// Shanqi Guo 1, * , Peiying Yang 1, * , Xingkang Jiang 2, * , Xiaojiang Li 1 , Yuanyuan Wang 1 , Xin Zhang 1 , Binxu Sun 1 , Yao Zhang 1 , Yingjie Jia 1 1 Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China 2 Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China * These authors contributed equally to this work Correspondence to: Yingjie Jia, email: Yingjie_jia@126.com Keywords: non-small cell lung cancer, miR-506-3p, COTL1, UCA1, LncRNA Received: July 22, 2016 Accepted: November 14, 2016 Published: November 22, 2016 ABSTRACT Although previous studies suggested that microRNA-506-3p (miR-506-3p) was frequently downregulated, and functioned as a tumor suppressor in several cancers, the biological role and intrinsic regulatory mechanisms of miR-506-3p in non-small cell lung cancer (NSCLC) remain elusive. The present study found miR-506-3p expression was downregulated in advanced NSCLC tissues and cell lines. The expression of miR-506-3p in NSCLC was inversely correlated with larger tumor size, advanced TNM stage and lymph node metastasis. In addition, we also found patients with lower expression of miR-506-3p had a poor prognosis than those patients with higher expression of miR-506-3p. Function studies demonstrated that aberrant miR-506-3p expression modulates tumor cell growth, cell mobility, cell migration and invasion in vitro and in vivo . Mechanistic investigations manifested that coactosin-like protein 1 (COTL1) was a direct downstream target of miR-506-3p. Knockdown of COTL1 mimicked the tumor-suppressive effects of miR-506-3p overexpression in A549 cells, whereas COTL1 overexpression enhanced the tumorigenic function in HCC827 cells. Importantly, we also found GATA3 transcriptionally actives miR-506-3p expression, and the long non-coding RNA urothelial carcinoma-associated 1 (UCA1) exerts oncogenic function in NSCLC by competitively ‘sponging’ miRNA-506. Together, our combined results elucidated genetic and epigenetic silencing of miR-506-3p enhances COTL1 oncogene expression to foster NSCLC progression.