Hung Le, Kumar Vijay
Virology Group, International Centre for Genetic Engineering and Biotechnology, P.O. Box 10504, Aruna Asaf Ali Marg, New Delhi-110067, India.
Biochem Biophys Res Commun. 2006 May 26;344(1):293-9. doi: 10.1016/j.bbrc.2006.03.103. Epub 2006 Mar 27.
Earlier we have shown that the X-myc transgenic mice develop hepatocellular carcinoma (HCC) due to co-expression of c-Myc and HBx protein of hepatitis B virus [R. Lakhtakia, V. Kumar, H. Reddi, M. Mathur, S. Dattagupta, S.K. Panda, Hepatocellular carcinoma in a hepatitis B 'x' transgenic mouse model: a sequential pathological evaluation. J. Gastroenterol. Hepatol. 18 (2003) 80-91]. With the aim to develop therapeutic strategies for HCC, we constructed several mono- and bicistronic antisense recombinants against HBx and c-myc genes to regulate their expression as well as transactivation function in a human hepatoma cell line. A dose-dependent inhibition in the expression levels of HBx and c-Myc was observed with monocistronic constructs. Likewise, the bicistronic recombinants also blocked the expression as well as transactivation functions of cognate genes with equal efficacy. Further, expression of the constituent genes from the X-myc transgene could also be inhibited by these antisense constructs in cell culture. Thus, our study points towards clinical implications of antisense regulation of tumor-promoting genes in the management of HCC.
我们之前已经表明，X-myc转基因小鼠由于c-Myc与乙型肝炎病毒的HBx蛋白共同表达而发生肝细胞癌（HCC）[R. Lakhtakia, V. Kumar, H. Reddi, M. Mathur, S. Dattagupta, S.K. Panda, 乙型肝炎“x”转基因小鼠模型中的肝细胞癌：序贯病理评估。《胃肠病学与肝病学杂志》18 (2003) 80 - 91]。为了开发针对HCC的治疗策略，我们构建了几种针对HBx和c-myc基因的单顺反子和双顺反子反义重组体，以调节它们在人肝癌细胞系中的表达以及反式激活功能。观察到单顺反子构建体对HBx和c-Myc表达水平有剂量依赖性抑制作用。同样，双顺反子重组体也能同等有效地阻断同源基因的表达以及反式激活功能。此外，在细胞培养中，这些反义构建体也能抑制X-myc转基因中组成基因的表达。因此，我们的研究指出了反义调节促肿瘤基因在HCC治疗中的临床意义。
