Interferon alfa (IFN-␣) has been shown to possess antiviral activity, antiproliferative activity, and various immunoregulatory activities including: 1) stimulation of cytotoxic activities of lymphocytes and macrophages, and of natural killer cell activity; and 2) induction of class I major histocompatibility complex antigens. 1 The effects of IFN-␣ are mediated through interaction with the specific cell-surface receptor, type I IFN receptor. This receptor consists of two chains, Hu-IFN-␣R1 and Hu-IFN-␣R2, which can be present in different forms. [2][3][4][5][6] The Hu-IFN-␣R1 chain is present as either the full chain (Hu-IFN-␣R1) or a splice-variant (Hu-IFN-␣R1s) lacking exons 4 and 5. Hu-IFN-␣R2 chain exists in soluble, short, and long forms (Hu-IFN-␣R2a, Hu-IFN-␣R2b, and Hu-IFN␣R2c, respectively). [2][3][4] Most likely, the Hu-IFN-␣R1 and Hu-IFN-␣R2c chains represent the predominantly active form. 2 Binding of the receptor and IFN-␣ induce transcription of IFN-inducible genes through the activation of the Jak/signal transducer and activator of transcription (STAT) signaling pathway. 7-9 Interferon regulatory factor (IRF)-1, a transcriptional activator, and its antagonistic repressor, IRF-2, have been identified as regulators of type I IFN (mainly IFN-␣ and IFN-) and IFN-inducible genes. 10-12 IRF-1 has recently been shown to inhibit cell proliferation, induce apoptosis, and manifest antioncogenic activities, 10,13-17 while IRF-2 has the oncogenic potential. 10 The IRF-1 gene itself is IFN-inducible and may thus be one of the critical target genes mediating IFN action. 11 Antivirus activity of IFN-␣ has attracted a great deal of attention, and IFN-␣ has been applied in treatment for hepatitis B virus (HBV)-and hepatitis C virus (HCV)-related chronic hepatitis in several countries (reviewed in Gutterman 18 ). In the liver of HCV-infected patients, expressions of Hu-IFN-␣R1 and Hu-IFN-␣R2 chains were investigated in terms of mRNA level, and the relationship between their expression levels and response to IFN-␣ therapy was reported. 19,20 Although IFN-␣ has been proven to have a curative potential in treatment of HBV-and HCV-associated chronic liver diseases, its effect on hepatocellular carcinoma (HCC), which is a common and often fatal complication of HBV-and HCV-related chronic liver diseases, 21 is not well known. Clinical trials of IFN-␣ in treatment of HCC did not achieve consistent results: one study showed beneficial effects, 22 and the other studies did not show significant antitumor effects. 23,24 In contrast, IFN-␣ has been shown to be useful for the treatment of several malignant diseases, including hairy-cell leukemia and chronic myelogenous leukemia (reviewed in Gutterman 18 ).Experimental studies showed that IFN-␣ can inhibit the growth of various normal and malignant cells in vitro by inducing cell-cycle changes (e.g., induction of G 0 /G 1 arrest and prolongation of the S phase) 25-34 and/or apoptoAbbreviations: IFN-␣, interferon alfa; STAT, signal transducer and activator of transcription; IRF, ...