Lu Lu, Luo Fei, Liu Yi, Liu Xinlu, Shi Le, Lu Xiaolin, Liu Qizhan
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China.
Toxicol Appl Pharmacol. 2015 Dec 1;289(2):276-85. doi: 10.1016/j.taap.2015.09.016. Epub 2015 Sep 28.
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.
肺癌被视为癌症相关死亡的主要原因，而吸烟是肺癌发生的最强风险因素之一。然而，香烟烟雾诱导肺癌发生的机制仍不清楚。本研究调查了一种微小RNA（miR-217）对一种长链非编码RNA（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（HBE）细胞上皮-间质转化（EMT）中的作用。在这些细胞中，CSE导致miR-217水平降低和lncRNA MALAT1水平升高。用模拟物过表达miR-217减弱了CSE诱导的MALAT1水平升高，而用抑制剂降低miR-217水平则增强了MALAT1的表达。此外，miR-217模拟物阻断了CSE诱导的MALAT1表达增加，表明miR-217负向调节MALAT1表达。敲低MALAT1可逆转CSE诱导的EZH2（zeste同源物2增强子）和H3K27me3水平升高。除了从上皮形态转变为纺锤状间质形态外，HBE细胞长期暴露于CSE还增加了EZH2、H3K27me3、波形蛋白和N-钙黏蛋白的水平，并降低了E-钙黏蛋白水平，而MALAT1 siRNA或EZH2 siRNA可逆转这些作用。结果表明，miR-217通过MALAT1对EZH2/H3K27me3的调节参与了CSE诱导的HBE细胞EMT和恶性转化。miR-217对MALAT1的转录后沉默通过EZH2在非编码RNA与EMT之间建立了联系，并为CSE诱导的肺癌发生建立了一种机制。
