Interferon-γ sensitizes hepatitis B virus-expressing hepatocarcinoma cells to 5-fluorouracil through inhibition of hepatitis B virus-mediated nuclear factor-κB activation

Nuclear factor (NF)-κB is important for immune responses and cell survival; however, abnormal activation of NF-κB is linked with many types of diseases, including hepatocellular carcinoma (HCC). Our previous report indicated that hepatitis B virus (HBV) induces NF-κB activation through NF-κB-inducing kinase (NIK), and this can be blocked specifically by interferon (IFN)-γ. In the present study, we report that HBV expression in HCC cell lines induces drug resistance against 5-fluorouracil (5-FU). This drug resistance was abolished by inhibition of NF-κB activation through small interfering RNA-mediated NIK ‘knockdown’ and IFN-γ treatment. In addition to the reduced NF-κB activation and drug resistance, the upregulated growth arrest- and DNA damage-inducible protein 45β (Gadd45β) in HBV-expressing HCC cell lines was downregulated by the small interfering RNA-mediated NIK knockdown and IFN-γ treatment. The overexpression of Gadd45β in HCC cell lines also induces drug resistance against 5-FU. Based on our data, we suggest that IFN-γ treatment might be helpful for chemotherapy in HBV-integrated HCC through inhibition of the NIK-mediated NF-κB activation and downregulation of the NF-κB target gene Gadd45β. (Cancer Sci 2007; 98: 1758–1766)