Hepatitis B virus integration and hepatocarcinogenesis
Chronic liver disease associated with long term hepatitis B virus (HBV) infection is an important contributor to the development of hepatocellular carcinoma (HCC). A feature of these chronic infections is the integration of subgenomic HBV DNA fragments into many different locations within the host DNA, suggesting that integration is random. Although this may promote genetic instability during liver regeneration which accompanies a bout of chronic liver disease, the actual role of integrated HBV DNA in hepatocarcinogenesis is uncertain. Importantly, most integration events retain the HBV open reading frame encoding the HBx antigen (HBxAg), which is the virus contribution to HCC. In addition, many integration events reported in the literature occur near or within fragile sites or other cancer associated regions of the human genome that are prone to instability in tumor development and progression. Genetic instability associated with integration potentially alters the expression of oncogenes, tumor suppressor genes, and microRNAs (miRNAs) that may contribute importantly to tumorigenesis. If so, then selected integration events may alter pathways that are rate limiting in hepatocarcinogenesis, thereby providing targets with diagnostic/prognostic potential and for therapeutic intervention.
For many years, it was thought that HBV DNA integration events were random with regard to their sites within the human genome, but when the relationship between fragile sites and virus integration events are compared, HBV DNA is found to integrate within or near many of these regions. In most cases, integration at a particular site has only been reported for a single or small number of tumors, but a closer look shows that individual integration sites alter the expression of different components in the same or redundant biochemical or signaling pathways that support hepatocellular growth and survival important for tumor development. HBxAg appears to alter some of these same pathways by other mechanisms, underscoring the likelihood that these pathways are important in carcinogenesis.
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Tags: Biology, Genetics, Health, Medicine, Microbiology, Science, Virology
