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

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Abstract
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)