MicroRNAs (miRNAs) is a novel class of small noncoding RNAs that post-transcriptionally regulate gene expression. Hypoxia-inducible factor (HIF-1\#945;) is a key regulator of angiogenesis which is important in cancer progression. Multiple HIF-1\#945; target genes have been shown to modulate angiogenesis by promoting the mitogenic and migratory activities of endothelial cells. Regulation of HIF-1\#945; has been discovered as multiple mechanisms controlled by hypoxia, growth factors, and cytokines. In the present study, we identified a target site of miR-519c in the HIF-1\#945; 3'UTR, as evidenced by that miR-519c expression significantly suppressed the reporter activity of HIF-1\#945; 3'UTR. We found that over-expression of miR-519c resulted in significant decrease in HIF-1\#945; protein level. Supporting, condition medium of CL1-5/miR-519c transfectants reduced the tubule formation ability in HUVEC cells, compared to these of CL1-5/miR-Vec. Also, transfection with miR-519c antagomir increased HIF-1\#945; protein level and enhanced angiogenesis activity in vitro. Furthermore, we found that miR-519c is regulated by hepatocyte growth factor (HGF), a known HIF-1\#945; inducer, through Akt-dependent pathway. Animal study shows that miR-519c over-expression dramatically reduced HIF-1\#945; expression and tumor growth, metastasis and angiogenesis. By using real-time RT-PCR to determine miR-519c expression profiles in 103 NSCLC patients, we found that miR-519c is over-expressed in early stage subgroups of lung cancer patients (p = 0.028). Taken together, our finding provides the first evidence indicating the role of miR-519c in HIF regulation, which may have prognostic or therapeutic implications for the future management of NSCLC patients.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2533.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009