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Herpesvirus-associated ubiquitin-specific protease (HAUSP) directly stabilizes the tumour suppressor p53 by de-ubiquitination. Therefore, theHAUSPgene might play an important role in carcinogenesis. In this paper,HAUSPexpression andp53gene status have been studied in relation to the expression ofp53target genes in 131 patients with non-small cell lung cancer (NSCLC).p53gene 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 ofHAUSP,p21, andbax. Immunohistochemistry was performed to evaluate the protein expression of p53, HAUSP, mdm2, p21, and bax. Fifty-nine carcinomas (45.0%) showed reduced expression ofHAUSP, and 58 carcinomas (44.3%) had mutations ofp53. Concerning tumour histology,HAUSPmRNA expression was significantly lower in adenocarcinomas than in squamous cell carcinomas (p= 0.0038), while the frequency ofp53mutation was significantly higher in squamous cell carcinomas than in adenocarcinomas (p= 0.0461). There was no significant difference inHAUSPmRNA expression according top53gene status. In total, 93 carcinomas (71.0%) showed either mutantp53or reducedHAUSPexpression. The down-regulation ofHAUSPwas associated with reduced p53 protein expression (p= 0.0593 in tumours with wild-type p53 andp= 0.0004 in tumours with mutant p53). Furthermore, p21 and bax protein expression was significantly lower in tumours with either mutantp53or reducedHAUSPexpression than in tumours with both wild-typep53and positiveHAUSPexpression (p= 0.0440 andp= 0.0046, respectively). In addition, the simultaneous evaluation of bothHAUSPexpression andp53gene status was a significant indicator of poor prognosis in adenocarcinoma patients (hazard ratio 4.840,p= 0.0357). These results suggest that reduction ofHAUSPgene expression may play an important role in NSCLC carcinogenesis, especially in adenocarcinomas, through p53-dependent pathways.