Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University Cancer Research Institute, Kyungpook National University, 807 Hogukno, Buk-gu, Daegu, 41404, Republic of Korea.
Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu, 41944, Republic of Korea.
J Cancer Res Clin Oncol. 2020 Jan;146(1):105-115. doi: 10.1007/s00432-019-03099-4. Epub 2019 Nov 28.
We aimed to identify biomarkers of response to preoperative CRT in patients with LARC using comprehensive miRNA analysis.
This study included 65 rectal cancer specimens and 89 serum samples from patients diagnosed with LARC and treated with preoperative. All specimens were collected before CRT for evaluation of biologic differences between the good and poor CRT response groups (ypStage 0/I versus II/III/IV). For specific miRNA discovery, 800 miRNAs in 20 rectal cancer specimens were analyzed with a NanoString assay. For validation, a total of 65 tissue and 89 serum samples were tested with reverse transcription-polymerase chain reaction (RT-PCR).
In the discovery set, 16 target miRNAs were detected. In the validation set, higher expression of three miRNAs (miR-199a/b-3p, miR-199a-5p, and miR-199b-5p) was significantly associated with better response to CRT. In the univariate survival analysis, upregulation of these three miRNAs was associated with superior relapse-free survival (RFS) and overall survival (OS). Meanwhile, only a higher level of tissue miR-199a-5p was associated with superior RFS [hazard ratio (HR), 0.0.91; 95% confidence interval (CI) 0.035-0.580; p = 0.002] and OS (HR, 0.272; 95% CI 0.023-0.658; p < 0.001) in the multivariate survival analysis. Also, a higher level of exosomal miR-199b-5p correlated with better response to CRT (p = 0.0397).
High expression of tissue miR-199a/b-3p, miR-199a-5p, and miR-199b-5p was significantly associated with response to CRT, and a high level of tissue miR-199a-5p was associated with superior survival outcomes. Also, upregulated exosomal miR-199b-5p correlated with CRT response, reflecting its promise as a circulating biomarker of CRT response in patients with LARC.
我们旨在通过全面的 miRNA 分析，确定接受术前放化疗（CRT）的局部晚期直肠癌（LARC）患者对治疗有反应的生物标志物。
本研究纳入了 65 例直肠癌标本和 89 例接受术前 CRT 治疗的 LARC 患者的血清样本。所有标本均在 CRT 前采集，以评估 CRT 反应良好和反应不良组（ypStage 0/I 与 II/III/IV）之间的生物学差异。为了进行特定 miRNA 的发现，使用 NanoString 检测对 20 例直肠癌标本中的 800 个 miRNA 进行了分析。为了验证，使用逆转录-聚合酶链反应（RT-PCR）对 65 个组织和 89 个血清样本进行了测试。
在发现组中，检测到 16 个靶 miRNA。在验证组中，三种 miRNA（miR-199a/b-3p、miR-199a-5p 和 miR-199b-5p）的高表达与更好的 CRT 反应显著相关。在单因素生存分析中，这三种 miRNA 的上调与更好的无复发生存（RFS）和总生存（OS）相关。同时，仅组织 miR-199a-5p 的高水平与更好的 RFS [风险比（HR），0.0.91；95%置信区间（CI）0.035-0.580；p=0.002]和 OS（HR，0.272；95%CI 0.023-0.658；p<0.001）相关。此外，外泌体 miR-199b-5p 水平升高与 CRT 反应相关（p=0.0397）。
组织 miR-199a/b-3p、miR-199a-5p 和 miR-199b-5p 的高表达与 CRT 反应显著相关，组织 miR-199a-5p 的高水平与更好的生存结果相关。此外，上调的外泌体 miR-199b-5p 与 CRT 反应相关，反映了其作为 LARC 患者 CRT 反应的循环生物标志物的潜力。
