H. hepaticus-induced liver tumor promotion is associated with increased serum bile acid and a persistent microbial-induced immune response
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Fox_H-Hepaticus-induced.pdf
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Author(s)
Garcia, Alexis
Zeng, Yu
Muthupalani, Sureshkumar
Ge, Zhongming
Potter, Amanda
Mobley, Melissa W.
Boussahmain, Chakib
Feng, Yan
Wishnok, John S.
Fox, James G.
Alternative Title
Helicobacter hepaticus–Induced Liver Tumor Promotion Is Associated with Increased Serum Bile Acid and a Persistent Microbial-Induced Immune Response
Date Issued
February 2011
Journal
Cancer Research
Publisher
American Association for Cancer Research
Citation
Garcia, A. et al. “Helicobacter hepaticus-Induced Liver Tumor Promotion Is Associated with Increased Serum Bile Acid and a Persistent Microbial-Induced Immune Response.” Cancer Research 71.7 (2011): 2529–2540.
Version
Author's final manuscript
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. Cancer Res; 71(7); 2529–40
Description
Author Manuscript: 2012 April 1.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
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Creative Commons Attribution-Noncommercial-Share Alike 3.0
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DOI of Published Version
https://doi.org/10.1158/0008-5472.CAN-10-1975
