The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways
The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways
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DOI：
10.1002/path.1931
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发表时间：
2006-04-01
影响因子：
7.3
通讯作者：
Sumitomo, S
中科院分区：
文献类型：
--
作者：
Masuya, D;Huang, C;Sumitomo, S
疱疹病毒相关的泛素特异性蛋白酶（HAUSP）通过去泛素化直接稳定肿瘤抑制因子p53。因此，HAUSP基因可能在肿瘤发生中起重要作用。本文研究了131例非小细胞肺癌（NSCLC）患者HAUSP表达和p53基因状态与p53靶基因表达的关系。采用聚合酶链反应-单链构象多态性分析（PCR-SSCP）和测序法检测p53基因的表达情况。采用定量逆转录聚合酶链反应（RT-PCR）检测HAUSP、p2 1和bax基因表达。免疫组化检测p53、HAUSP、mdm 2、p21和bax蛋白表达。59例癌（45.0%）HAUSP表达降低，58例癌（44.3%）有p53突变。关于肿瘤组织学，HAUSP mRNA表达在腺癌中显著低于鳞状细胞癌（p = 0.0038），而p53突变频率在鳞状细胞癌中显著高于腺癌（p = 0.0461）。根据p53基因状态，HAUSP mRNA表达无显著差异。总共有93例癌（71.0%）显示突变型p53或HAUSP表达降低。HAUSP的下调与p53蛋白表达的降低有关（在具有野生型p53的肿瘤中p = 0.0593，在具有突变型p53的肿瘤中p = 0.0004）。此外，与野生型p53和阳性HAUSP表达的肿瘤相比，突变型p53或HAUSP表达降低的肿瘤中p21和bax蛋白表达显著降低（分别为p = 0.0440和p = 0.0046）。此外，同时评估HAUSP表达和p53基因状态是腺癌患者预后不良的重要指标（风险比4.840，p = 0.0357）。这些结果表明，HAUSP基因表达的减少可能通过p53依赖性途径在NSCLC癌变中发挥重要作用，特别是在腺癌中。版权所有（c）2006大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Herpesvirus-associated ubiquitin-specific protease (HAUSP) directly stabilizes the tumour suppressor p53 by de-ubiquitination. Therefore, the HAUSP gene might play an important role in carcinogenesis. In this paper, HAUSP expression and p53 gene status have been studied in relation to the expression of p53 target genes in 131 patients with non-small cell lung cancer (NSCLC). p53 gene status was evaluated by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by sequencing. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) was performed to evaluate the gene expression of HAUSP, p 2 1, and bax. Immunohistochemistry was performed to evaluate the protein expression of p53, HAUSP, mdm2, p21, and bax. Fifty-nine carcinomas (45.0%) showed reduced expression of HAUSP, and 58 carcinomas (44.3%) had mutations of p53. Concerning tumour histology, HAUSP mRNA expression was significantly lower in adenocarcinomas than in squamous cell carcinomas (p = 0.0038), while the frequency of p53 mutation was significantly higher in squamous cell carcinomas than in adenocarcinomas (p = 0.0461). There was no significant difference in HAUSP mRNA expression according to p53 gene status. In total, 93 carcinomas (71.0%) showed either mutant p53 or reduced HAUSP expression. The down-regulation of HAUSP was associated with reduced p53 protein expression (p = 0.0593 in tumours with wild-type p53 and p = 0.0004 in tumours with mutant p53). Furthermore, p21 and bax protein expression was significantly lower in tumours with either mutant p 53 or reduced HAUSP expression than in tumours with both wild-type p53 and positive HAUSP expression (p = 0.0440 and p = 0.0046, respectively). In addition, the simultaneous evaluation of both HAUSP expression and p53 gene status was a significant indicator of poor prognosis in adenocarcinoma patients (hazard ratio 4.840, p = 0.0357). These results suggest that reduction of HAUSP gene expression may play an important role in NSCLC carcinogenesis, especially in adenocarcinomas, through p53-dependent pathways. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.