Yang Yonghua, Huang Jingyu, Xie Nianlin, Huang Hu, Xu Shaogan, Cai Jun, Qi Shuai
Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China.
Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China.
Onco Targets Ther. 2018 Jun 22;11:3649-3657. doi: 10.2147/OTT.S165290. eCollection 2018.
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase () is identified as an important pathogenic factor in patients with non-small-cell lung cancer (NSCLC) and could induce a stem-like phenotype in NSCLC cells. Crizotinib is commonly used for EML4-ALK NSCLC treatment, but its acquired resistance results in tumor recurrence. Long intergenic noncoding RNA, regulator of reprogramming (lincROR) is related to the acquisition and maintenance of self-renewal and stemness features of cancer stem cells. It has been documented that lincROR is implicated in chemoresistance. However, the correlations of lincROR and in stem cell-like properties and of lincROR and crizotinib resistance in NSCLC cells are yet to be elucidated.
In the present study, we investigated the expression profile of lincROR in EML-ALK NSCLC tissues, and the potential role of lincROR in prognosis was then analyzed. Subsequently, its association with stem cell-like properties of EML-ALK NSCLC cells was determined. Furthermore, the correlation of lincROR with crizotinib and the effects of lincROR and crizotinib on cell viability of EML4-ALK NSCLC cells were all explored.
The results showed that lincROR expression was upregulated in EML4-ALK NSCLC tissues relative to EML4-ALK NSCLC tissues. Low-expressed lincROR was related to a favorable prognosis of patients with EML-ALK NSCLC. lincROR overexpression could enhance the stemness features of EML-ALK NSCLC cells which were repressed by ALK knockdown.
We found that lincROR expression was significantly inhibited because of the increased concentration of crizotinib in EML4-ALK NSCLC cells. Furthermore, lincROR overexpression increased cell viability of EML4-ALK NSCLC cells, which was impaired by crizotinib. Conjointly, these results suggested the important role of lincROR in EML-ALK NSCLC. lincROR may serve as a potential therapeutic target to overcome chemotherapy resistance in EML-ALK NSCLC.
棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶（EML4-ALK）被确定为非小细胞肺癌（NSCLC）患者的重要致病因素，并且可在NSCLC细胞中诱导干细胞样表型。克唑替尼常用于EML4-ALK NSCLC的治疗，但其获得性耐药会导致肿瘤复发。长链基因间非编码RNA，重编程调节因子（lincROR）与癌症干细胞自我更新和干性特征的获得及维持有关。已有文献记载lincROR与化疗耐药有关。然而，lincROR与NSCLC细胞干细胞样特性以及lincROR与克唑替尼耐药之间的相关性尚待阐明。
在本研究中，我们调查了lincROR在EML-ALK NSCLC组织中的表达谱，然后分析了lincROR在预后中的潜在作用。随后，确定了其与EML-ALK NSCLC细胞干细胞样特性的关联。此外，还探讨了lincROR与克唑替尼的相关性以及lincROR和克唑替尼对EML4-ALK NSCLC细胞活力的影响。
结果显示，相对于EML4-ALK NSCLC组织，lincROR在EML4-ALK NSCLC组织中的表达上调。低表达的lincROR与EML-ALK NSCLC患者的良好预后相关。lincROR过表达可增强EML-ALK NSCLC细胞的干性特征，而这种特征会被ALK敲低所抑制。
我们发现，由于克唑替尼在EML4-ALK NSCLC细胞中的浓度增加，lincROR表达受到显著抑制。此外，lincROR过表达增加了EML4-ALK NSCLC细胞的活力，而克唑替尼会损害这种活力。综合来看，这些结果表明lincROR在EML-ALK NSCLC中起重要作用。lincROR可能作为克服EML-ALK NSCLC化疗耐药的潜在治疗靶点。
