TY - JOUR
T1 - Gut microbiota promotes obesity-associated liver cancer through pge2-mediated suppression of antitumor immunity
AU - Loo, Tze Mun
AU - Kamachi, Fumitaka
AU - Watanabe, Yoshihiro
AU - Yoshimoto, Shin
AU - Kanda, Hiroaki
AU - Arai, Yuriko
AU - Nakajima-Takagi, Yaeko
AU - Iwama, Atsushi
AU - Koga, Tomoaki
AU - Sugimoto, Yukihiko
AU - Ozawa, Takayuki
AU - Nakamura, Masaru
AU - Kumagai, Miho
AU - Watashi, Koichi
AU - Taketo, Makoto M.
AU - Aoki, Tomohiro
AU - Narumiya, Shuh
AU - Oshima, Masanobu
AU - Arita, Makoto
AU - Hara, Eiji
AU - Ohtani, Naoko
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-16-0932
DO - 10.1158/2159-8290.CD-16-0932
M3 - Article
C2 - 28202625
AN - SCOPUS:85017373900
SN - 2159-8274
VL - 7
SP - 522
EP - 538
JO - Cancer Discovery
JF - Cancer Discovery
IS - 5
ER -
