Department of Thoracic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Oncol Rep. 2017 Dec;38(6):3347-3354. doi: 10.3892/or.2017.6056. Epub 2017 Oct 24.
Drug resistance is the major factor contributing to the failure of chemotherapy in non-small cell lung cancer (NSCLC) patients. Emerging evidence suggests that autophagy plays a vital role in the chemoresistance of many types of tumors. However, the exact mechanism underlying the chemoresistance of NSCLC is still elusive, and it is unclear whether lncRNA-XIST is involved in autophagy and chemoresistance of NSCLC. In the present study, we demonstrated that lncRNA-XIST was overexpressed in NSCLC tumor samples, and knockdown of lncRNA-XIST significantly decreased autophagy by regulation of ATG7 as determined by qPCR and by western blotting. Furthermore, we found that miR-17 was upregulated following knockdown of lncRNA-XIST, and miR-17 mimics decreased the protein levels of ATG7 by directly targeting the 3'-untranslated region of ATG7 mRNA as determined by RT-qPCR and by western blotting. Furthermore, we found that the expression level of lncRNA-XIST was markedly increased in cisplatin-resistant A549 cells as determined by q-PCR. Knockdown of lncRNA-XIST restored the chemosensitivity of cisplatin-resistant A549 cells to cisplatin, which was reversed by miR-17 inhibitor and overexpression of ATG7 as determined by CCK8 assays. This study provides evidence that lncRNA-XIST may be a potential marker of poor response to cisplatin chemotherapy in NSCLC patients and the pathway 'lncRNA-XIST/miR-17/autophagy' may be a promising target for patients with chemoresistant NSCLC.
耐药性是非小细胞肺癌（NSCLC）患者化疗失败的主要因素。新出现的证据表明，自噬在许多类型肿瘤的耐药性中起着至关重要的作用。然而，NSCLC 耐药的确切机制仍不清楚，lncRNA-XIST 是否参与 NSCLC 的自噬和耐药性也不清楚。在本研究中，我们证明 lncRNA-XIST 在 NSCLC 肿瘤样本中过表达，并且通过 qPCR 和 Western blot 确定 lncRNA-XIST 的敲低显着通过调节 ATG7 降低自噬。此外，我们发现 lncRNA-XIST 的敲低后 miR-17 上调，并且 miR-17 模拟物通过直接靶向 ATG7 mRNA 的 3'-非翻译区降低 ATG7 蛋白水平，如 RT-qPCR 和 Western blot 所示。此外，我们发现 q-PCR 显示 lncRNA-XIST 的表达水平在顺铂耐药的 A549 细胞中显着增加。lncRNA-XIST 的敲低恢复了顺铂耐药的 A549 细胞对顺铂的化疗敏感性，如 CCK8 测定所示，该敏感性被 miR-17 抑制剂和 ATG7 的过表达逆转。这项研究提供了证据表明，lncRNA-XIST 可能是非小细胞肺癌患者对顺铂化疗反应不良的潜在标志物，并且“lncRNA-XIST/miR-17/自噬”途径可能是治疗耐药性非小细胞肺癌患者的有前途的靶点。
