title: MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression.
abstract: 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-1α 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-1α and VEGF expression and angiogenesis. Moreover, inhibition of HIF-1α expression alone abolished miR-21-inducing tumor angiogenesis, indicating that HIF-1α 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-1α and VEGF expression; HIF-1α is a key downstream target of miR-21 in regulating tumor angiogenesis.
authors.affiliation: Lab of Reproductive Medicine, Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
authors.forename: Chongyong
authors.initials: C
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Jing
authors.forename: Richard
authors.initials: R
authors.lastname: Carpenter
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Lihui
authors.initials: L
authors.lastname: Lai
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D015151:Immunoblotting; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases