Abstract
Understanding the transcriptional regulatory elements that influence the progression of liver disease in the presence of hepatitis C virus (HCV) infection is critical for the development of diagnostic and therapeutic approaches. Systems biology provides a roadmap by which these elements may be integrated. In this study, a previously published dataset of 124 microarray samples was analyzed in order to determine differentially expressed genes across four tissue types/conditions (normal, cirrhosis, cirrhosis HCC, and HCC). Differentially expressed genes were assessed for their functional clustering and those genes were annotated with their potential transcription factors and miRNAs. Transcriptional regulatory networks were constructed for each pairwise comparison between the 4 tissue types/conditions. Based on our analysis, it is predicted that the disruption in the regulation of transcription factors such as AP-1, PPARγ, and NF-κB could contribute to the liver progression from cirrhosis to steatosis and eventually to HCC. Whereas the condition of the liver digresses, the downregulation of miRNAs’ (such as miR-27, Let-7, and miR-106a) expression makes the transition of the liver through each pathological stage more apparent. This preliminary data can be used to guide future experimental work. An understanding of the transcriptional regulatory attributes acts as a road map to help design interference strategies in order to target the key regulators of progression of HCV induced HCC.
Highlights
IntroductionAt the onset of hepatitis C virus (HCV) infection, the liver begins to react to the virus in many ways
hepatitis C virus (HCV) is an epidemic affecting an estimated 160 million individuals worldwide[1]
The 124 samples used in this study were obtained from the Gene Expression Omnibus (GEO) with the identification number GSE14323
Summary
At the onset of HCV infection, the liver begins to react to the virus in many ways. For the majority of cases, HCV digresses the condition of the liver from cirrhosis, to steatosis, and eventually carcinoma. Symptoms of end-stage liver disease can appear. Another condition that can hasten the development of cirrhosis in the liver and lead to the progression of end-stage liver disease in the presence of HCV infection is hepatic steatosis. The development of HCV-induced HCC is progressive and may occur over a period of 20–40 years (ref.). This multi-step progression involves establishment of chronic HCV infection, chronic hepatic inflammation, www.nature.com/scientificreports/. A major obstacle for the understanding of the mechanisms linking HCV infection, inflammation and carcinogenesis is the lack of an in vitro and in vivo model systems[8]
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