循环微小 RNA 与小肠神经内分泌肿瘤：一种用于诊断和评估手术切除效果的潜在工具。

Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors: A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection.

机构信息

Department of Surgery & Cancer, Imperial College, Hammersmith Hospital campus, Du Cane Road, London, UK.

Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland.

出版信息

Ann Surg. 2021 Jul 1;274(1):e1-e9. doi: 10.1097/SLA.0000000000003502.

DOI:10.1097/SLA.0000000000003502

PMID:31373926

Abstract

OBJECTIVE

To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions.

BACKGROUND

MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response.

METHODS

This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months).

RESULTS

Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD).

CONCLUSIONS

Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

摘要

目的

发现用于小肠神经内分泌肿瘤（SBNET）的基于血清的 microRNA（miRNA）生物标志物，以帮助指导临床决策。

背景

miRNAs 是参与许多癌症的发生和进展的小非编码 RNA 分子。miRNAs 在体液中非常稳定，并且有可能转化为具有临床应用价值的生物标志物。在 SBNET 中需要新型生物标志物来确定疾病的侵袭性，选择治疗患者，检测早期复发并监测反应。

方法

本研究分 3 个阶段（发现、验证和前瞻性纵向评估）进行。发现阶段包括对来自 SBNET 患者（n = 11）与健康对照者（HC；n = 3）的血清中的 376 种 miRNA 进行全局分析。随后在另外的 SBNET（n = 33）和 HC 血清（n = 14）中验证上调的 miRNA；然后在 SBNET 切除后（n = 12）进行纵向评估，进行连续血清采样（术前第 0 天；术后第 1 周、1 个月和 12 个月）。

结果

基于多种归一化策略，基于多个归一化策略，有 4 种血清 miRNA（miR-125b-5p、-362-5p、-425-5p 和-500a-5p）在 SBNET 中显著上调（P < 0.05；倍数变化> 2），并通过 RT-qPCR 验证。该组合能够以 0.951 的曲线下面积区分 SBNET 与 HC。纵向评估显示，在无疾病的患者中，miR-125b-5p 在术后 1 个月时恢复至 HC 水平，而在有残留疾病（RSD）的患者中仍保持上调。在术后 12 个月时也是如此。此外，miR-362-5p 在 RSD 和复发性疾病（RCD）中在 12 个月时似乎上调。