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

Abstract

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