Bagnoli Marina, De Cecco Loris, Granata Anna, Nicoletti Roberta, Marchesi Edoardo, Alberti Paola, Valeri Barbara, Libra Massimo, Barbareschi Mattia, Raspagliesi Francesco, Mezzanzanica Delia, Canevari Silvana
Depts. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Oncotarget. 2011 Dec;2(12):1265-78. doi: 10.18632/oncotarget.401.
A major challenge in advanced-stage epithelial ovarian cancer (EOC) is prediction of chemoresistant relapse. Our aim was to identify a microRNA (miRNA) signature associated with early relapse in advanced-stage EOC patients. miRNA expression was assessed by microarray profiling in training (n = 55) and test (n = 30) sets selected on the basis of time to relapse (TTR), followed by internal quantitative reverse transcriptase-PCR validation on a set of 45 consecutive cases unselected for clinical response and external in silico validation on publicly available datasets. Thirty-two differentially expressed miRNAs in early vs. late relapsing patients were identified in the training set. In the test set, 8 of these, belonging to a cluster located on chrXq27.3, were down-modulated in early relapsing patients. Hierarchical clustering of the internal validation set according to chrXq27.3 miRNA expression associated low miRNA expression with shorter TTR (log-rank P=0.00074, HR 2.44). The cluster was an independent prognostic factor in both internal and external validation sets. Forced expression of chrXq27.3-cluster selected miRNAs in human EOC cellular models was associated to reduction of cell proliferation and increased sensitivity to cisplatin. The role of down-modulation of the chrXq27.3 miRNA cluster in early relapse of advanced-stage EOC patients and its association to a reduced sensitivity to chemotherapeutic treatments warrant further investigation.
晚期上皮性卵巢癌（EOC）的一个主要挑战是预测化疗耐药性复发。我们的目的是确定与晚期EOC患者早期复发相关的微小RNA（miRNA）特征。通过基于复发时间（TTR）选择的训练集（n = 55）和测试集（n = 30）中的微阵列分析评估miRNA表达，随后对一组45例未根据临床反应进行选择的连续病例进行内部定量逆转录酶 - PCR验证，并在公开可用的数据集中进行外部计算机验证。在训练集中鉴定出早期与晚期复发患者中32种差异表达的miRNA。在测试集中，其中8种属于位于chrXq27.3上的一个簇，在早期复发患者中下调。根据chrXq27.3 miRNA表达对内部验证集进行层次聚类，发现低miRNA表达与较短的TTR相关（对数秩P = 0.00074，HR 2.44）。该簇在内部和外部验证集中都是独立的预后因素。在人EOC细胞模型中强制表达chrXq27.3簇选择的miRNA与细胞增殖减少和顺铂敏感性增加相关。chrXq27.3 miRNA簇下调在晚期EOC患者早期复发中的作用及其与化疗治疗敏感性降低的关联值得进一步研究。
