Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
J Transl Med. 2019 Jan 3;17(1):1. doi: 10.1186/s12967-018-1762-6.
Neoadjuvant chemotherapy (NAC) has become the standard of care for resectable esophageal squamous cell carcinoma (ESCC) which is one of the most lethal cancers, to improve resectability and prognosis. On this basis, to provide individually optimized therapy for ESCC, a minimally-invasive biomarker for response to NAC is strongly desired. This study aimed to identify the miRNA signature in serum specimens taken from ESCC patients undergoing NAC through genome-wide microarray technology.
Comprehensive miRNA-expression profiles of serum specimens from ESCC patients before initial treatment were analyzed using microarray. A qPCR assay was performed to test the robustness of identified serum-based miRNA signature for discriminating response to NAC with serum specimens taken from 100 ESCC cases undergoing NAC.
We prioritized 62 miRNAs differentially expressed between responders and non-responders (absolute log fold change > 1.0, corresponding P < 0.05) and from the 62 miRNAs, we selected the miR-23a-5p, miR-193b-5p, and miR-873-3p, which were highly expressed in non-responders. Following qPCR analysis indicated the expression of miR-193b-5p and miR-873-3p in serum specimens were significantly higher in non-responders among three selected miRNAs (P = 0.004 and 0.001, respectively). Subsequently, we developed 2-miR-model (miR-193b-5p and miR-873-3p), 3-miR-model, and 2-miR + lymphatic invasion (ly) model based on logistic regression analysis, which achieved the better area under the receiver operating characteristic curves than those of single miRNAs as 2-miR-model, 0.70 (95% CI 0.57 to 0.82); 3-miR-model, 0.70 (95% CI 0.57 to 0.83); and 2-miR + ly, 0.73 (95% CI 0.60-0.86), respectively. Furthermore, we compared the detective power of the combined model: 2-miR + ly for discriminating non-responders to NAC, to other pretreatment clinical features. Consequently, 2-miR + ly model was superior to serum SCC antigen with great significance (P = 0.01) and to ly, and clinical T stage with marginal significance (P = 0.18, 0.07, respectively).
Collectively, we demonstrated that the potential of a multi-miRNA biomarker for identifying NAC response in ESCC is realistic, and can be used in the clinic with the further validation.
新辅助化疗（NAC）已成为可切除食管鳞癌（ESCC）的标准治疗方法，以提高可切除性和预后。在此基础上，为了为 ESCC 提供个体化优化治疗，强烈需要一种用于 NAC 反应的微创生物标志物。本研究旨在通过全基因组微阵列技术鉴定接受 NAC 的 ESCC 患者血清标本中的 miRNA 特征。
使用微阵列分析 ESCC 患者初始治疗前血清标本的综合 miRNA 表达谱。使用 qPCR 检测从 100 例接受 NAC 的 ESCC 病例中采集的 NAC 血清标本中识别出的基于血清的 miRNA 特征区分 NAC 反应的稳健性。
我们优先考虑了 62 个在应答者和非应答者之间差异表达的 miRNA（绝对对数倍数变化 > 1.0，对应 P < 0.05），并从这 62 个 miRNA 中，我们选择了 miR-23a-5p、miR-193b-5p 和 miR-873-3p，它们在非应答者中高表达。qPCR 分析表明，在三个选定的 miRNA 中，miR-193b-5p 和 miR-873-3p 在非应答者中的血清标本表达明显更高（P = 0.004 和 0.001）。随后，我们基于逻辑回归分析建立了 2-miR 模型（miR-193b-5p 和 miR-873-3p）、3-miR 模型和 2-miR+ly 模型，与单个 miRNA 相比，这些模型的受试者工作特征曲线下面积更好，分别为 2-miR 模型，0.70（95%CI 0.57 至 0.82）；3-miR 模型，0.70（95%CI 0.57 至 0.83）；和 2-miR+ly，0.73（95%CI 0.60-0.86）。此外，我们比较了联合模型（2-miR+ly）用于区分 NAC 对非应答者的检测能力：与其他预处理临床特征。结果表明，2-miR+ly 模型优于血清 SCC 抗原（具有显著意义，P=0.01），优于 ly 和临床 T 期（具有边缘意义，P=0.18，0.07）。
总的来说，我们证明了多 miRNA 生物标志物识别 ESCC 中 NAC 反应的潜力是现实的，并可在进一步验证的基础上在临床上使用。
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