Journal
PLOS ONE
Volume 6, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0019139
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Funding
- National Basic Research Program of China [2007CB947002, 2007CB947001]
- National Natural Science Foundation of China [30470361, 30570962]
- State High Technology Developing Project [2008AA02Z115]
- National Cancer Institute, National Institutes of Health (NIH) [CA109460]
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MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1 alpha and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated kinases (ERK) 1/2 are activated by miR-21. Inhibition of miR-21 by the antigomir blocked this process. Overexpression of the miR-21 target, PTEN, also inhibited tumor angiogenesis by partially inactivating AKT and ERK and decreasing the expression of HIF-1 and VEGF. The AKT and ERK inhibitors, LY294002 and U0126, suppressed HIF-1 alpha and VEGF expression and angiogenesis. Moreover, inhibition of HIF-1 alpha expression alone abolished miR-21-inducing tumor angiogenesis, indicating that HIF-1 alpha is required for miR-21-upregulated angiogenesis. Therefore, we demonstrate that miR-21 induces tumor angiogenesis through targeting PTEN, leading to activate AKT and ERK1/2 signaling pathways, and thereby enhancing HIF-1 alpha and VEGF expression; HIF-1 alpha is a key downstream target of miR-21 in regulating tumor angiogenesis.
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