miRNA-mRNA Correlation-Network Modules in Human Prostate Cancer and the Differences between Primary and Metastatic Tumor Subtypes

PLOS ONE, June 2012

22768240

Wensheng Zhang, Andrea Edwards, Wei Fan, Erik K. Flemington, Kun Zhang

Recent studies have shown the contribution of miRNAs to cancer pathogenesis. Prostate cancer is the most commonly diagnosed cancer in men. Unlike other major types of cancer, no single gene has been identified as being mutated in the majority of prostate tumors. This implies that the expression profiling of genes, including the non-coding miRNAs, may substantially vary across individual cases of this cancer. The within-class variability makes it possible to reconstruct or infer disease-specific miRNA-mRNA correlation and regulatory modular networks using high-dimensional microarray data of prostate tumor samples. Furthermore, since miRNAs and tumor suppressor genes are usually tissue specific, miRNA-mRNA modules could potentially differ between primary prostate cancer (PPC) and metastatic prostate cancer (MPC). We herein performed an in silico analysis to explore the miRNA-mRNA correlation network modules in the two tumor subtypes. Our analysis identified 5 miRNA-mRNA module pairs (MPs) for PPC and MPC, respectively. Each MP includes one positive-connection (correlation) module and one negative-connection (correlation) module. The number of miRNAs or mRNAs (genes) in each module varies from 2 to 8 or from 6 to 622. The modules discovered for PPC are more informative than those for MPC in terms of the implicated biological insights. In particular, one negative-connection module in PPC fits well with the popularly recognized miRNA-mediated post-transcriptional regulation theory. That is, the 3'UTR sequences of the involved mRNAs (∼620) are enriched with the target site motifs of the 7 modular miRNAs, has-miR-106b, -191, -19b, -92a, -92b, -93, and -141. About 330 GO terms and KEGG pathways, including TGF-beta signaling pathway that maintains tissue homeostasis and plays a crucial role in the suppression of the proliferation of cancer cells, are over-represented (adj.p<0.05) in the modular gene list. These computationally identified modules provide remarkable biological evidence for the interference of miRNAs in the development of prostate cancers and warrant additional follow-up in independent laboratory studies.