MicroRNA-138 acts as a tumor suppressor in non small cell lung cancer via targeting YAP1.
MicroRNA-138 acts as a tumor suppressor in non small cell lung cancer via targeting YAP1.
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MicroRNA-138 通过靶向 YAP1 作为非小细胞肺癌的肿瘤抑制因子
DOI：
10.18632/oncotarget.9480
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Liu ZQ
中科院分区：
文献类型：
--
作者：
Xiao L;Zhou H;Li XP;Chen J;Fang C;Mao CX;Cui JJ;Zhang W;Zhou HH;Yin JY;Liu ZQ
MicroRNA(MiR)-138被发现对不同人类肿瘤的生长和转移具有抑制作用。本研究旨在探讨miR-138在非小细胞肺癌(NSCLC)中的调控机制。我们应用实时定量聚合酶链式反应(qRT-PCR)检测了21例非小细胞肺癌组织和细胞系中miR-138的表达水平，并进行了生物信息学预测、荧光素酶报告基因分析和蛋白质印迹分析，以确定miR-138的靶基因。我们还应用细胞转染法、四甲基偶氮唑盐比色法、Transwell和伤口愈合实验来揭示miR-138在非小细胞肺癌细胞增殖和恶性转化中的作用。我们观察到，miR-138在非小细胞肺癌组织中的表达水平显著低于其匹配的邻近正常组织。与正常肺上皮细胞相比，在分化较差、晚期或有淋巴结转移的组织中，以及在几个非小细胞肺癌细胞系中，它的表达也下调。我们进一步确定YAP1是miR-138的直接靶基因，并观察到在NSCLC A549细胞中，miR-138负调控YAP1的蛋白水平。此外，miR-138过表达显著抑制A549细胞的生长、侵袭和迁移，而敲除miR-138则增强这些能力。进一步研究表明，与miR-138组相比，miR-138+YAP1组的细胞增殖能力更强，提示YAP1的过表达挽救了miR-138上调对NSCLC细胞增殖的抑制作用。然而，我们发现miR-138+YAP1组和miR-138组的细胞侵袭和迁移能力没有差异。最后，与癌旁正常组织相比，YAP1在非小细胞肺癌组织中的表达明显上调。其在NSCLC组织中的表达水平与miR-138的表达水平呈负相关。综上所述，我们的研究提示miR-138在NSCLC细胞的生长和转移中可能发挥抑制作用，至少部分是通过靶向YAP1来实现的。
MicroRNA (miR)-138 was found to have suppressive effects on the growth and metastasis of different human cancers. In this study, we aimed to investigate the regulatory mechanism of miR-138 in non-small cell lung cancer (NSCLC). We applied the Quantitative real-time PCR (qRT-PCR) to detect the miR-138 levels in NSCLC tissues (n=21) and cell lines, Bioinformatical predication, luciferase reporter assay and western blot to identify the target gene of miR-138. We also applied Cell transfection, MTT, transwell, and wound healing assays to reveal the role of miR-138 in NSCLC cell proliferation and malignant transformation. We observed that miR-138 expression level was significantly decreased in NSCLC tissues compared to their matched adjacent normal tissues. It was also downregulated in tissues with poor differentiation, advanced stage or lymph nodes metastasis, as well as in several NSCLC cell lines compared to normal lung epithelial cell. We further identified YAP1 as a direct target gene of miR-138, and observed that the protein level of YAP1 was negatively mediated by miR-138 in NSCLC A549 cells. Moreover, overexpression of miR-138 significantly inhibited A549 cell growth, invasion and migration, while knockdown of miR-138 enhanced such capacities. Further investigation showed that the cell proliferation capacity was higher in the miR-138+YAP1 group, when compared with that in the miR-138 group, suggesting that overexpression of YAP1 rescued the suppressive effects of miR-138 upregulation on NSCLC cell proliferation. However, we found no difference of cell invasion and migration capacities between miR-138+YAP1 group and miR-138 group. Finally, YAP1 was markedly upregulated in NSCLC tissues compared to their marched adjacent normal tissues. Its mRNA levels were reversely correlated with the miR-138 levels in NSCLC tissues. In summary, our study suggests that miR-138 may play a suppressive role in the growth and metastasis of NSCLC cells partly at least by targeting YAP1.
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