The presence of an intronic deletion in p73 and high levels of ZEB1 alter the TAp73/DeltaTAp73 ratio in colorectal carcinomas.
TAp73 variants largely mimic p53 suppressor activities, while DeltaTAp73 forms act as oncogenes through the inactivation of p53 and TAp73. The present study analysed how TAp73 and DeltaTAp73 levels might be affected by the presence of a 73 bp deletion in a regulatory region of p73. The clinical relevance of this deletion was also examined. ZEB1 can bind to the region repressing p73 transcription in vitro. The relationship between ZEB1 and p73 variant expression levels was studied in the context of this deletion and the levels of the ZEB1 cofactors p300 and CtBP. Tumour and normal tissue from 81 colorectal cancer patients was analysed to evaluate firstly the levels of TAp73, DeltaTAp73 (DeltaEx2p73, DeltaEx2/3p73, and DeltaNp73), ZEB1, p300, and CtBP by quantitative real-time RT-PCR, and secondly the presence of the 73 bp deletion. Tumour characteristics were examined in each patient. Suppressor and oncogenic isoforms of p73 were co-up-regulated in tumour tissues. Overexpression of p73 variants was associated with adverse tumour features. The 73 bp deletion was present in 40% of the patients and was associated with adverse pathological parameters of the tumours and also with TAp73 down-regulation. In those cases harbouring the deletion, the levels of ZEB1 and those of DeltaEx2p73, DeltaEx2/3p73, and DeltaNp73 correlated directly. Variations in the concentration of p300 affected the observed correlations between ZEB1 and the different p73 variants. In conclusion, in colorectal cancer, the 73 bp deletion in the first intron of the p73 gene and different expression levels of ZEB1 and p300 may act in concert to affect the ratio of TAp73/DeltaTAp73 forms, favouring p73 oncogenic variants. In addition, up-regulation of p73 oncogenic isoforms predicts a poor prognosis based on its relationship with advanced tumour stage.
Domínguez
G
G
Department of Medical Oncology, Hospital Universitario Puerta de Hierro, Madrid, Spain. domingg@hotmail.com
Peña
C
C
Silva
J
J
García
J M
JM
García
V
V
Rodríguez
R
R
Cantos
B
B
Citores
M J
MJ
España
P
P
Bonilla
F
F
D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D050881:E1A-Associated p300 Protein / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D047668:Inteins / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C486307:ZEB1 protein, human; D029961:Zebrafish Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1; C000606369:delta Np73 protein, human; C477072:tp73 protein, zebrafish; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human