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The expression of miRNAs in cancer has been widely studied and has allowed the definition of oncomirs and oncosuppressors. We note that it is often underestimated that many mRNAs are expressed, but translationally silent. In spite of this, systematic identification of miRNAs in equilibrium with their target mRNAs on polysomes has not been widely exploited. To identify biologically active oncomirs, we performed a screen for miRNAs acting on the polysomes of malignant mesothelioma (MPM) cells. Only a small percentage of expressed miRNAs physically associated with polysomes. On polysomes, we identified miRNAs already characterized in MPM, as well as novel ones like miR-24-3p, which acted as a promigratory miRNA in all cancer cells tested. miR-24-3p positively regulated Rho-GTP activity, and inhibition of miR-24-3p reduced growth in MPM cells. Analysis of miR-24-3p common targets, in two mesothelioma cell lines, identified a common subset of downregulated genes. These same genes were downregulated during the progression of multiple cancer types. Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibits Rho-GTP activity. Overexpression of miR-24-3p only partially abrogated cingulin mRNA, but completely abrogated cingulin protein, confirming its action via translational repression. We suggest that miR-24-3p is an oncomir and speculate that identification of polysome-associated miRNAs efficiently sorts out biologically active miRNAs from inactive ones. Significance: Subcellular localization of miRNAs may predict their role in cancer and identify novel oncogenic miRNAs involved in cancer progression. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5741/F1.large.jpg Cancer Res; 78(20); 5741-53. ©2018 AACR .

A Polysome-Based microRNA Screen Identifies miR-24-3p as a Novel Promigratory miRNA in Mesothelioma