Identification of Ovarian Cancer Metastatic miRNAs

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2–4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.

浆液性上皮性卵巢癌（EOC）患者常死于侵袭性转移性疾病，但目前对卵巢癌转移的行为特征与遗传学机制仍知之甚少。本研究旨在探讨网膜转移灶与原发肿瘤的差异，以及此类差异如何影响化疗疗效。本研究采用miRNA Taqman定量聚合酶链反应（qPCR）芯片，对9例患者的原发性EOC肿瘤及其对应的网膜转移灶进行微小RNA（microRNA, miRNA）表达谱分析。研究发现，与原发肿瘤相比，网膜病灶中共存在17种差异表达的miRNA。其中，miR-21、miR-150及miR-146a在多数原发肿瘤中呈低表达，而在网膜病灶中表达显著上调；同时，基于信使RNA（messenger RNA, mRNA）表达分析预测的其靶向mRNA的表达则出现下调。研究发现miR-150与miR-146a可调控细胞球体的大小。当暴露于致死剂量的顺铂（cisplatin）时，miR-146a与miR-150均可使残余存活细胞数量增加2~4倍。上述结果表明，在网膜病灶中表达上调的miR-146a与miR-150这两种miRNA，可促进癌细胞存活并提高其药物耐受性。本研究结果提示，网膜肿瘤中的癌细胞与原发肿瘤的关键miRNA表达模式存在差异，且其中至少部分微小RNA可能是耐药性疾病发生的关键调控因子。