Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
Department of Surgery, Kyoto Second Red Cross Hospital, 355-5 Kamanzadoori Marutamachi Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan.
Sci Rep. 2017 Jul 18;7(1):5708. doi: 10.1038/s41598-017-06137-8.
This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.
本研究旨在探讨胰腺癌（PCa）患者中肿瘤抑制性 microRNA（miRNA）血浆水平降低的现象，以明确其作为新型生物标志物和治疗靶点的潜力。我们采用 miRNA 芯片技术，通过比较 PCa 患者与健康志愿者的血浆水平，筛选候选 miRNA。结果显示，与健康志愿者相比，6 种下调的 miRNA（miR-107、miR-126、miR-451、miR-145、miR-491-5p 和 miR-146b-5p）在 PCa 患者中表达下调。对 100 例 PCa 患者和 80 例健康志愿者的样本进行了小样本和大样本分析，结果表明 miR-107 是 PCa 患者中下调最明显的 miRNA（P < 0.0001；受试者工作特征曲线下面积，0.851）。miR-107 血浆水平较低与肿瘤进展的 T 分期、N 分期和肝转移显著相关，是预测 PCa 患者预后不良的独立因素（P = 0.0424；风险比，2.95）。在 PCa 细胞中过表达 miR-107 可诱导 G1/S 期阻滞，产生 p21，并通过 Notch2 的转录调控抑制细胞增殖。在体内，miR-107 血浆水平的恢复和维持可显著抑制小鼠肿瘤的进展。肿瘤抑制性 miR-107 在血浆中的耗竭与肿瘤进展和不良预后有关。恢复血浆 miR-107 水平可能成为 PCa 的一种新的抗癌治疗策略。
