Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome

Shin Yoshimoto, Tze Mun Loo, Koji Atarashi, Hiroaki Kanda, Seidai Sato, Seiichi Oyadomari, Yoichiro Iwakura, Kenshiro Oshima, Hidetoshi Morita10, Masahisa Hattori, Kenya Honda, Yuichi Ishikawa, Eiji Hara, Naoko Ohtani, Nature. 499:97-101 (2013)

Speaker: Meng-Hsuan Tsai (蔡孟暄)                            Time: 15:00~16:00, Sep. 25, 2013

Commentator: Dr. Wei-Chen Lin (林威辰 老師)     Place: Room 601

Abstract

  The incidence of obesity is increasing in the world and has been linked to high risk of developing various cancers. There are several events proposed to be involved in obesity-associated cancers, but the underlying mechanisms are poorly understood. Among these events, interleukin (IL)-6, a pro-inflammatory cytokine and also a major component of senescence-associated secretory phenotype (SASP), is known to increase cancer risk in obesity. As SASP has been reported to promote tumorigenesis, the authors proposed that SASP may contribute to obesity-associated cancer. In this study, they fed senescence-reporter mice with high-fat diet (HFD) or normal diet under combined treatment with a chemical carcinogen, and surprisingly found that only HFD-fed obese mice developed hepatocellular carcinoma (HCC) with concurrent induction of a senescent marker p21^Waf1/Cip1 in liver. A similar result was also observed in genetically obese mice. In this context, only activated hepatic stellate cells (HSCs) were senescent in HCC and expressed DNA damage markers as well as IL-1β- induced SASP factors (IL-6, Gro-α and CXCL9). Notably, the authors found that altered intestinal mircobiota and their metabolite deoxycholic acid (DCA) are the key links between obesity and HCC. Treatment with vancomycin, which preferentially targets Gram-positive bacteria, inhibited HFD-induced SASP and HCC development. Meanwhile, serum DCA and DCA-producing intestinal Clostridium cluster XI increased in HFD-fed mice. HSC senescence and HCC development were promoted by ectopic DCA treatment, while were inhibited by reduction of DCA. In summary, obesity alters intestinal microbiota and thus causes the increment of DCA, and DCA-induced SASP facilitates HCC development. Therefore, this study provides an integrated explanation of the association among obesity, gut microbiota and cancer.

Reference

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2   Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology 6, 2853-2868, (2008).