Original Article/Biliary
Expression of HBx protein in hepatitis B virus-infected intrahepatic cholangiocarcinoma

https://doi.org/10.1016/S1499-3872(12)60219-7Get rights and content

Background

Hepatitis B virus (HBV) is an etiological factor of intrahepatic cholangiocarcinoma (ICC), but the pathogenic mechanisms remain unclear. This study aimed to investigate the expression and possible role of HBx, an HBV-encoded potentially oncogenic protein, in HBV-infected ICC.

Methods

Tissue samples were obtained from 54 specimens of HBV-infected ICC. Forty-four specimens were of peripheral type and 10 hilar type. Formalin-fixed, paraffin-embedded sections of the specimens were immunohistochemically stained for HBx and p53.

Results

HBx expression was found in 70.4% (38/54) of the specimens, and it was more frequently seen in the peripheral type than in the hilar type (79.5% vs 30.0%, P=0.002). All three well-differentiated ICCs expressed HBx, whereas 76.9% (30/39) moderately-differentiated and 41.7% (5/12) poorly-differentiated ICCs had HBx expression (P=0.033). Patients with HBx expression had a significantly higher prevalence of elevated serum alpha-fetoprotein (P=0.033). p53 protein expression was found in 18 of 54 cases (33.3%), and was not correlated with that of HBx.

Conclusions

HBx may contribute to the pathogenesis of ICC, particularly the peripheral type. p53 abnormality may not play a significant role in HBx-mediated oncogenicity during ICC carcinogenesis.

References (23)

  • M Tanaka et al.

    Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus

    J Viral Hepat

    (2010)
  • Cited by (20)

    • The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

      2019, Biochimica et Biophysica Acta - Reviews on Cancer
      Citation Excerpt :

      Transgenic overexpression of Hbx induces liver carcinogenesis in rodent models [129,130], which is also found to be upregulated in human liver cancer specimens [131]. Increased HBx expression is also observed in intrahepatic cholangiocarcinoma [132] and adenoid cystic carcinoma [133], suggesting a general involvement of HBx in promoting tumorigenesis. Mechanistically, apart from its involvement in HBV replication, SMC5/6 also has a vital role in regulating cell division and proliferation while HBx could interact with apoptotic machinery to stimulate downstream oncogenes [134,135], which together explain the oncogenic impact of HBx in human cancers (Tables 3 and 5).

    • Effect of Nucleos(t)ide Analogue Therapy on Risk of Intrahepatic Cholangiocarcinoma in Patients With Chronic Hepatitis B

      2018, Clinical Gastroenterology and Hepatology
      Citation Excerpt :

      Although HBV can be found in bile duct epithelial cells and tumor tissues of CCA,12,13,24 the precise pathogenic mechanisms of HBV-mediated CCA remain largely unclear.14 In previous pathologic studies for HBV-related CCA, the detection rate of hepatitis B virus X protein could be as high as 60%–70%.24,25 In a zebrafish model, liver fibrosis and ICC were induced by dual expression of hepatitis B virus X and hepatitis C virus core protein, and the signaling pathway of transforming growth factor beta 1 was involved.26

    • Antiviral therapy improves survival in patients with HBV infection and intrahepatic cholangiocarcinoma undergoing liver resection

      2018, Journal of Hepatology
      Citation Excerpt :

      It is possible that HBV x protein (HBx) acts as a trans-activating protein by binding to nuclear transcription factors to stimulate the intracellular signaling pathways that promote tumor cell growth.11 HBV infection may also induce liver progenitor cell activation, which when accompanied by abnormal genetic changes caused by HBx activation, contributes to malignant transformation.12 The association between HBV infection and outcomes after surgical and systemic treatments has been reported in HBV-infected patients with HCC or other malignancies.13–16

    • Hepatitis B and Risk of Non–Hepatocellular Carcinoma Malignancy

      2016, Clinics in Liver Disease
      Citation Excerpt :

      Similarly, a common pathway of inflammation, cirrhosis, and carcinogenesis has been proposed because of evidence of greater inflammation and scarring in HBV ICC versus non–-HBV-related ICC.27 In addition, similar to HCC, the HBx and p53 proteins have been shown to be present in liver tissue surrounding resected ICC.28 The association between chronic hepatitis B and extrahepatic malignancy, particularly NHL, warrants further study to define the possible pathogenic mechanisms.

    • Clinical presentation, risk factors and staging systems of cholangiocarcinoma

      2015, Best Practice and Research: Clinical Gastroenterology
      Citation Excerpt :

      In patients with bile-duct cysts the incidence of CCA in the first decade of their life and the risk of malignancy decreases after cyst excision [41,42,44–46]. Other confirmed risk factors are virus infection with hepatitis B (HBV) and hepatitis C (HCV) [47–54]. However, the contribution of hepatitis infection differs between Western countries and Asia, where HBV is endemic.

    View all citing articles on Scopus
    View full text