Data from Genomic Loss of <i>miR-486</i> Regulates Tumor Progression and the <i>OLFM4</i> Antiapoptotic Factor in Gastric Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC).</p><p><b>Experimental Design:</b> Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors.</p><p><b>Results:</b> Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified <i>hsa</i>-<i>miR-486</i> (<i>miR-486</i>) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of <i>miR-486</i> expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting <i>miR-486</i> expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the <i>miR-486</i> locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting <i>miR-486</i>, consistent with <i>miR-486</i> playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein <i>OLFM4</i> as a potential <i>miR-486</i> target. Restoring <i>miR-486</i> expression in GC cells decreased endogenous <i>OLFM4</i> transcript and protein levels, and also inhibited expression of luciferase reporters containing an <i>OLFM4</i> 3′ untranslated region with predicted <i>miR-486</i> binding sites. Supporting the biological relevance of <i>OLFM4</i> as a <i>miR-486</i> target, proliferation in GC cells was also significantly reduced by <i>OLFM4</i> silencing.</p><p><b>Conclusions:</b><i>miR-486</i> may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of <i>OLFM4</i>. <i>Clin Cancer Res; 17(9); 2657–67. ©2011 AACR</i>.</p></div>