Regulation of vascular endothelial growth factor expression by insulin-like growth factor-1 in endometrial adenocarcinoma cells

Angiogenesis is crucial for tumor growth and dissemination. Vascular endoth elial growth factor (VEGF) is a potent angiogenic factor that promotes endo thelial cell proliferation and chemotaxis. VEGF occurs as 5 isoforms, as a result of an alternatively spliced transcript that originates from one gene , of which the 2 majors are the VEGF 121 and 165 isoforms. Our aim was firs tly to determine the role of Insulin-like Growth Factor-1 (IG F-l) in the r egulation of VEGF expression in endometrial adenocarcinoma cells and then t he mechanism by which this regulation occurs, IGF-I treatment of HEC-1A cel ls provoked an increase of VEGF mRNA expression that peaked at 48 hr with a 165 isoform mRNA more abundant than the 121 isoform. The IGF-I action was confirmed at the protein level, whose concentration was increased in the co nditioned media. In experiments using transient transfection of VEGF promot er-luciferase constructs, the IGF-I failed to increase the activity of the VEGF promoter after a 24-hr period of IGF-I treatment, while the addition o f Actinomycin D showed an increase of the VEGF mRNA half-life. Most interes tingly, Northern blot analysis showed a different stability of the 2 major VEGF isoform mRNAs (VEGF I 2 I and 165), of which the 121 isoform was more stable than the 165 isoform, The IGF-I treatment prolonged the half-life of both of the VEGF isoform mRNAs, Our results suggest that IGF-I regulates V EGF expression in endometrial adenocarcinoma cells at the post-transcriptio nal level by enhancing the stabilization of the 2 major VEGF isoform mRNAs (VEGF(121) and VEGF(165)) In addition to its proliferative functions, IGF-I induces VEGF expression and participates in the maintenance of an angiogen ic phenotype. (C) 2000 Wiley-Liss, Inc.