Sun Cheng-Cao, Li Shu-Jun, Li De-Jia
Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China.
Wuhan Hospital for The Prevention and Treatment of Occupational Diseases, Wuhan, P. R. China.
Oncotarget. 2016 Jun 14;7(24):35960-35978. doi: 10.18632/oncotarget.8482.
Hsa-miRNA-134 (miR-134) has recently been discovered to have anticancer efficacy in different organs. However, the role of miR-134 on non-small cell lung cancer (NSCLC) is still ambiguous. In this study, we investigated the role of miR-134 on the development of NSCLC. The results indicated that miR-134 was significantly down-regulated in primary tumor tissues and very low levels were found in NSCLC cell lines. Ectopic expression of miR-134 in NSCLC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-134 induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-134 inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene CCND1 was revealed to be a putative target of miR-134, which was inversely correlated with miR-134 expression in NSCLC. Taken together, our results demonstrated that miR-134 played a pivotal role on NSCLC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic CCND1.
人源微小RNA-134（miR-134）最近被发现对不同器官具有抗癌功效。然而，miR-134在非小细胞肺癌（NSCLC）中的作用仍不明确。在本研究中，我们调查了miR-134在NSCLC发生发展中的作用。结果表明，miR-134在原发性肿瘤组织中显著下调，且在NSCLC细胞系中水平极低。通过细胞活力测定、集落形成测定和BrdU染色证实，在NSCLC细胞系中异位表达miR-134可显著抑制细胞生长，其机制是通过抑制细胞周期蛋白D1、细胞周期蛋白D2、细胞周期蛋白依赖性激酶4（CDK4）以及上调p57（Kip2）和p21（Waf1/Cip1）。此外，miR-134可诱导细胞凋亡，表现为关键凋亡蛋白裂解型半胱天冬酶-3上调，抗凋亡蛋白Bcl2下调。而且，miR-134通过抑制基质金属蛋白酶（MMP）-7和MMP-9来抑制细胞迁移和侵袭。进一步研究发现，癌基因CCND1是miR-134的一个假定靶点，其在NSCLC中的表达与miR-134呈负相关。综上所述，我们的结果表明，miR-134通过靶向致癌基因CCND1抑制细胞增殖、迁移、侵袭并促进凋亡，从而在NSCLC中发挥关键作用。
