The presence of an intronic deletion inp73and high levels ofZEB1alter theTAp73/ΔTAp73ratio in colorectal carcinomas

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TAp73 variants largely mimic p53 suppressor activities, while ΔTAp73 forms act as oncogenes through the inactivation of p53 and TAp73. The present study analysed howTAp73andΔTAp73levels might be affected by the presence of a 73 bp deletion in a regulatory region ofp73. The clinical relevance of this deletion was also examined. ZEB1 can bind to the region repressingp73transcriptionin vitro. The relationship betweenZEB1andp73variant expression levels was studied in the context of this deletion and the levels of theZEB1cofactorsp300andCtBP. Tumour and normal tissue from 81 colorectal cancer patients was analysed to evaluate firstly the levels ofTAp73, ΔTAp73(ΔEx2p73, ΔEx2/3p73, andΔNp73),ZEB1,p300, andCtBPby 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 ofp73were co-up-regulated in tumour tissues. Overexpression ofp73variants 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 withTAp73down-regulation. In those cases harbouring the deletion, the levels ofZEB1and those ofΔEx2p73, ΔEx2/3p73, andΔNp73correlated directly. Variations in the concentration ofp300affected the observed correlations betweenZEB1and the differentp73variants. In conclusion, in colorectal cancer, the 73 bp deletion in the first intron of thep73gene and different expression levels ofZEB1andp300may act in concert to affect the ratio ofTAp73/ΔTAp73forms, favouringp73oncogenic variants. In addition, up-regulation ofp73oncogenic isoforms predicts a poor prognosis based on its relationship with advanced tumour stage.

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