title: Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.
abstract: Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation, and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota and TLR4 activation in non-bone-marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC, suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.
authors.affiliation: Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. rfs2102@columbia.edu
authors.forename: Dianne H
authors.initials: DH
authors.lastname: Dapito
authors.forename: Ali
authors.initials: A
authors.lastname: Mencin
authors.forename: Geum-Youn
authors.initials: GY
authors.lastname: Gwak
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pradere
authors.forename: Myoung-Kuk
authors.initials: MK
authors.lastname: Jang
authors.forename: Ingmar
authors.initials: I
authors.lastname: Mederacke
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Caviglia
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemi
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkowitch
authors.forename: Maureen
authors.initials: M
authors.lastname: Bower
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018988:Bacterial Translocation; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066260:Epiregulin; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D008107:Liver Diseases / Q000150:complications / Q000382:microbiology*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004815:Epidermal Growth Factor