microRNA Dysregulation in Prostate Cancer: Network Analysis Reveals Preferential Regulation of Highly Connected Nodes

microRNAs (miRNAs) are small RNAs shown to contribute to a number of cellular processes including cell growth, differentiation, and apoptosis. MiRNAs regulate gene expression of their targets post-transcriptionally by binding to messenger RNA (mRNA), causing translational inhibition or mRNA degradation. Dysregulation of miRNA expression can promote cancer formation and progression. Research has largely focused on the function and expression of single miRNAs. However, complex physiological processes require the interaction, regulation and coordination of many molecules including miRNAs and proteins. Highly connected molecules often serve important roles in the cell. A proteinprotein interaction network of established miRNA targets confirmed these proteins to be highly connected and essential to the cell, affecting tumorigenesis, cell growth/proliferation, cellular death, cell assembly, and maintenance pathways. This analysis showed that miRNAs contribute to the overall health of the prostate, and their aberrant expression destabilized homeostatic balance. This integrative network approach can reveal important miRNAs and proteins in prostate cancer that will be useful to identify specific disease biomarkers, which may be used as targets for therapeutics or drugs in themselves. Introduction. - Cancer is a highly heterogeneous, multifactorial disease that results from numerous genetic mutations, aberrant gene expression, and microRNA (miRNA) dysregulation (1). Prostate cancer (CaP) is the second leading cause of cancer related deaths of men in the United States with 193,000 men diagnosed in 2009. It is predicted that nearly 27,000 will eventually succumb to the disease, and likely that one of every six men will develop CaP during their lifetime. A variety of genetic and epigenetic factors such as age, race, heredity, diet, sexual frequency, and physical activity are known to influence the development of prostate tumors (2). In recent years, miRNAs have emerged as an important class of non-coding RNAs that influence post-transcriptional protein levels. In the presence of external cues and environmental stressors, miRNAs have the ability to induce rapid changes in the proteome allowing the cell to respond in a rapid, more precise, and energy-efficient mechanism (3). Numerous cellular processes are affected by miRNA, including differentiation, growth/hypertrophy, cell-cycle control, and apoptosis (4). Mature miRNAs are ca. 22 nucleotides in length and regulate protein levels by binding mostly to the 3'-untranslated region (3'-UTR) of a messenger RNA, inducing translational