P73 Isoforms Affect Vegf, Vegf(165)B And Pedf Expression In Human Colorectal Tumors: Vegf(165)B Downregulation As A Marker Of Poor Prognosis

The secreted mitogen vascular endothelial growth factor, VEGF, plays a pivotal role in angiogenesis. Hypoxia, inactivation of p53 and oncogenic K-Ras induce VEGF expression. Other factors such as p73 may also affect VEGF levels. Curiously, p73 may also regulate angiogenesis by affecting the expression of the pigment epithelium-derived factor, PEDF. Additionally, VEGF might harbor additional functions through the activation of E2F transcription factors. Recently, a new VEGF variant formed by alternative splicing, VEGF(165)b, has been described as exerting anti-angiogenic activity. We study here whether p73 isoforms levels -TAp73 and Delta TAp73- and p53 and K-Ras status affect the expression of the above-mentioned angiogenesis-related genes (through the correlation between their expressions), the prognostic value of VEGF(165)b and PEDF and the correlation between VEGF and E2F-1 levels. Tumor and normal tissue of 112 colorectal cancer patients was analyzed to evaluate: (i) levels of TAp73, Delta TAp73, VEGF, VEGF(165)b, PEDF and E2F-1 by quantitative real-time RT-PCR, (H) p53 status by immunohistochemistry and (iii) mutations in the first exon of K-Ras by PCR-SSCP. Tumor characteristics were examined in each patient. Associations were observed between: (i) specific p73 isoforms and VEGF and VEGF(165)b expression; (ii) Delta Ex2p73 variant and downregulation of PEDF; (iii) VEGF and PEDF expression; (iv) inactive p53 and VEGF(165)b levels; (v) oncogenic K-Ras and PEDF downregulation; (vi) E2F-1 and VEGF expressions; (vii) VEGF(165)b downregulation and poor prognosis parameters of tumors. We conclude that the levels of p73 isoforms could affect the expression of VEGF, VEGF(165)b and PEDF. This scenario becomes complicated because a feedback between VEGF and PEDF may exist. VEGF may activate the E2F-1 factor. Mutations in K-Ras could negatively regulate PEDF expression. p53 inactivation might result in compensatory mechanisms such as over-expression of VEGF(165)b. Our data support the role of VEGF(165)b as a tumor suppressor factor in colorectal carcinogenesis and its possible prognosis value. (C) 2008 Wiley-Liss, Inc.