regulation of hif-1α and vegf by mir-20b tunes tumor cells to adapt to the alteration of oxygen concentration监管hif-1α和vegf mir-20b曲调肿瘤细胞适应氧浓度的改变.pdfVIP

Regulation of HIF-1a and VEGF by miR-20b Tunes Tumor Cells to Adapt to the Alteration of Oxygen Concentration Zhang Lei, Bo Li, Zhuoshun Yang, Haoshu Fang, Gui-Mei Zhang, Zuo-Hua Feng, Bo Huang* Department of Biochemistry Molecular Biology, Tongji Medical College, Huazhong University of Science Technology, Wuhan, The People’s Republic of China Abstract The regulation of HIF-1a is considered to be realized by pVHL-mediated ubiquitin-26S proteasome pathway at a post- transcriptional level. The discovery of a class of small noncoding RNAs, called microRNAs, implies alternative mechanism of regulation of HIF-1a. Here, we show that miR-20b plays an important role in fine-tuning the adaptation of tumor cells to oxygen concentration. The inhibition of miR-20b increased the protein levels of HIF-1a and VEGF in normoxic tumor cells; the increase of miR-20b in hypoxic tumor cells, nevertheless, decreased the protein levels of HIF-1a and VEGF. By using luciferase reporter vector system, we confirmed that miR-20b directly targeted the 39UTR of Hif1a and Vegfa. On the other hand, the forced overexpression of HIF-1a in normoxic tumor cells downregulated miR-20b expression. However, HIF-1a knockdown in hypoxic tumor cells caused the increase of miR-20b. The differential expression of miR-20b has important biological significance in tumor cells, either enhancing the growth or favoring the survival of tumor cells upon the oxygen supply. Thus, we identify a novel molecular regulation mechanism through which miR-20b regulates HIF-1a and VEGF and is regulated by HIF-1a so to keep tumor cells adapting to different oxygen concentrations. Citation: Lei Z, Li B, Yang Z, Fang H, Zhang G-M, et al. (2009) Regulation of HIF-1a and VEGF by miR-20b Tunes Tumor Cells to Adapt to the Alteration of Oxygen Concentration. PLoS ONE 4(10): e7629. doi:10.1371/journal.pone.0007629 Editor: Michael P