Li Yan-Li, Wang Ju, Zhang Cai-Yan, Shen Yu-Qing, Wang Hui-Min, Ding Lei, Gu Yu-Chen, Lou Jia-Tao, Zhao Xin-Tai, Ma Zhong-Liang, Jin You-Xin
School of Life Sciences, Shanghai University, Shanghai 200444, China.
Department of Laboratory Medicine, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200030, China.
Oncotarget. 2016 Sep 13;7(37):59287-59298. doi: 10.18632/oncotarget.11040.
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 xengroft mouse models, and CCND1 and CCND2 were downregulated in miR-146a-5p overexpressed xengroft 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.
先前的研究表明，miR-146a-5p在几种类型的癌症中作为癌基因发挥作用，但在其他癌症中则作为肿瘤抑制基因。在非小细胞肺癌（NSCLC）中，一份报告显示它表达下调并发挥肿瘤抑制作用。然而，另一项研究表明，与健康对照相比，NSCLC患者血清中miR-146a-5p过表达。因此，显然有必要进一步研究miR-146a-5p在NSCLC中的功能，以充分了解其重要性。在此，我们已经证实miR-146a-5p在NSCLC中作为肿瘤抑制因子发挥作用。我们的数据显示，与对照相比，几种人NSCLC细胞系中miR-146a-5p的表达水平显著降低，并且在人NSCLC组织中也较少。此外，我们观察到miR-146a-5p在体外和体内均可抑制细胞增殖。我们的结果还表明，miR-146a-5p直接靶向CCND1和CCND2 mRNA的3'-UTR，并在mRNA和蛋白质水平上降低它们的表达，导致细胞周期停滞在G0/G1期。此外，siRNA介导的CCND1或CCND2下调对增殖和细胞周期停滞产生的影响与NSCLC细胞系中miR-146a-5p上调产生的影响相同。我们证实miR-146a-5p的表达与CCND1或CCND2呈负相关。此外，我们还发现miR-146a-5p可以抑制裸鼠模型中的肿瘤生长，并且在miR-146a-5p过表达的裸鼠肿瘤组织中CCND1和CCND2下调。总之，我们的结果表明，miR-146a-5p可以通过抑制CCND1和CCND2的表达来抑制NSCLC细胞的增殖和细胞周期进程。
