Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Department of Surgery, Faculty Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Cancer Genomics Proteomics. 2020 May-Jun;17(3):249-257. doi: 10.21873/cgp.20185.
BACKGROUND/AIM: Rectal cancer accounts for approximately one-third of all colorectal cancers. Currently, the standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) with capecitabine or 5-fluorouracil followed by curative surgery. Unfortunately, only 20% of patients with LARC present complete pathological response after CRT, whereas in 20-40% cases the response is poor or absent. The aim of our study was to evaluate whether microRNAs (miRNAs) in tumor biopsy specimen have the potential to predict therapeutic response in LARC patients.
In total 87 LARC patients treated by CRT were enrolled in our prospective study. To identify predictive miRNAs, we used small RNA sequencing in 40 tumor biopsy samples of LARC patients (20 responders, 20 non-responders) and qPCR validation of selected miRNA candidates.
In the discovery phase of the study, we identified 69 miRNAs to have significantly different expression between the group of responders (TRG 1,2) and a group of non-responders (TRG 4,5) to neoadjuvant CRT. Among these miRNAs, 48 showed a lower expression and 21 showed higher expression in tumor tissues from poorly responding LARC patients. Five miRNAs were selected for validation, but only miR-487a-3p was confirmed to have a significantly higher expression in the tumor biopsy specimens of non-responders to neoadjuvant CRT (p<0.0006, AUC=0.766). Gene Ontology (GO) clustering and pathway enrichment analysis of the miR-487a-3p mRNA targets, revealed potential mechanisms behind miR-487a-3p roles in chemoradioresistance (e.g. TGF-beta signaling pathway, protein kinase activity, double-stranded DNA binding, or microRNAs in cancer).
By combination of miRNA expression profiling and integrative computational biology we identified miR-487a-3p as a potential predictive biomarker of CRT response in LARC patients.
背景/目的：直肠癌约占所有结直肠癌的三分之一。目前，局部晚期直肠癌（LARC）的标准治疗方法是卡培他滨或氟尿嘧啶联合新辅助放化疗（CRT），然后进行根治性手术。不幸的是，只有 20%的 LARC 患者在 CRT 后出现完全病理缓解，而在 20-40%的病例中，反应不佳或不存在。我们的研究目的是评估肿瘤活检标本中的 microRNAs（miRNAs）是否有潜力预测 LARC 患者的治疗反应。
我们前瞻性研究了 87 例接受 CRT 治疗的 LARC 患者。为了鉴定预测性 miRNAs，我们使用小 RNA 测序对 40 例 LARC 患者的肿瘤活检样本（20 例缓解者，20 例无缓解者）进行分析，并对选定的 miRNA 候选物进行 qPCR 验证。
在研究的发现阶段，我们在对新辅助 CRT 有反应（TRG 1、2）和无反应（TRG 4、5）的两组患者中鉴定出 69 个 miRNA 存在显著差异表达。其中，48 个 miRNA 的表达水平较低，21 个 miRNA 的表达水平较高。选择了 5 个 miRNA 进行验证，但只有 miR-487a-3p 在新辅助 CRT 无反应的肿瘤活检标本中表达显著升高（p<0.0006，AUC=0.766）。miR-487a-3p 的 mRNA 靶基因的基因本体（GO）聚类和通路富集分析，揭示了 miR-487a-3p 在化疗耐药中的潜在作用机制（如 TGF-β信号通路、蛋白激酶活性、双链 DNA 结合或癌症中的 microRNAs）。
通过 miRNA 表达谱分析和综合计算生物学方法，我们发现 miR-487a-3p 是 LARC 患者 CRT 反应的潜在预测生物标志物。
