Posttranscriptional silencing of the lncRNA MALAT1 by miR-217 inhibits the epithelial-mesenchymal transition via enhancer of zeste homolog 2 in the malignant transformation of HBE cells induced by cigarette smoke extract
Posttranscriptional silencing of the lncRNA MALAT1 by miR-217 inhibits the epithelial-mesenchymal transition via enhancer of zeste homolog 2 in the malignant transformation of HBE cells induced by cigarette smoke extract
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miR-217 对 lncRNA MALAT1 的转录后沉默通过 zeste 同源物 2 的增强子抑制香烟烟雾提取物诱导的 HBE 细胞恶性转化中的上皮-间质转化
DOI：
10.1016/j.taap.2015.09.016
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发表时间：
2015-12-01
影响因子：
3.8
通讯作者：
Liu, Qizhan
中科院分区：
文献类型：
--
作者：
Lu, Lu;Luo, Fei;Liu, Qizhan
肺癌被认为是癌症相关死亡的主要原因，而吸烟是肺癌发展的最大危险因素之一。然而，吸烟诱发肺癌的机制尚不清楚。本研究调查了miRNA （miR-217）对lncRNA （MALAT1）水平的影响，并研究了这些因素在香烟烟雾提取物（CSE）诱导的人支气管上皮细胞上皮-间质转化（EMT）中的作用。在这些细胞中，CSE导致miR-217水平降低，lncRNA MALAT1水平升高。用模拟物过表达miR-217减弱了cse诱导的MALAT1水平的升高，通过抑制剂降低了miR-217水平，增强了MALAT1的表达。此外，cse诱导的MALAT1表达增加被miR-217模拟物阻断，表明miR-217负性调节MALAT1表达。MALAT1的敲低逆转了cse诱导的EZH2 （zeste同源物增强子2）和H3K27me3水平的升高。除了从上皮到梭状间质形态的改变外，慢性暴露于CSE的HBE细胞增加了EZH2、H3K27me3、vimentin和N-cadherin的水平，并降低了E-cadherin的水平，这种效应被MALAT1 siRNA或EZH2 siRNA逆转。结果表明，miR-217通过MALAT1调控EZH2/H3K27me3参与了cse诱导的EMT和HBE细胞的恶性转化。miR-217对MALAT1的转录后沉默通过EZH2提供了ncrna与EMT之间的联系，并建立了cse诱导的肺癌发生机制。(C) 2015爱思唯尔公司版权所有。
Lung cancer is regarded as the leading cause of cancer-related deaths, and cigarette smoking is one of the strongest risk factors for the development of lung cancer. However, the mechanisms for cigarette smoke-induced lung carcinogenesis remain unclear. The present study investigated the effects of an miRNA (miR-217) on levels of an lncRNA (MALAT1) and examined the role of these factors in the epithelial-mesenchymal transition (EMT) induced by cigarette smoke extract (CSE) in human bronchial epithelial (HBE) cells. In these cells, CSE caused decreases of miR-217 levels and increases in lncRNA MALAT1 levels. Over-expression of miR-217 with a mimic attenuated the CSE-induced increase of MALAT1 levels, and reduction of miR-217 levels by an inhibitor enhanced expression of MALAT1. Moreover, the CSE-induced increase of MALAT1 expression was blocked by an miR-217 mimic, indicating that miR-217 negatively regulates MALAT1 expression. Knockdown of MALAT1 reversed CSE-induced increases of EZH2 (enhancer of zeste homolog 2) and H3K27me3 levels. In addition to the alteration from epithelial to spindle-like mesenchymal morphology, chronic exposure of HBE cells to CSE increased the levels of EZH2, H3K27me3, vimentin, and N-cadherin and decreased E-cadherin levels, effects that were reversed by MALAT1 siRNA or EZH2 siRNA. The results indicate that miR-217 regulation of EZH2/H3K27me3 via MALAT1 is involved in CSE-induced EMT and malignant transformation of HBE cells. The posttranscriptional silencing of MALAT1 by miR-217 provides a link, through EZH2, between ncRNAs and the EMT and establishes a mechanism for CSE-induced lung carcinogenesis. (C) 2015 Elsevier Inc. All rights reserved.