microRNA-451 regulates macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells

Abstract

Purpose:microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression.R ecent evidence has shown that somemiRNAs can act as oncogenes or tumor suppressors.This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer. Experimental Design: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation.We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data. Results:The results revealed that down-regulation ofmiR-451was associatedwithworse prognosis. m iR-451was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues.O verexpression of miR-451in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy.Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451.In fact, overexpression of miR- 451down-regulatedmRNA and proteinlevels ofMIF and decreased expression of reporter genes with MIF target sequences.M oreover, we found a significant inverse correlation between miR- 451and MIF expression in tumoral gastric biopsies. Conclusions:These findings support the role ofmiR-451as a regulatorof cancerproliferationand opennewperspectives for thedevelopmentof effectivetherapies forchemoradioresistantcancers