Liu Mei, An Jusheng, Huang Manni, Wang Liming, Tu Binbin, Song Yan, Ma Kai, Wang Yu, Wang Shuren, Zhu Hongxia, Xu Ningzhi, Wu Lingying
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.
Department of Gynecological Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.
Mol Carcinog. 2018 Jan;57(1):32-43. doi: 10.1002/mc.22717. Epub 2017 Aug 28.
MicroRNAs (miRNAs) are small non-coding RNA that target protein-coding mRNAs at the post-transcriptional level. The aim of this study was to define the role of miR-492 in cervical squamous cell carcinomas. After microRNA profiling and comparison, we firstly detected miR-492 expression in 104 tumor tissues biopsies derived from advanced staged (FIGO IIB-IIIB) cervical squamous cell carcinoma patients before receiving concomitant chemoradiotherapy and found miR-492 expression was significantly higher in the specimens that were sensitive to concomitant chemoradiotherapy, as compared with insensitive cancer specimens (P < 0.05). Moreover, higher expression of miR-492 was associated with pelvic lymph node metastasis (LNM) (P < 0.05). Further studies illustrated ectopic miR-492 overexpression in SiHa cells promoted cell proliferation, migration, and enhanced the sensitivity of cervical cancer cells to irradiation by promoting apoptosis. In addition, we identified TIMP2 as a direct miR-492 target, which has been shown to be critical in modulating cancer cell migration and invasion. We also confirmed that miR-492 expression levels in positive pelvic LNM were much higher than negative LNM and miR-492 played a vital role in pelvic lymph node metastasis via regulating miR-492/TIMP2/MMP10 axis. In particular, miR-492 was correlated with prognosis in the subgroup of patients with negative pelvic LNM (P < 0.05) and had a promising value in predicting treatment response in the subgroup of patients with positive pelvic LNM (an AUC of 85%, 75.00% specificity, and 95.24% sensitivity). Taken together, the results suggested that miR-492 may serve as a potential biomarker for cervical cancer treatment and prognosis.
微小RNA（miRNA）是一类小的非编码RNA，可在转录后水平靶向蛋白质编码mRNA。本研究的目的是确定miR-492在宫颈鳞状细胞癌中的作用。经过微小RNA谱分析和比较，我们首先检测了104例来自晚期（国际妇产科联盟IIB-IIIB期）宫颈鳞状细胞癌患者在接受同步放化疗前的肿瘤组织活检标本中miR-492的表达，发现与不敏感的癌标本相比，对同步放化疗敏感的标本中miR-492表达显著更高（P<0.05）。此外，miR-492的高表达与盆腔淋巴结转移（LNM）相关（P<0.05）。进一步研究表明，SiHa细胞中异位miR-492过表达促进细胞增殖、迁移，并通过促进凋亡增强宫颈癌细胞对辐射的敏感性。此外，我们确定TIMP2是miR-492的直接靶点，已证明其在调节癌细胞迁移和侵袭中起关键作用。我们还证实，盆腔LNM阳性患者的miR-492表达水平远高于LNM阴性患者，且miR-492通过调节miR-492/TIMP2/MMP10轴在盆腔淋巴结转移中起重要作用。特别是，miR-492与盆腔LNM阴性患者亚组的预后相关（P<0.05），并且在预测盆腔LNM阳性患者亚组的治疗反应方面具有良好价值（曲线下面积为85%，特异性为75.00%，敏感性为95.24%）。综上所述，结果表明miR-492可能作为宫颈癌治疗和预后的潜在生物标志物。
