Iorio Marilena V, Visone Rosa, Di Leva Gianpiero, Donati Valentina, Petrocca Fabio, Casalini Patrizia, Taccioli Cristian, Volinia Stefano, Liu Chang-Gong, Alder Hansjuerg, Calin George A, Ménard Sylvie, Croce Carlo M
Molecular Biology Unit, Department of Experimental Oncology, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milano, Italy.
Cancer Res. 2007 Sep 15;67(18):8699-707. doi: 10.1158/0008-5472.CAN-07-1936.
Epithelial ovarian cancer (EOC) is the sixth most common cancer in women worldwide and, despite advances in detection and therapies, it still represents the most lethal gynecologic malignancy in the industrialized countries. Unfortunately, still relatively little is known about the molecular events that lead to the development of this highly aggressive disease. The relatively recent discovery of microRNAs (miRNA), a class of small noncoding RNAs targeting multiple mRNAs and triggering translation repression and/or RNA degradation, has revealed the existence of a new level of gene expression regulation. Multiple studies involving various types of human cancers proved that miRNAs have a causal role in tumorigenesis. Here we show that, in comparison to normal ovary, miRNAs are aberrantly expressed in human ovarian cancer. The overall miRNA expression could clearly separate normal versus cancer tissues. The most significantly overexpressed miRNAs were miR-200a, miR-141, miR-200c, and miR-200b, whereas miR-199a, miR-140, miR-145, and miR-125b1 were among the most down-modulated miRNAs. We could also identify miRNAs whose expression was correlated with specific ovarian cancer biopathologic features, such as histotype, lymphovascular and organ invasion, and involvement of ovarian surface. Moreover, the levels of miR-21, miR-203, and miR-205, up-modulated in ovarian carcinomas compared with normal tissues, were significantly increased after 5-aza-2'-deoxycytidine demethylating treatment of OVCAR3 cells, suggesting that the DNA hypomethylation could be the mechanism responsible for their overexpression. Our results indicate that miRNAs might play a role in the pathogenesis of human EOC and identify altered miRNA gene methylation as a possible epigenetic mechanism involved in their aberrant expression.
上皮性卵巢癌（EOC）是全球女性中第六大常见癌症，尽管在检测和治疗方面取得了进展，但在工业化国家，它仍然是最致命的妇科恶性肿瘤。不幸的是，对于导致这种高度侵袭性疾病发生的分子事件，我们仍然知之甚少。相对较新发现的微小RNA（miRNA），这是一类靶向多个mRNA并引发翻译抑制和/或RNA降解的小非编码RNA，揭示了基因表达调控存在新的层面。多项涉及各种类型人类癌症的研究证明，miRNA在肿瘤发生中具有因果作用。在此我们表明，与正常卵巢相比，miRNA在人类卵巢癌中异常表达。整体miRNA表达能够清晰地区分正常组织与癌组织。表达上调最为显著的miRNA是miR - 200a、miR - 141、miR - 200c和miR - 200b，而miR - 199a、miR - 140、miR - 145和miR - 125b1是下调最为明显的miRNA。我们还能够鉴定出其表达与特定卵巢癌生物病理特征相关的miRNA，如组织类型、淋巴管和器官侵犯以及卵巢表面受累情况。此外，与正常组织相比，在卵巢癌中上调的miR - 21、miR - 203和miR - 205的水平，在对OVCAR3细胞进行5 - 氮杂 - 2'-脱氧胞苷去甲基化处理后显著升高，这表明DNA低甲基化可能是其过度表达的机制。我们的结果表明，miRNA可能在人类EOC的发病机制中发挥作用，并确定miRNA基因甲基化改变是涉及其异常表达的一种可能的表观遗传机制。
