p73 Isoforms affect VEGF, VEGF165b and PEDF expression in human colorectal tumors: VEGF165b 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 DeltaTAp73- 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, DeltaTAp73, VEGF, VEGF(165)b, PEDF and E2F-1 by quantitative real-time RT-PCR, (ii) 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) DeltaEx2p73 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.
Department of Medical Oncology, Hospital Universitario Puerta de Hierro, 28035 Madrid, Spain.
Raquel
R
Díaz
Cristina
C
Peña
Javier
J
Silva
Yolanda
Y
Lorenzo
Vanesa
V
García
José M
JM
García
Antonio
A
Sánchez
Pablo
P
Espinosa
Rosario
R
Yuste
Félix
F
Bonilla
Gemma
G
Domínguez
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009389:Neovascularization, Pathologic; D009414:Nerve Growth Factors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D000099174:Pigment Epithelium-Derived Factor
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D005136:Eye Proteins; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D015843:Serpins; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C000606460:TP73 protein, human; C467484:VEGFA protein, human