HBX plays a potential role in developing hepatocellular carcinoma in chronic HBV carriers, a series of evidences suggesting plausible oncogenic factor

Abstract

Background: Chronic Hepatitis caused by HBV is one of the principal causative agent for incidence of hepatocellular carcinoma around the world. In this respect, HBV viral protein HBX is possibly the most probable target that reinforces the prevalence of HBV mediated HCC. In this study HBX is used to delineate the molecular pathway it follows to develop oncogenesis. Methods & Materials: Around 500 complete genome sequences of HBV and respective HBX sequences were extracted from NCBI and UNIPROT database. They were subjected to multiple sequence alignment. Using maximum likelihood method the phylogenetic tree was reconstructed, engaging 1000 bootstrap replicates. Representative sequence from each genotype was selected to develop molecular model of HBX. By means of structural and thermodynamic refinements HBX dimers were constructed on basis of geometrical complementarity. Evidences suggests that longitudinal positioning of residues may lead to variations in the dimerization of HBX among different genotypes and subsequently their related functions. However, the dimer interaction region showed a region which could further be exploited for designing disruptor/small inhibitor. Moreover, selected sequences were predicted for post translational modifications analyses by different kinases to associate their molecular and biological functions. Results: HBX is intrinsically disordered protein structurally, providing justification for subsequent multiple molecular and biological roles including HBV associated carcinoma. HBX contains a Zinc Finger domain, which is an unambiguous evidence of protein-nucleic acid interaction. Structural variance is observed in molecular models inferring varying role in HBV associated hcc. Conformation of dimerization and variations in the post translational modification profile strengthens this fact further. PTM analysis exhibited 14 different kinases involved in the cell cycle regulation, regulate gene expression, signal transduction, apoptosis, cell metabolism, immune response and neuron differentiation tends to alter most of the sequences of HBX pointing towards their role in carcinogenesis. Conclusion: This study delineates the structural and functional polymorphism of HBX and provides enough evidence, suggesting HBX a plausible oncogene. HBX gene is found to be associated with development of hepatocellular carcinoma. This may also augment in understanding the molecular pathway followed by HBX in development of oncogenesis. Amplified with the further studies the present investigation may elucidate potential targets for therapeutic intervention.