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Insulin Up-Regulates Vascular Endothelial Growth Factor and Stabilizes Its Messengers in Endometrial Adenocarcinoma Cells¹

Service d’Oncologie et d’Endocrinologie Moléculaires (Centre Hospitalier Universitaire Besançon and Institut d’Etude et de Transfert de Gènes) and Contract Recherche INSERM 96.01 (L.B., F.La., F.Lo., S.F., G.L.A.), 25000 Besançon, France; Investigate Treatment Division, National Cancer Center Research Institute East (H.E.), Kashiwa, Chiba 277, Japan; and Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli (A.W.), 80138 Naples, Italy

Address all correspondence and requests for reprints to: Gérard L. Adessi, M.D., Ph.D., Bâtiment Inserm, 240 route de Dole, 25000 Besançon, France. E-mail: gerard.adessi{at}ufc-chu.univ-fcomte.fr

Angiogenesis is crucial for tumor growth and dissemination. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that promotes vascular growth and therefore tumoral growth and metastasis. Overweight, frequently associated with hyperinsulinemia, constitutes the major risk factor for endometrial carcinoma. Thus, elevated insulin levels may partly explain the increased risk of endometrial cancer observed in obese postmenopausal women. The aim of the present work was to test the role of insulin in the control of VEGF expression in endometrial carcinoma cells (HEC-1A). We have shown that insulin induced a biphasic expression of VEGF messenger ribonucleic acid, with an early, but low, induction (4 h of stimulation) and a delayed, but high, induction (24 h). The delayed effect of insulin on VEGF expression involved transcriptional and posttranscriptional regulation, as evidenced by the increased rate of VEGF transcription and the prolonged half-life of VEGF messenger ribonucleic acid. Simultaneously we observed higher levels of VEGF protein in the conditioned medium of stimulated cells compared with 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.

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