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Androgen Enhances Aflatoxin-induced Genotoxicity and Inflammation to Liver Cancer in Male Hepatitis B Patients

  • Sheng-Han Wang
    Affiliations
    Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
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  • Shiou-Hwei Yeh
    Affiliations
    NTU Centers of Genomic and Precision Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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  • Pei-Jer Chen
    Correspondence
    Correspondence Address correspondence to: Pei-Jer Chen, National Taiwan University College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan, Province of China 00100.
    Affiliations
    Hepatitis Research Center, National Taiwan University Hospital, NTU Centers of Genomic and Precision Medicine, College of Medicine, National Taiwan University, Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Open AccessPublished:November 22, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.11.001
      Hepatocellular carcinoma (HCC) is a male-predominant liver malignancy worldwide. Particularly striking is the male/female ratio in hepatitis B virus (HBV)-related HCC, which increases to 6 to 8:1.
      • Wang S.H.
      • Yeh S.H.
      • Lin W.H.
      • Wang H.Y.
      • Chen D.S.
      • Chen P.J.
      Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B.
      One possible explanation for this comes from molecular studies, which have identified androgen receptor response elements in the enhancer I of the HBV genome. These cis-elements are predicted to increases HBV transcription and viral titer, a documented risk for HCC, principally in males.
      • Wang S.H.
      • Yeh S.H.
      • Lin W.H.
      • Wang H.Y.
      • Chen D.S.
      • Chen P.J.
      Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B.
      In addition, most HBV-related HCCs contain integrated HBV DNAs in which the retained viral enhancer I elevates the host oncogene transcription. Amplification of these transcripts by testosterone is another mechanism favoring HCC in males.
      • Li C.L.
      • Li C.Y.
      • Lin Y.Y.
      • Ho M.C.
      • Chen D.S.
      • Chen P.J.
      • Yeh S.H.
      Androgen receptor enhances hepatic telomerase reverse transcriptase gene transcription after hepatitis B virus integration or point mutation in promoter region.
      In addition to HBV infection, environment factors, especially aflatoxin exposure, increases HCC risk among males approximately 3- to 4-fold. Aflatoxin is a well-characterized genotoxic chemical that produced aflatoxin B1-N7-guanine adduct.
      • Wu H.C.
      • Santella R.
      The role of aflatoxins in hepatocellular carcinoma.
      How HBV and aflatoxin work together to enhance liver cancer in males is a clinically significant topic that merits further study.
      In this issue of Cellular and Molecular Gastroenterology and Hepatology, Xu et al
      • Xu C.
      • Chen K.
      • Song Q.
      • Liu C.
      • Fan C.
      • Zhang R.
      • Zhu Q.
      • Wu Z.
      • Wang Y.
      • Fan J.
      • Zheng H.
      • Lu L.
      • Chen T.
      • Zhao H.
      • Jiao Y.
      • Qu C.
      Sex differences in genomic features of hepatitis B associated hepatocellular carcinoma with distinct antitumor immunity.
      took advantage of the unique HCC cohort in Qidong (QD), a coastal city with high aflatoxin exposure in China, to investigate the interaction among environmental and male risk factors in HCC. First, the authors studied the somatic mutation profiles and gene expression patterns of male and female QD-HCC patients. The authors found that the male QD-HCC had higher expression of metabolic genes for aflatoxin response (AHR and CYP1A1), but lower levels of DNA repair factors for nonhomologous end joining (XRCC4, LIG4, and MRE11) than females. Supporting the biologic relevance of these associations, in cultured cell lines with HBV persistence, treatment with testosterone enhanced aflatoxin-induced genotoxicity but reduced cellular DNA repair capacities. In addition, the authors observed increased release of nuclear DNAs into the cytoplasm in the treated cells, which stimulated the cGAS-STING pathway to activate type I interferon (IFN-I) signaling. Significantly, in HCC tissues, the IFN-I pathway was upregulated in males but not in females, and it was accompanied by increased PD1+/CD8+ T-cell infiltration in male HCC tumor tissues. The authors went on to show that the presence of this immunosuppressive cell infiltrate was recapitulated in murine HCC xenograft models, and that anti-PD-1 therapy against established HCC tumors was synergistically enhanced by pretreatment of tamoxifen. These findings highlight the therapeutic potential of combined checkpoint inhibitor/hormonal therapy for HBV-related HCC males.
      In summary, Xu et al
      • Xu C.
      • Chen K.
      • Song Q.
      • Liu C.
      • Fan C.
      • Zhang R.
      • Zhu Q.
      • Wu Z.
      • Wang Y.
      • Fan J.
      • Zheng H.
      • Lu L.
      • Chen T.
      • Zhao H.
      • Jiao Y.
      • Qu C.
      Sex differences in genomic features of hepatitis B associated hepatocellular carcinoma with distinct antitumor immunity.
      present an interesting framework for how HBV, aflatoxin, and androgens interact to amplify aflatoxin-induced DNA damage and a permissive inflammatory response that together enhance liver carcinogenesis. The observation that nuclear and/or mitochondrial DNA activates cGAS-STING pathway in HCC linked to combined HBV and aflatoxin exposure is also innovative and worthy of further investigation. Going forward, 3 additional areas of research deserve attention. The first regards the role of HBV, which was not explored in the current report. HBV X protein has been shown closely to interact with androgen receptor to increase its activity,
      • Wang S.H.
      • Yeh S.H.
      • Lin W.H.
      • Wang H.Y.
      • Chen D.S.
      • Chen P.J.
      Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B.
      so its carcinogenic role in aflatoxin-exposed male HBV patients should be investigated. The second involves mechanistic studies to understand how increased IFN-α leads to an immune-suppressive environment. Specifically, the identification of effectors produced by HBV-infected hepatocytes or HCC that mediate CD8+ T-cell chemotaxis. Third, the genetic mutation profiles in QD-HBV-HCC were distinct (eg, only 41% harboring HBV DNA integration, much lower than nonaflatoxin areas in which viral integration is detected in 80% of HBV-related HCC).
      • Li C.L.
      • Li C.Y.
      • Lin Y.Y.
      • Ho M.C.
      • Chen D.S.
      • Chen P.J.
      • Yeh S.H.
      Androgen receptor enhances hepatic telomerase reverse transcriptase gene transcription after hepatitis B virus integration or point mutation in promoter region.
      ,
      • Zhao L.H.
      • Liu X.
      • Yan H.X.
      • Li W.Y.
      • Zeng X.
      • Yang Y.
      • Zhao J.
      • Liu S.P.
      • Zhuang X.H.
      • Lin C.
      • et al.
      Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.
      It would be important to determine whether aflatoxin-induced genotoxicity drives carcinogenesis in the absence of HBV DNA integration in some patients. Finally, it would be also interesting to evaluate the efficacy of anti-HBV nucleos(t)ide analogues in patients from the QD region, as compared with low aflatoxin exposure areas, especially in male patients.

