title: Helicobacter hepaticus--induced liver tumor promotion is associated with increased serum bile acid and a persistent microbial-induced immune response.
abstract: Chronic microbial infection influences cancer progression, but the mechanisms that link them remain unclear. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates enzymes involved in endobiotic and xenobiotic metabolism. CAR activation is a mechanism of xenobiotic tumor promotion; however, the effects of chronic microbial infection on tumor promotion have not been studied in the context of CAR function. Here, we report that CAR limits the effects of chronic infection-associated progression of liver cancer. CAR knockout (KO) and wild-type (WT) male mice were treated with or without the tumor initiator diethylnitrosamine (DEN) at 5 weeks of age and then orally inoculated with Helicobacter hepaticus (Hh) or sterile media at 8 weeks of age. At approximately 50 weeks postinoculation, mice were euthanized for histopathologic, microbiological, molecular, and metabolomic analyses. Hh infection induced comparable hepatitis in WT and KO mice with or without DEN that correlated with significant upregulation of Tnfα and toll receptor Tlr2. Notably, DEN-treated Hh-infected KO mice exhibited increased numbers of liver lobes with dysplasia and neoplasia and increased multiplicity of neoplasia, relative to similarly treated WT mice. Enhanced tumor promotion was associated with decreased hepatic expression of P450 enzymes Cyp2b10 and Cyp3a11, increased expression of Camp, and increased serum concentrations of chenodeoxycholic acid. Together, our findings suggest that liver tumor promotion is enhanced by an impaired metabolic detoxification of endobiotics and a persistent microbial-induced immune response.
authors.affiliation: Division of Comparative, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: García
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Ge
authors.forename: Amanda
authors.initials: A
authors.lastname: Potter
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Mobley
authors.forename: Chakib
authors.initials: C
authors.lastname: Boussahmain
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: John S
authors.initials: JS
authors.lastname: Wishnok
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D001647:Bile Acids and Salts / Q000097:blood* / Q000276:immunology; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000097:blood* / Q000276:immunology* / Q000382:microbiology; D044923:Helicobacter hepaticus; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000276:immunology* / Q000382:microbiology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2