Integrative analysis of transcriptome and miRNome unveils the key regulatory connections involved in different stages of hepatocellular carcinoma

Dysregulated molecular processes are the major factors that drive and feed the signaling processes involved in carcinogenesis. In recent years, regulation of mRNAs by microRNAs (miRNAs) has been found to play a vital role in many cancers including hepatocellular carcinoma (HCC). However, genomewide studies defining molecular regulatory circuits at both mRNA and miRNA levels are just emerging. To uncover the molecular and functional processes involved in liver tumorigenesis at mRNA and miRNA level, a co-expression-based network of miRNAs was constructed from multiple miRNA profiles. The applicability of the network approach to microRNA expression profiles was assessed. Although the clustering consistency of miRNAs across the profiles was found moderate, miRNA networking has been found informative. Furthermore, microRNA network modules were integrated with the functionally defined mRNA modules derived from an mRNA co-expression network of an earlier study. Three highly clustered regulatory circuits of mRNA-miRNA modules have been identified as involved in hepatocyte, inflammatory-stress and proliferative process activated subcategories of HCC. A subset of the proliferative miRNA module was found clustered in the 14q32.31 chromosomal region. The current integrative network analysis of mRNA-miRNA modules shows the intricate miRNA-mRNA functional circuits and signaling interactions involved in liver tumorigenesis.