Tumor suppressive microRNA-124a inhibits sternness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14
Tumor suppressive microRNA-124a inhibits sternness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14
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肿瘤抑制性 microRNA-124a 通过靶向泛素特异性蛋白酶 14 抑制非小细胞肺癌细胞的 Sternness 并增强吉非替尼敏感性
DOI：
10.1016/j.canlet.2018.04.022
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Fu, Da
中科院分区：
文献类型：
--
作者：
Yu, Fei;Liu, Ji-Bin;Fu, Da
越来越多的证据表明，microRNAs （miRNAs）在癌症干细胞（CSC）诱导的非小细胞肺癌（NSCLC）的进展和治疗耐药中通过直接调节各自的靶点发挥重要的功能作用。本研究发现，与正常肺细胞和组织相比，hsa-miR-124a在NSCLC细胞系SPC-A1和NCI-H1650以及NSCLC组织的球体形成过程中下调。hsa-miR-124a表达较低的患者总生存期（OS）和无进展生存期（PFS）较短。此外，泛素特异性蛋白酶14 （USP14）被证实是hsa-miR-124a的直接靶点。此外，伴随低hsa-miR-124a表达和高USP14表达与NSCLC患者中位OS和PFS较短相关。细胞功能分析证实肿瘤抑制因子hsa-miR-124a通过抑制其靶基因USP14负向调节细胞生长和自我更新，促进肺癌干细胞凋亡和吉非替尼敏感性。我们的研究结果首次证明USP14是hsamiR-124a的直接靶点，hsa-miR-124a通过靶向USP14抑制NSCLC细胞的严厉性并增强吉非替尼的敏感性。因此，hsa-miR-124a和USP14可能作为肿瘤生物标志物用于非小细胞肺癌的诊断和治疗。(C) 2018 Elsevier B.V.版权所有
Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR-124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsamiR-124a, and that hsa-miR-124a inhibits sternness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC. (C) 2018 Elsevier B.V. All rights reserved.