Abstract
Worldwide, an estimated 350 million people are chronically infected with the Hepatitis B Virus (HBV); chronic infection with HBV is associated with the development of severe liver diseases including hepatitis and cirrhosis. Individuals who are chronically infected with HBV also have a significantly higher risk of developing hepatocellular carcinoma (HCC) than uninfected individuals. The HBV X protein (HBx) is a key regulatory HBV protein that is important for HBV replication, and likely plays a cofactor role in the development of HCC in chronically HBV-infected individuals. Although some of the functions of HBx that may contribute to the development of HCC have been characterized, many HBx activities, and their putative roles during the development of HBV-associated HCC, remain incompletely understood. HBx is a multifunctional protein that localizes to the cytoplasm, nucleus, and mitochondria of HBV‑infected hepatocytes. HBx regulates numerous cellular signal transduction pathways and transcription factors as well as cell cycle progression and apoptosis. In this review, we will summarize reports in which the impact of HBx expression on cellular apoptotic pathways has been analyzed. Although various effects of HBx on apoptotic pathways have been observed in different model systems, studies of HBx activities in biologically relevant hepatocyte systems have begun to clarify apoptotic effects of HBx and suggest mechanisms that could link HBx modulation of apoptotic pathways to the development of HBV-associated HCC.
Highlights
Epidemiological studies indicate that chronic infection with Hepatitis B Virus (HBV) is the leading cause for the development of hepatocellular carcinoma (HCC) [1]
While inflammation-mediated destruction of HBV-infected hepatocytes and subsequent liver regeneration contribute to the development of HBV-associated HCC, the results of studies in mice, established cell lines, and cultured primary hepatocytes suggest that activities associated with expression of HBV X protein (HBx) can regulate HBV replication, alter hepatocyte physiology, and modulate cell signaling pathways that may impact the development of HBV-associated HCC [14,34]
The results of this study demonstrated that the transcriptional activation function of HBx was not required for inducing apoptosis in these cells; a truncated HBx mutant that localized to mitochondria but had lost its transcriptional activation function was sufficient to cause mitochondrial membrane depolarization leading to apoptosis [49]
Summary
Epidemiological studies indicate that chronic infection with Hepatitis B Virus (HBV) is the leading cause for the development of hepatocellular carcinoma (HCC) [1]. Three factors have been proposed to influence HCC development in a chronically HBV infected individual These factors are: integration of viral DNA into the genome of. HBx is the major regulatory protein encoded by the HBV genome, and the results of numerous studies strongly suggest that HBx is involved in the development of HBV-associated HCC [14,34]. Both mammalian and avian hepadnaviruses can establish chronic infections in their hosts, only chronic infections with the mammalian hepadnaviruses are associated with the development of liver cancer, and only the mammalian hepadnaviruses encode an X protein [6]. Alterations of normal apoptotic processes have been linked to the development of HCC [42], suggesting that an understanding of how HBx impacts apoptotic pathways in hepatocytes may help identify molecular mechanisms that influence the development of HBV-associated HCC and potential contributions of HBx in this process
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