MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2.
MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2.
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DOI：
10.18632/oncotarget.11040
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发表时间：
2016-09-13
期刊：
影响因子：
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通讯作者：
Jin YX
中科院分区：
文献类型：
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作者：
Li YL;Wang J;Zhang CY;Shen YQ;Wang HM;Ding L;Gu YC;Lou JT;Zhao XT;Ma ZL;Jin YX
先前的研究表明，miR-146a-5p在几种类型的癌症中作为致癌基因，但在其他类型的癌症中作为肿瘤抑制基因。在非小细胞肺癌（non-small cell lung cancer， NSCLC）中，有报道显示其下调，发挥抑瘤作用。然而，另一项研究表明，与健康对照组相比，miR-146a-5p在NSCLC患者的血清中过表达。因此，为了充分了解miR-146a-5p在NSCLC中的重要性，显然有必要进一步研究其功能。本文中，我们已经证实miR- 146a- 5p在非小细胞肺癌中起肿瘤抑制作用。我们的数据显示，与对照组相比，miR-146a-5p在几种人NSCLC细胞系中的表达水平显著降低，在人NSCLC组织中的表达水平也较低。此外，我们观察到miR-146a-5p在体外和体内都可以抑制细胞增殖。我们的研究结果还表明，miR-146a-5p直接靶向CCND1和CCND2 mRNA的3 ' -UTR，并在mRNA和蛋白水平上降低它们的表达，导致细胞周期阻滞在G0/G1期。此外，sirna介导的CCND1或CCND2的下调与miR-146a-5p上调在NSCLC细胞系中对增殖和细胞周期阻滞产生相同的影响。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xengroft小鼠模型的肿瘤生长，并且在miR-146a-5p过表达的xengroft肿瘤组织中，CCND1和CCND2下调。综上所述，我们的研究结果表明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。
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.