Xu Xiaoyue, Yu Shaorong, Sun Wenbo, Qin Xiaobing, Chen Yan, Zhou Leilei, Lou Rui, Dong Shuchen, Shen Bo, Wu Jianzhong, Zang Jialan, Cao Haixia, Shi Meiqi, Zhang Qin, Feng Jifeng
Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Baiziting No.42, Nanjing, 210009, Jiangsu, China.
Department of Neurosurgery, Nanjing Medical University Affiliated Brain Hospital, Nanjing, Jiangsu, China.
J Cancer Res Clin Oncol. 2018 Mar;144(3):431-438. doi: 10.1007/s00432-017-2562-8. Epub 2017 Dec 29.
Accumulating literature proved that miRNAs can regulate the sensitivity of platinum and act as a promising candidate to predict the response of patients with lung adenocarcinoma to chemotherapy. However, most studies on miRNAs were restricted to in vitro experiments. This study aimed to evaluate whether miRNAs alone or in combination (miRNA signature) can act as predictive biomarkers of platinum-based chemotherapy in patients with lung adenocarcinoma.
Eight miRNAs that most probably predict the efficacy of platinum were screened in 111 tumor tissues of lung adenocarcinoma. Univariate and multivariate Cox analyses, Kaplan-Meier survival curve analysis, Chi-square test, and univariate and multivariate logistic regression analyses were employed to determine whether miRNA expression is associated with the response of patients to platinum-based chemotherapy. The maximum significant odds ratio value was acquired by multiple cycles of multivariate logistic regression analysis. The cut-off points of miRNAs were obtained. A miRNA chemo-sensibility index (CI) formula was established, and its prediction performance was confirmed in another independent set (n = 31).
Underexpression of three miRNAs (miRNA-21, miRNA-125b, and miRNA-224) was independently associated with the chemotherapy sensitivity of patients with lung adenocarcinoma. The miRNA CI formula containing these three miRNAs was calculated as (1.364 × miR-21) + (1.323 × miR-125b) + (1.131 × miR-224). A high CI was related to platinum-based chemotherapy resistance, and its prediction performance was confirmed in the testing set. The MAPK, PI3K-Akt, Ras, and cGMP-PKG signaling pathways were considered to be most probably correlated with platinum resistance.
Our miRNA CI formula can act as an independent predictor to predict the response of patients with lung adenocarcinoma to platinum-based chemotherapy.
越来越多的文献证明，微小RNA（miRNA）可调节铂类药物敏感性，并有望成为预测肺腺癌患者化疗反应的指标。然而，大多数关于miRNA的研究仅限于体外实验。本研究旨在评估单独的miRNA或其组合（miRNA特征）能否作为肺腺癌患者铂类化疗的预测生物标志物。
在111例肺腺癌肿瘤组织中筛选出最有可能预测铂类疗效的8种miRNA。采用单因素和多因素Cox分析、Kaplan-Meier生存曲线分析、卡方检验以及单因素和多因素逻辑回归分析，以确定miRNA表达是否与患者对铂类化疗的反应相关。通过多轮多因素逻辑回归分析获得最大显著比值比。确定miRNA的截断点。建立miRNA化疗敏感性指数（CI）公式，并在另一个独立队列（n = 31）中验证其预测性能。
三种miRNA（miRNA-21、miRNA-125b和miRNA-224）的低表达与肺腺癌患者的化疗敏感性独立相关。包含这三种miRNA的miRNA CI公式计算为（1.364×miR-21）+（1.323×miR-125b）+（1.131×miR-224）。高CI与铂类化疗耐药相关，且其预测性能在测试队列中得到验证。丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）、Ras和环磷酸鸟苷-蛋白激酶G（cGMP-PKG）信号通路被认为最可能与铂类耐药相关。
我们的miRNA CI公式可作为独立预测指标，预测肺腺癌患者对铂类化疗的反应。
