Li Liang-Liang, Qu Li-Li, Fu Han-Jiang, Zheng Xiao-Fei, Tang Chuan-Hao, Li Xiao-Yan, Chen Jian, Wang Wei-Xia, Yang Shao-Xing, Wang Lin, Zhao Guan-Hua, Lv Pan-Pan, Zhang Min, Lei Yang-Yang, Qin Hai-Feng, Wang Hong, Gao Hong-Jun, Liu Xiao-Qing
Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
Department of Oncology, 309th Hospital of PLA, Beijing, China.
Oncotarget. 2017 Jul 11;8(28):45399-45414. doi: 10.18632/oncotarget.17535.
Circulating microRNAs are potential diagnostic and predictive biomarkers, but have not been investigated for patients with anaplastic lymphoma kinase (ALK)-positive lung cancer. In this exploratory study, we sought to identify potential plasma biomarkers for ALK-positive non-small cell lung cancer (NSCLC). A microRNA microarray was used to select ALK-related microRNAs in ALK-positive NSCLC (n = 3), ALK-negative NSCLC (n = 3), and healthy subjects (n = 3). Plasma levels of 21 microRNAs were differentially expressed for ALK-positive and ALK-negative NSCLC, including 14 down-regulated and 7 up-regulated microRNAs. We also identified 5s rRNA as the most stable endogenous control gene using geNorm and NormFinder algorithms. Candidate microRNAs in plasma from ALK-positive (n = 41) and ALK-negative NSCLC patients (n = 32) were quantified using real-time reverse transcriptase quantitative polymerase chain reaction. The expression levels of miR-28-5p, miR-362-5p, and miR-660-5p were all down-regulated in ALK-positive NSCLC, compared with ALK-negative NSCLC. The areas under the receiver operating characteristic curves of miR-28-5p, miR-362-5p, miR-660-5p, and 3-microRNAs panel were 0.873, 0.673, 0.760, and 0.876, respectively. The positive predictive values of miR-28-5p, miR-362-5p, and miR-660-5p were 96.43%, 80.77%, and 83.87%, respectively. Increased plasma levels of miR-660-5p after crizotinib treatment predicted good tumor response (p = 0.012). The pre-crizotinib levels of miR-362-5p were significantly associated with progression-free survival (p = 0.015). Thus, in this preliminary investigation, we identified a potential panel of 3 microRNAs for distinguishing between patients with ALK-positive and ALK-negative NSCLC. We also identified miR-660-5p and miR-362-5p as potential predictors for response to crizotinib treatment.
循环微RNA是潜在的诊断和预测生物标志物，但尚未在间变性淋巴瘤激酶（ALK）阳性肺癌患者中进行研究。在这项探索性研究中，我们试图鉴定ALK阳性非小细胞肺癌（NSCLC）的潜在血浆生物标志物。使用微RNA微阵列在ALK阳性NSCLC（n = 3）、ALK阴性NSCLC（n = 3）和健康受试者（n = 3）中选择与ALK相关的微RNA。21种微RNA的血浆水平在ALK阳性和ALK阴性NSCLC中差异表达，包括14种下调和7种上调的微RNA。我们还使用geNorm和NormFinder算法将5s rRNA鉴定为最稳定的内参基因。使用实时逆转录定量聚合酶链反应对ALK阳性（n = 41）和ALK阴性NSCLC患者（n = 32）血浆中的候选微RNA进行定量。与ALK阴性NSCLC相比，miR-28-5p、miR-362-5p和miR-660-5p的表达水平在ALK阳性NSCLC中均下调。miR-28-5p、miR-362-5p、miR-660-5p和3种微RNA组合的受试者工作特征曲线下面积分别为0.873、0.673、0.760和0.876。miR-28-5p、miR-362-5p和miR-660-5p的阳性预测值分别为96.43%、80.77%和83.87%。克唑替尼治疗后血浆miR-660-5p水平升高预示肿瘤反应良好（p = 0.012）。克唑替尼治疗前miR-362-5p水平与无进展生存期显著相关（p = 0.015）。因此，在这项初步研究中，我们鉴定出一组潜在的3种微RNA，用于区分ALK阳性和ALK阴性NSCLC患者。我们还将miR-660-5p和miR-362-5p鉴定为克唑替尼治疗反应的潜在预测指标。
