loo, T. M., Kamachi, F., Watanabe, Y., Yoshimoto, S., Kanda, H., Arai, Y., ... Ohtani, N. (2017). Gut microbiota promotes obesity-associated liver cancer through pge2-mediated suppression of antitumor immunity. Cancer Discovery, 7(5), 522-538. https://doi.org/10.1158/2159-8290.CD-16-0932

Gut microbiota promotes obesity-associated liver cancer through pge2-mediated suppression of antitumor immunity. / Loo, Tze Mun; Kamachi, Fumitaka; Watanabe, Yoshihiro; Yoshimoto, Shin; Kanda, Hiroaki; Arai, Yuriko; Nakajima-Takagi, Yaeko; Iwama, Atsushi; Koga, Tomoaki; Sugimoto, Yukihiko; Ozawa, Takayuki; Nakamura, Masaru; Kumagai, Miho; Watashi, Koichi; Taketo, Makoto M.; Aoki, Tomohiro; Narumiya, Shuh; Oshima, Masanobu; Arita, Makoto; Hara, Eiji; Ohtani, Naoko.

In: Cancer Discovery, Vol. 7, No. 5, 01.05.2017, p. 522-538.

Research output: Contribution to journalArticle

Loo, TM, Kamachi, F, Watanabe, Y, Yoshimoto, S, Kanda, H, Arai, Y, Nakajima-Takagi, Y, Iwama, A, Koga, T, Sugimoto, Y, Ozawa, T, Nakamura, M, Kumagai, M, Watashi, K, Taketo, MM, Aoki, T, Narumiya, S, Oshima, M, Arita, M, Hara, E & Ohtani, N 2017, 'Gut microbiota promotes obesity-associated liver cancer through pge2-mediated suppression of antitumor immunity', Cancer Discovery, vol. 7, no. 5, pp. 522-538. https://doi.org/10.1158/2159-8290.CD-16-0932
Loo, Tze Mun ; Kamachi, Fumitaka ; Watanabe, Yoshihiro ; Yoshimoto, Shin ; Kanda, Hiroaki ; Arai, Yuriko ; Nakajima-Takagi, Yaeko ; Iwama, Atsushi ; Koga, Tomoaki ; Sugimoto, Yukihiko ; Ozawa, Takayuki ; Nakamura, Masaru ; Kumagai, Miho ; Watashi, Koichi ; Taketo, Makoto M. ; Aoki, Tomohiro ; Narumiya, Shuh ; Oshima, Masanobu ; Arita, Makoto ; Hara, Eiji ; Ohtani, Naoko. / Gut microbiota promotes obesity-associated liver cancer through pge2-mediated suppression of antitumor immunity. In: Cancer Discovery. 2017 ; Vol. 7, No. 5. pp. 522-538.
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