Yang Hua, Kong William, He Lili, Zhao Jian-Jun, O'Donnell Joshua D, Wang Jiawang, Wenham Robert M, Coppola Domenico, Kruk Patricia A, Nicosia Santo V, Cheng Jin Q
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
Cancer Res. 2008 Jan 15;68(2):425-33. doi: 10.1158/0008-5472.CAN-07-2488.
MicroRNAs (miRNA) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers. However, aberrant miRNA expression and its clinicopathologic significance in human ovarian cancer have not been well documented. Here, we show that several miRNAs are altered in human ovarian cancer, with the most significantly deregulated miRNAs being miR-214, miR-199a*, miR-200a, miR-100, miR-125b, and let-7 cluster. Further, we show the frequent deregulation of miR-214, miR-199a*, miR-200a, and miR-100 in ovarian cancers. Significantly, miR-214 induces cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3'-UTR largely abrogates miR-214-induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.
微小RNA（miRNA）代表一类新型基因，其作为基因表达的负调控因子发挥作用。最近，miRNA与多种癌症有关。然而，miRNA表达异常及其在人类卵巢癌中的临床病理意义尚未得到充分记录。在此，我们表明几种miRNA在人类卵巢癌中发生改变，其中失调最显著的miRNA是miR-214、miR-199a*、miR-200a、miR-100、miR-125b和let-7簇。此外，我们显示miR-214、miR-199a*、miR-200a和miR-100在卵巢癌中频繁失调。值得注意的是，miR-214通过靶向PTEN的3'-非翻译区（UTR）诱导细胞存活和顺铂耐药，这导致PTEN蛋白下调和Akt途径激活。使用Akt抑制剂API-2/曲西立滨抑制Akt或引入缺乏3'-UTR的PTEN cDNA在很大程度上消除了miR-214诱导的细胞存活。这些发现表明miRNA失调是人类卵巢癌中的一个反复出现的事件，并且miR-214主要通过靶向PTEN/Akt途径诱导细胞存活和顺铂耐药。
