Giannakakis Antonis, Sandaltzopoulos Raphael, Greshock Joel, Liang Shun, Huang Jia, Hasegawa Kosei, Li Chunsheng, O'Brien-Jenkins Ann, Katsaros Dionyssios, Weber Barbara L, Simon Celeste, Coukos George, Zhang Lin
Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Cancer Biol Ther. 2008 Feb;7(2):255-64. doi: 10.4161/cbt.7.2.5297. Epub 2007 Nov 14.
Tumor growth results in hypoxia. Understanding the mechanisms of gene expression reprogramming under hypoxia may provide important clues to cancer pathogenesis. We studied miRNA genes that are regulated by hypoxia in ovarian cancer cell lines by TaqMan miRNA assay containing 157 mature miRNAs. MiR-210 was the most prominent miRNA consistently stimulated under hypoxic conditions. We provide evidence for the involvement of the HIF signaling pathway in miR-210 regulation. Biocomputational analysis and in vitro assays demonstrated that e2f transcription factor 3 (e2f3), a key protein in cell cycle, is regulated by miR-210. E2F3 was further confirmed to be downregulated at the protein level upon induction of miR-210. Importantly, we found remarkably high frequency of miR-210 gene copy deletions in ovarian cancer patients (64%, n = 114) and that gene copy number correlates with miR-210 expression levels. Taken together, our results indicate that miR-210 plays a crucial role in tumor onset as a key regulator of the hypoxia response and provide evidence for a link between hypoxia and the regulation of cell cycle.
肿瘤生长会导致缺氧。了解缺氧条件下基因表达重编程的机制可能为癌症发病机制提供重要线索。我们通过包含157种成熟miRNA的TaqMan miRNA检测法，研究了卵巢癌细胞系中受缺氧调控的miRNA基因。MiR-210是在缺氧条件下持续受到刺激的最显著的miRNA。我们提供了HIF信号通路参与miR-210调控的证据。生物计算分析和体外实验表明，细胞周期中的关键蛋白E2F转录因子3（E2F3）受miR-210调控。在诱导miR-210后，E2F3在蛋白水平进一步被证实下调。重要的是，我们发现卵巢癌患者中miR-210基因拷贝缺失的频率非常高（64%，n = 114），并且基因拷贝数与miR-210表达水平相关。综上所述，我们的结果表明，miR-210作为缺氧反应的关键调节因子在肿瘤发生中起关键作用，并为缺氧与细胞周期调控之间的联系提供了证据。
