<p>microRNA-612 suppresses the malignant development of non-small-cell lung cancer by directly targeting bromodomain-containing protein 4</p>

Abstract

<b>Background:</b> Aberrant expression of microRNAs (miRNAs) in non-small-cell lung cancer (NSCLC) has been reported. Dysregulation of miRNAs exerts tumor-suppressing or tumor-promoting actions on the pathology and biological behaviors of NSCLC. miR-612 is associated with many types of human cancer; however, the expression, potential roles, and regulatory mechanisms of miR-612 in NSCLC remain unclear. <b>Material and methods:</b> Here, the expression level of miR-612 in NSCLC tissue specimens and a panel of cell lines were evaluated by RT-qPCR. Cell-Counting Kit 8, flow cytometry, Transwell migration and invasion, and <i>in vivo</i> tumor growth assays were performed to determine the functional role of miR-612 in malignant phenotypes of NSCLC cells. The molecular mechanism underlying the tumor-suppressive roles of miR-612 in NSCLC was investigated. <b>Results:</b> miR-612 was expressed at low levels in NSCLC, and low miR-612 expression was significantly correlated with TNM stage and lymph node metastasis. NSCLC patients with low miR-612 expression had shorter overall survival rate than those with high levels. Exogenous miR-612 expression decreased proliferation, migration, and invasion, and promoted apoptosis of NSCLC cells <i>in vitro</i>. miR-612 upregulation hindered NSCLC tumor growth <i>in vivo</i>. Bromodomain-containing protein 4 (<i>BRD4</i>) was confirmed as a direct target gene of miR-612 in NSCLC cells. BRD4 was obviously overexpressed in human NSCLC tissues and inverse correlated with miR-612 expression. Inhibition of BRD4 expression simulated the tumor-suppressive functions of miR-612 overexpression in NSCLC cells. Reintroduction of miR-612 expression abrogated the miR-612-mediated suppressive effects on NSCLC cells. BRD4 upregulation inhibited activation of the PI3K/Akt pathway in NSCLC cells <i>in vitro</i> and <i>in vivo</i>. <b>Conclusion:</b> This study supports the first evidence that miR-612 exerts tumor-suppressive roles in the aggressive behaviors of NSCLC cells <i>in vitro</i> and <i>in vivo</i> through direct targeting BRD4 and deactivating the PI3K/Akt pathway. Thus, miR-612 might be a promising target for anticancer therapies in patients with NSCLC.