As an important class of non-coding regulatory RNAs, microRNAs (miRNAs) play a key role in a range of biological processes. These molecules serve as post-transcriptional regulators of gene expression and their regulatory activity has been implicated in disease pathophysiology and pharmacological traits. We sought to investigate the impact of miRNAs on cellular proliferation to gain insight into the molecular basis of complex traits that depend on cellular growth, including, most prominently, cancer. We examined the relationship between miRNA expression and intrinsic cellular growth (iGrowth) in the HapMap lymphoblastoid cell lines derived from individuals of different ethnic backgrounds. We found a substantial enrichment for miRNAs (53 miRNAs, FDR < 0.05) correlated with cellular proliferation in pooled CEU (Caucasian of northern and western European descent) and YRI (individuals from Ibadan, Nigeria) samples. Specifically, 119 miRNAs (59 %) were significantly correlated with iGrowth in YRI; of these miRNAs, 18 were correlated with iGrowth in CEU. To gain further insight into the effect of miRNAs on cellular proliferation in cancer, we showed that over-expression of miR-22, one of the top iGrowth-associated miRNAs, leads to growth inhibition in an ovarian cancer cell line (SKOV3). Furthermore, over-expression of miR-22 down-regulates the expression of its target genes (MXI1 and SLC25A37) in this ovarian cancer cell line, highlighting an miRNA-mediated regulatory network potentially important for cellular proliferation. Importantly, our study identified miRNAs that can be used as molecular targets in cancer therapy.
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Acknowledgments We are grateful for the excellent technical support provided by Pharmacogenomics of anti-cancer agent research (Paar) group cell line core. this study was supported by national Institute of Health/national Cancer Institute grant (r21 Ca139278) and by national Institute of Health/national Institute of General Medical sciences grant (UO1GM61393). rsH also received support from national Institute of Health/national Institute of General Medical sciences grant (K08GM089941), Circle of service Foundation early Career Investigator award, University of Chicago Cancer Center support Grant (#P30 Ca14599), Breast Cancer sPOre Career Development award (Ca125183) a Conquer Cancer Foundation of asCO translational research Professorship award In Memory of Merrill J. egorin, MD, and pilot grant from national Institute of Health/national Center advancing translational sciences grant (Ul1rr024999).