Título del libro: Vascular Endothelial Growth Factor (vegf): Biology, Regulation And Clinical Significance
Título del capítulo: Regulation of VEGF expression by progesterone and estradiol in normal and cancer cells
OLIVIA TANIA HERNANDEZ HERNANDEZ; IGNACIO CAMACHO ARROYO;
Autores externos:
Idioma:
Inglés
Año de publicación:
2013
Resumen:
Vascular endothelial growth factor (VEGF) is one of the most potent and specific angiogenic factors. The physiologic roles of VEGF in humans include neovascularization and endometrium implantation, and in pathological processes VEGF has been involved in the initiation, growth, and metastasis of tumors. Many cancers depend on progesterone (P4) and estradiol (E2) for growth and metastasis, especially cancers of reproductive tissues. Several studies provide evidence that VEGF expression is induced by P4 and E2, and its induction correlates with an increase in proliferation of normal and cancer cells. P4 and E2 regulate many cell functions through their interaction with specific intracellular receptors (PR and ER, respectively), which are ligand-dependent transcription factors. It has been shown that natural and synthetic progestins increase VEGF mRNA and protein levels in human endometrium and in human breast cancer cells (BT-474, T47D and HCC-1428), while PR antagonist, RU 486, suppresses progestin-dependent VEGF induction, indicating that this response is PR-dependent. In Ishikawa cells derived from human endometrial adenocarcinoma, cotransfected with human VEGF gene promoter and expression vectors encoding either PR-A or PR-B, the treatment with the progestins R5020 and medroxyprogesterone acetate resulted in a significant increase in luciferase activity, whereas pretreatment with RU 486 or the PR pure antagonist ZK299 drastically reduced the progestin effect. Three consensus progesterone response elements (PRE) have been identified in the VEGF promoter region, PRE1 (TGTACA) from-1865 to 1860, PRE2 (TGTACA) from-716 to-711, and PRE3 (TGTTCT) from +679 to +684. Deletion of one PRE is sufficient to reduce the activation of VEGF gene transcription by progestins. Site-directed mutagenesis of all three PRE did not fully abrogate VEGF transcription. Therefore, other response elements and/or transcription factors play an important role in the regulation of VEGF by P4. It has also been determined that ligand-activated PR modulates the promoter activity of some genes through Sp1 and AP-1 sites. More than 6 AP-1 sites, 10 Sp1 sites and 1 estrogen response elements (ERE) are located in the VEGF gene promoter, and these are widely distributed across the 3-kb stretch of the promoter sequence. PR and ER complexes have been reported to activate AP-1 sites. It has been demonstrated that VEGF induction is mediated by activation of ER and that this effect is inhibited by treatment with the pure antiestrogen ICI 182,780 or the agonist/antagonist tamoxifen in human breast cancer cells (MCF-7 and T47D). The understanding of the molecular mechanisms involved in the regulation of VEGF expression by P4 and E2 will be helpful for the development of new cancer therapies, particulary in sex steroid responsive tumors. © 2013 Nova Science Publishers, Inc. All rights reserved.
Entidades citadas de la UNAM:
ISBN:
9781626186552
Editorial:
Nova Science Publishers, Inc. Nombre de la publicación:
Regulation of VEGF expression by progesterone and estradiol in normal and cancer cells
Página inicial:
169
Página final:
182
Tipo de producto:
Capítulo de un Libro
