Antisense regulation of expression and transactivation functions of the tumorigenic HBx and c-myc genes.
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.
Hung
Le
L
Virology Group, International Centre for Genetic Engineering and Biotechnology, P.O. Box 10504, Aruna Asaf Ali Marg, New Delhi-110067, India.
Kumar
Vijay
V
D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D016373:DNA, Antisense / Q000235:genetics*; D004274:DNA, Recombinant / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D054334:Viral Regulatory and Accessory Proteins
D016373:DNA, Antisense; D004274:DNA, Recombinant; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein