Multifaceted enrichment analysis of RNA-RNA crosstalk reveals cooperating micro-societies in human colorectal cancer

Nucleic Acids Res. 2016 May 19;44(9):4025-36. doi: 10.1093/nar/gkw245. Epub 2016 Apr 11.


Alterations in the balance of mRNA and microRNA (miRNA) expression profiles contribute to the onset and development of colorectal cancer. The regulatory functions of individual miRNA-gene pairs are widely acknowledged, but group effects are largely unexplored. We performed an integrative analysis of mRNA-miRNA and miRNA-miRNA interactions using high-throughput mRNA and miRNA expression profiles obtained from matched specimens of human colorectal cancer tissue and adjacent non-tumorous mucosa. This investigation resulted in a hypernetwork-based model, whose functional backbone was fulfilled by tight micro-societies of miRNAs. These proved to modulate several genes that are known to control a set of significantly enriched cancer-enhancer and cancer-protection biological processes, and that an array of upstream regulatory analyses demonstrated to be dependent on miR-145, a cell cycle and MAPK signaling cascade master regulator. In conclusion, we reveal miRNA-gene clusters and gene families with close functional relationships and highlight the role of miR-145 as potent upstream regulator of a complex RNA-RNA crosstalk, which mechanistically modulates several signaling pathways and regulatory circuits that when deranged are relevant to the changes occurring in colorectal carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks / genetics*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • MAP Kinase Signaling System / genetics
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Multigene Family / genetics*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / metabolism*


  • MIRN145 microRNA, human
  • MicroRNAs
  • RNA, Messenger