MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2

Abstract

// Yan-Li Li 1, * , Ju Wang 1, * , Cai-Yan Zhang 1, * , Yu-Qing Shen 1 , Hui-Min Wang 1 , Lei Ding 1 , Yu-Chen Gu 1 , Jia-Tao Lou 2 , Xin-Tai Zhao 3 , Zhong-Liang Ma 1 , You-Xin Jin 1 1 School of Life Sciences, Shanghai University, Shanghai 200444, China 2 Department of Laboratory Medicine, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200030, China 3 Shanghai Shines Pharmaceuticals Co., Ltd., Shanghai 200032, China * These authors contributed equally to this work Correspondence to: You-Xin Jin, email: jinyouxin@shu.edu.cn Zhong-Liang Ma, email: zlma@shu.edu.cn Keywords: miR-146a-5p, non-small cell lung cancer, tumor suppressor gene, cell cycle, CCND1 Received: March 02, 2016      Accepted: June 03, 2016      Published: August 03, 2016 ABSTRACT Previous studies have indicated that miR-146a-5p acts as an oncogene in several types of cancer, yet a tumor suppressor gene in others. In non-small cell lung cancer (NSCLC), one report showed that it was downregulated and played the role of tumor suppressor. However, another study showed that miR-146a-5p was overexpressed in the serum of NSCLC patients compared to healthy controls. Therefore, it is obvious that further study of the function of miR-146a-5p in NSCLC is necessary to fully understand its importance. Herein, we have verified that miR- 146a- 5p acts as a tumor suppressor in NSCLC. Our data revealed that the expression level of miR-146a-5p was significantly decreased in several human NSCLC cell lines, and also less abundant in human NSCLC tissues, when compared with controls. Moreover, we observed that miR-146a-5p could suppress cell proliferation, both in vitro and in vivo . Our results also showed that miR-146a-5p directly targeted the 3′-UTR of CCND1 and CCND2 mRNAs as well as decreased their expression at both mRNA and protein levels, causing cell cycle arrest at the G0/G1 phase. Furthermore, siRNA-mediated downregulation of CCND1 or CCND2 yielded the same effects on proliferation and cell cycle arrest as miR-146a-5p upregulation did in the NSCLC cell lines. We confirmed that the expression of miR-146a-5p had negative relationship with CCND1 or CCND2. Besides, we also found that miR-146a-5p could inhibit tumor growth in xenograft mouse models, and CCND1 and CCND2 were downregulated in miR-146a-5p overexpressed xenograft tumor tissues. In summary, our results demonstrated that miR-146a-5p could suppress the proliferation and cell cycle progression in NSCLC cells by inhibiting the expression of CCND1 and CCND2.