Specific inhibition of gene expression and transactivation functions of hepatitis B virus X protein and c‐myc by small interfering RNAs

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Abstract
With a view to developing therapeutic strategies against hepatocellular carcinoma (HCC), we have recently shown that co‐expression of c‐myc and the X protein of hepatitis B virus (HBx) resulted in the development of HCC in the X‐myc transgenic mice [Lakhtakia et al., J. Gastroenterol. Hepatol. 18 (2003) 80–91]. We now show in cell culture‐based studies that small interfering RNA (siRNA) corresponding to HBx and c‐myc can regulate expression and transactivation of the target genes. Expression vectors for small hairpin RNAs (shRNAs) against two different regions each of the HBx and c‐myc open reading frames were constructed and their regulatory effects were investigated in COS‐1 cells. A dose‐dependent specific inhibition in the expression levels of HBx and c‐myc was observed with individual shRNAs. Further, the recombinantly expressed shRNAs also blocked the transactivation functions of their cognate genes. Though each shRNA worked at a different efficiency, the inhibitory effects with two different shRNAs were cumulative. These results appear promising for developing a siRNA‐based therapy for HCC.