Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210002, China.
Eur J Cancer. 2014 Nov;50(17):3050-67. doi: 10.1016/j.ejca.2014.09.008. Epub 2014 Oct 10.
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 re-expression 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-3β) 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-3β 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.
上皮-间充质转化（EMT）已被报道在肿瘤转移以及化疗耐药中发挥重要作用。然而，涉及化疗诱导的 EMT 的分子机制仍不清楚。miRNA（miRNA）的表达和功能已被报道有助于肿瘤细胞的表型特征。为了研究 miRNA 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肺腺癌细胞模型（SPC-A1/DTX 和 H1299/DTX），它们表现出 EMT 样特性，并获得了增加的侵袭或迁移活性。研究发现，miR-451 在多西紫杉醇耐药的 LAD 细胞中显著下调，miR-451 的重新表达可以逆转 EMT 为间充质-上皮转化（MET），并抑制多西紫杉醇耐药 LAD 细胞的体外和体内侵袭和转移。原癌基因 c-Myc 被鉴定为 miR-451 的直接和功能靶标，进一步的研究证实，c-Myc 的过表达诱导细胞外信号调节激酶（ERK）依赖性糖原合酶激酶-3β（GSK-3β）失活和随后的 snail 激活，对于由 miR-451 缺失诱导的 EMT 表型的获得是必不可少的。此外，与多西紫杉醇反应性组织相比，多西紫杉醇非反应性 LAD 组织中 c-Myc 的表达显著上调，并且其表达与 miR-451 的表达呈负相关。本研究首次报道了 miR-451/c-Myc/ERK/GSK-3β 信号轴参与多西紫杉醇耐药 LAD 细胞 EMT 表型的获得，提示重新表达 miR-451 或靶向 c-Myc 将成为治疗化疗耐药 LAD 患者的潜在策略。
