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World J Gastroenterol. Aug 14, 2014; 20(30): 10238-10248
Published online Aug 14, 2014. doi: 10.3748/wjg.v20.i30.10238
Hepatitis B virus, HBx mutants and their role in hepatocellular carcinoma
Ashraf Ali, Hany Abdel-Hafiz, Mohd Suhail, Amany Al-Mars, Mohammad Khalid Zakaria, Kaneez Fatima, Sultan Ahmad, Esam Azhar, Adeel Chaudhary, Ishtiaq Qadri
Ashraf Ali, Mohd Suhail, Amany Al-Mars, Sultan Ahmad, Adeel Chaudhary, Ishtiaq Qadri, Department of Medical Biotechnology, King Fahad Medical Research Center, King Abdul Aziz University, PO Box 80216, Jeddah 21589, Saudi Arabia
Hany Abdel-Hafiz, Division of Endocrinology, Department of Medicine and Metabolism, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045, United States
Mohammad Khalid Zakaria, Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India
Kaneez Fatima, IQ Institute of Infection and Immunity, Lahore 54000, Pakistan
Esam Azhar, Special Infectious Agents Unit-Biosafety Level 3, King Fahd Medical Research Center, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
Esam Azhar, Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
Author contributions: Ali A and Qadri I conceived the idea, carried out the literature search, manuscript writing and final editing; Abdel-Hafiz H edited the manuscript while Suhail M, Mars A, Sultan A and Fatima K helped in referencing, editing and figure preparation and rectifying some grammatical errors; Financial and technical assistance to Ali A and Suhail M was provided by Azhar E and Chaudhary A.
Correspondence to: Ishtiaq Qadri, PhD, Professor, Head Medical Biotechnology, Head Liver Biology, Head Translational Research, Department of Medical Biotechnology, King Fahd Medical Research Center, King Abdul Aziz University, PO Box 80216, Jeddah 21589, Saudi Arabia. ishtiaq80262@yahoo.com
Telephone: +966-640-1000 Fax: +966-6952-5321
Received: February 23, 2014
Revised: April 30, 2014
Accepted: May 25, 2014
Published online: August 14, 2014
Processing time: 176 Days and 1.6 Hours
Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of death induced by cancer in the modern world and majority of the cases are related to chronic hepatitis B virus (HBV) infection. HBV-encoded X protein (HBx) is known to play a pivotal role in the pathogenesis of viral induced HCC. HBx is a multifunctional protein of 17 kDa which modulates several cellular processes by direct or indirect interaction with a repertoire of host factors resulting in HCC. HBX might interfere with several cellular processes such as oxidative stress, DNA repair, signal transduction, transcription, protein degradation, cell cycle progression and apoptosis. A number of reports have indicated that HBx is one of the most common viral ORFs that is often integrated into the host genome and its sequence variants play a crucial role in HCC. By mutational or deletion analysis it was shown that carboxy terminal of HBx has a likely role in protein-protein interactions, transcriptional transactivation, DNA repair, cell, signaling and pathogenesis of HCC. The accumulated evidence thus far suggests that it is difficult to understand the mechanistic nature of HBx associated HCC, and HBx mediated transcriptional transactivation and signaling pathways may be a major determinant. This article addresses the role of HBx in the development of HCC with particular emphasis on HBx mutants and their putative targets.

Keywords: Hepatitis B virus; Hepatocellular carcinoma; Transcription factors; Apoptosis; Epigenetics; Mutants; Tumor necrosis factor; Activating protein; Transforming growth factor; Mitogen activated protein kinase

Core tip: The available evidence supports a well-defined for the hepatitis B virus-encoded X protein (HBx) protein in viral-induced hepatocellular carcinoma. The progression cell cycle, transactivation potential, compromised DNA repair, inhibition the tumor suppressor gene and senescence-related factors are few of the key pathways by which HBx is known to promote pathogenesis. The activation and inhibition of cellular calcium and tyrosine kinase signaling pathways are some of the other pathways modulated by HBx expression. Individually charged amino acids (K-130, V-131, D-120, 121) and or steches of amino acids (132-140) present in the carboxy-terminus of HBx protein seems to enhance the protein’s ability to deregulates cellular processes.