      References

        • Wang S.H.
        • Yeh S.H.
        • Lin W.H.
        • Wang H.Y.
        • Chen D.S.
        • Chen P.J.
        Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B.
        Hepatology. 2009; 50: 1392-1402
        • Li C.L.
        • Li C.Y.
        • Lin Y.Y.
        • Ho M.C.
        • Chen D.S.
        • Chen P.J.
        • Yeh S.H.
        Androgen receptor enhances hepatic telomerase reverse transcriptase gene transcription after hepatitis B virus integration or point mutation in promoter region.
        Hepatology. 2019; 69: 498-512
        • Wu H.C.
        • Santella R.
        The role of aflatoxins in hepatocellular carcinoma.
        Hepat Mon. 2012; 12e7238
        • Xu C.
        • Chen K.
        • Song Q.
        • Liu C.
        • Fan C.
        • Zhang R.
        • Zhu Q.
        • Wu Z.
        • Wang Y.
        • Fan J.
        • Zheng H.
        • Lu L.
        • Chen T.
        • Zhao H.
        • Jiao Y.
        • Qu C.
        Sex differences in genomic features of hepatitis B associated hepatocellular carcinoma with distinct antitumor immunity.
        Cell Mol Gastroenterol Hepatol. 2022; XX (XXX–XXX)
        • Zhao L.H.
        • Liu X.
        • Yan H.X.
        • Li W.Y.
        • Zeng X.
        • Yang Y.
        • Zhao J.
        • Liu S.P.
        • Zhuang X.H.
        • Lin C.
        • et al.
        Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.
        Nat Commun. 2016; 712992

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