title: Toll-like Receptor 4 on Macrophage Promotes the Development of Steatohepatitis-related Hepatocellular Carcinoma in Mice.
abstract: The role of Toll-like receptor (TLR) signaling has attracted much attention in the development of hepatic inflammation and hepatocellular carcinoma (HCC). We herein sought to determine the role of TLRs and responsible cells in steatohepatitis-related HCC. We used hepatocyte-specific Pten-deficient (Pten(Δ) (hep)) mice, which exhibit steatohepatitis followed by liver tumor formation, including HCC. We then generated Pten(Δ) (hep)/Tlr4(-/-) and Pten(Δ) (hep)/Tlr2(-/-) double-mutant mice and investigated the role of macrophages using reconstitution of bone marrow (BM)-derived cells, chemical depletion of macrophages, and isolated macrophages. Tlr4 but not Tlr2 deficiency in the Pten(Δ) (hep) mice suppressed tumor growth as well as hepatic inflammation. Gut sterilization by an antibiotic mixture reduced the portal LPS levels as well as tumor growth in the Pten(Δ) (hep) mice. Tumor growth was also decreased by reconstitution of BM-derived cells to Tlr4(-/-) BM cells. In addition, chemical depletion of macrophages significantly reduced tumor size and numbers. Macrophages expressing Ly6C were increased in number, which was associated with inflammation and tumor progression in the Pten(Δ) (hep) mice. Hepatic macrophages isolated from the Pten(Δ) (hep) mice abundantly expressed the Ly6C gene and produced much more IL-6 and TNFα in response to LPS. These proinflammatory cytokines induced the proliferation of HCC cells as well as oval cells, putative cancer progenitor cells. Indeed, putative cancer progenitor cells emerged before the development of macroscopic liver tumors and then increased in number under sustained inflammation. TLR4 on macrophages contributes to the development of steatohepatitis-related HCC in mice.
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan miura116@doc.med.akita-u.ac.jp.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Miura
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ishioka
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Minami
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Ohshima
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Goto
authors.affiliation: From the Department of Gastroenterology and Hepato-Biliary-Pancreatology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Ohnishi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D016207:Cytokines; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: hepatocellular carcinoma; inflammation; macrophage; phosphatase and tensin homolog (PTEN); toll-like receptor (TLR)