Insulin up-regulates vascular endothelial growth factor and stabilizes itsmessengers 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 vasc ular growth and therefore tumoral growth and metastasis. Overweight, freque ntly associated with hyperinsulinemia, constitutes the major risk factor fo r endometrial carcinoma. Thus, elevated insulin levels may partly explain t he increased risk of endometrial cancer observed in obese postmenopausal wo men. The aim of the present work was to test the role of insulin in the con trol of VEGF expression in endometrial carcinoma cells (HEC-1A). We have sh own that insulin induced a biphasic expression of VEGF messenger ribonuclei c acid, with an early, but low, induction (4 h of stimulation) and a delaye d, but high, induction (24 h). The delayed effect of insulin on VEGF expres sion involved transcriptional and posttranscriptional regulation, as eviden ced by the increased rate of VEGF transcription and the prolonged half-life of VEGF messenger ribonucleic acid. Simultaneously we observed higher leve ls of VEGF protein in the conditioned medium of stimulated cells compared w ith unstimulated ones. Therefore, insulin could contribute to the increased risk of endometrial carcinoma due to its ability to induce VEGF expression and thus participate in the maintenance of an angiogenic phenotype.