Dissection of miRNA-miRNA interaction in esophageal squamous cell carcinoma.

The relationships between miRNAs and their regulatory influences in esophageal carcinoma remain largely unknown. Accumulated evidence suggests that delineation of subpathways within an entire pathway can underlie complex diseases. To analyze the regulation of differentially expressed miRNAs in subpathways of esophageal squamous cell carcinoma (ESCC), we constructed bipartite miRNA and subpathway networks to determine miRNA regulatory influences on subpathways. The miRNA-subpathway network indicated that miRNAs regulate numerous subpathways. Two principal biological networks were derived from the miRNA-subpathway network by the hypergeometric test. This miRNA-miRNA network revealed the co-regulation of subpathways between the upregulated and downregulated miRNAs. Subpathway-subpathway networks characterized scale free, small world, and modular architecture. K-clique analysis revealed co-regulation of subpathways between certain downregulated and upregulated miRNAs. When ESCC patients were grouped according to their expression levels of paired upregulation of miR-31 and downregulation of miR-338-3p, survival time analysis revealed a significant difference based on miR-31-miR-338-3p interaction. These findings can facilitate the understanding of the biological meaning of miRNA-miRNA interactions with either the same or opposite expression trend.