The presence of an intronic deletion in p73 and high levels of ZEB1 alter the TAp73/ΔTAp73 ratio in colorectal carcinomas
The presence of an intronic deletion in p73 and high levels of ZEB1 alter the TAp73/ΔTAp73 ratio in colorectal carcinomas
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DOI：
10.1002/path.2066
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发表时间：
2006-12-01
影响因子：
7.3
通讯作者：
Bonilla, F.
中科院分区：
文献类型：
--
作者：
Dominguez, G.;Pena, C.;Bonilla, F.
TAp 73变体在很大程度上模拟p53抑制活性，而Δ TAp 73形式通过p53和TAp 73的失活而充当癌基因。本研究分析了TAp 73和Δ TAp 73水平可能受到p73调控区73 bp缺失的影响。还检查了这种缺失的临床相关性。ZEB 1在体外可与抑制p73转录的区域结合。ZEB 1和p73变体表达水平之间的关系进行了研究，在这种缺失和ZEB 1辅因子p300和CtBP的水平。分析来自81名结直肠癌患者的肿瘤和正常组织，首先通过定量实时RT-PCR评估TAp 73、Δ TAp 73（Δ Ex 2 p73、Δ Ex 2/3 p73和Δ Np 73）、ZEBI、p300和CtBP的水平，其次评估73 bp缺失的存在。检查每例患者的肿瘤特征。抑癌基因和致癌亚型p73共同上调肿瘤组织。p73变异体的过表达与不良肿瘤特征相关。73 bp缺失存在于40%的患者中，并且与肿瘤的不良病理学参数以及TAp 73下调相关。在那些携带缺失的病例中，ZEB 1的水平与Delta Ex 2 p73、Delta Ex 2/3 p73和Delta Np 73的水平直接相关。p300浓度的变化影响了ZEB 1和不同p73变体之间的相关性。总之，在结直肠癌中，p73基因第一内含子中的73 bp缺失以及ZEB 1和p300的不同表达水平可能共同影响TAp 73/Delta TAp 73形式的比例，有利于p73致癌变体。此外，p73致癌异构体的上调预测预后不良的基础上，其与先进的肿瘤分期。版权所有（c）2006大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
TAp73 variants largely mimic p53 suppressor activities, while Delta TAp73 forms act as oncogenes through the inactivation of p53 and TAp73. The present study analysed how TAp73 and Delta TAp73 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, Delta TAp73 (Delta Ex2p73, Delta Ex2/3p73, and Delta Np73), ZEBI, 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 Delta Ex2p73, Delta Ex2/3p73, and Delta Np73 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/Delta TAp73 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. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.