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Liver‐gender mosaicism and not androgen signaling correlates with hepatocellular carcinoma in male mice
Author(s) -
Rogers Arlin B.,
Theve Elizabeth J.,
Feng Yan,
Fox James G.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a71-c
Subject(s) - hepatocellular carcinoma , androgen , androgen receptor , medicine , liver cancer , castration , endocrinology , biology , dihydrotestosterone , cancer research , cancer , prostate cancer , hormone
Hepatocellular carcinoma (HCC) is a male‐predominant cancer. Like human viral hepatitis, Helicobacter hepaticus infection of A/JCr mice produces chronic hepatitis and HCC with a male bias. We used this model to test the hypothesis that androgen ablation of mature mice with hepatitis would protect against HCC, and conversely that androgen receptor agonism would promote tumors. At 1 year of age, mice with and without H. hepaticus were distributed into 4 groups: surgical castration, chemical castration, castration with dihydrotestosterone (DHT) oversupplementation, or intact controls. At 21 months, ~60% of infected mice had chronic hepatitis regardless of intervention. Inflammation was most severe in intact males. Unexpectedly, neither castration nor DHT oversupplementation had any effect on HCC incidence. As shown by microarray and qRT‐PCR, 13% of all liver genes were sensitive to castration. Of these, 38% were altered in mice with HCC, demonstrating a participatory bias of gender‐dimorphic genes in tumorigenic hepatitis. Liver‐gender mosaicism, defined as the dyscoordinated expression of sexually dimorphic genes, was strongly associated with hepatitis and HCC. In summary, liver cancer in mice is male‐predominant, maturationally imprinted and androgen receptor‐independent. Transcriptional liver‐gender mosaicism and not androgen signaling may account for male predisposition to HCC.