MicroRNA-451 induces epithelial-mesenchymal transition in docetaxel-resistant lung adenocarcinoma cells by targeting proto-oncogene c-Myc
MicroRNA-451 induces epithelial-mesenchymal transition in docetaxel-resistant lung adenocarcinoma cells by targeting proto-oncogene c-Myc
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DOI：
10.1016/j.ejca.2014.09.008
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发表时间：
2014-11-01
影响因子：
8.4
通讯作者：
Chen, Longbang
中科院分区：
文献类型：
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作者：
Chen, Dongqin;Huang, Jiayuan;Chen, Longbang
据报道，上皮-间充质转化(EMT)在肿瘤转移和化疗耐药中起重要作用。然而，化疗诱导EMT的分子机制仍不清楚。据报道，microRNA(MiRNA)的表达和功能与肿瘤细胞的表型特征有关。为了研究miRNAs在化疗诱导的EMT中的作用，我们建立了两个多西紫杉醇耐药的肺腺癌(LAD)细胞模型(SPC-A1/DTX和H1299/DTX)，它们具有EMT样特性，并获得了更强的侵袭或迁移活性。在多西紫杉醇耐药的LAD细胞中，miR-451的表达显著下调，并且miR-451的重新表达可以逆转EMT向间充质-上皮转化(MET)的转变，并在体内外抑制多西紫杉醇耐药的LAD细胞的侵袭和转移。原癌基因c-Myc被确定为miR-451的直接和功能靶点，进一步的研究证实，c-Myc的过度表达导致细胞外信号调节激酶(ERK)依赖的糖原合成酶-3β(GSK-3β)失活并随后激活蜗牛，这是由于miR-451缺失而导致的EMT表型的获得所必需的。此外，与紫杉醇敏感的LAD组织相比，多西紫杉醇无反应的LAD组织中c-Myc的表达显著上调，其表达与miR-451的表达呈负相关。本研究首次报道miR-451/c-Myc/ERK/GSK-3β信号轴参与了多西紫杉醇耐药LAD细胞EMT表型的获得，提示重新表达miR-451或靶向c-Myc将是治疗化疗耐药LAD患者的一种潜在策略。(C)2014爱思唯尔有限公司。保留所有权利。
Epithelial-mesenchymal transition (EMT) has been reported to play a significant role in tumour metastasis as well as chemoresistance. However, the molecular mechanisms involved in chemotherapy-induced EMT are still unclear. MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumour cells. To investigate the roles of miRNAs in chemotherapy-induced EMT, we established two docetaxel-resistant lung adenocarcinoma (LAD) cell models (SPC-A1/DTX and H1299/DTX), which display EMT-like properties and gain increased invasion or migration activity. MiR-451 was found to be significantly downregulated in docetaxel-resistant LAD cells, and reexpression of miR-451 could reverse EMT to mesenchymal-epithelial transition (MET) and inhibit invasion and metastasis of docetaxel-resistant LAD cells both in vitro and in vivo. The proto-oncogene c-Myc was identified as a direct and functional target of miR-451, and further researches confirmed that overexpression of c-Myc which induced extracellular-signal-regulated kinase (ERK)-dependent glycogen synthase kinase-3 beta (GSK-3 beta) inactivation and subsequent snail activation is essential for acquisition of EMT phenotype induced by loss of miR-451. Furthermore, c-Myc was significantly upregulated in docetaxel-non-responding LAD tissues in comparison with docetaxel-responding tissues, and its expression was inversely correlated with miR-451 expression. This study first reported the involvement of miR-451/c-Myc/ERK/GSK-3 beta signalling axis in the acquisition of EMT phenotype in docetaxel-resistant LAD cells, suggesting that re-expression of miR-451 or targeting c-Myc will be a potential strategy for the treatment of chemoresistant LAD patients. (C) 2014 Elsevier Ltd. All rights reserved.