The HAUSP gene plays an important role in non‐small cell lung carcinogenesis through p53‐dependent pathways

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 p 53 gene status have been studied in relation to the expression of p 53 target genes in 131 patients with non‐small cell lung cancer (NSCLC). p 53 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 21 , 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 p 53 . Concerning tumour histology, HAUSP mRNA expression was significantly lower in adenocarcinomas than in squamous cell carcinomas ( p = 0.0038), while the frequency of p 53 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 p 53 gene status. In total, 93 carcinomas (71.0%) showed either mutant p 53 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 p 53 and positive HAUSP expression ( p = 0.0440 and p = 0.0046, respectively). In addition, the simultaneous evaluation of both HAUSP expression and p 53 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 © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.