Loss of MDM2 expression in human head and neck squamous cell carcinomas and clinical significance

The transforming potential of the MDM2 oncogene has been attributed to the overproduction of the protein. In order to investigate regulation of MDM2 e xpression in head and neck squamous cell carcinomas, we analysed MDM2 gene amplification, and mRNA and protein expression in tumour specimens from 62 patients, in cell lines, and in normal epithelium adjacent to tumours or ob tained from healthy patients. Additionally, TP53-induced MDM2-P2 transcript ion was evaluated and compared with TP53 status. MDM2 gene amplification an d mRNA over-expression is infrequent, 7 and 9%. respectively. The predomina nt transcript codes for full-length MDM2 protein (90kD) and the level of al ternatively spliced forms is not significant. We show that only 47% of tumo urs exhibit MDM2 immunostaining in more than one third of the neoplastic ce lls, and thus more than half of the tumours display no or low levels of MDM 2 protein. In contrast, MDM2 protein is always detectable in basal and para basal cells of morphologically normal epithelium outside the invasively gro wing tumour, as well as in a normal uvula sample. Similarly, the total amou nt of MDM2 transcripts analysed by reverse transcriptase-polymerase chain r eaction is reduced in tumour samples compared to normal tissues, essentiall y due to a decrease in P2 transcript levels. The relationship between mutat ed p53 status and low levels of MDM2 found in cell lines is also observed t o a certain extent in primary tumour samples. Overall, there is a high freq uency or TP53 mutation and under-expression of MDM2 in the head and neck tu mours. Moreover, a significant association of decreased MDM2 expression is observed with advanced tumour stage and 3 years survival. (C) 2001 Elsevier Science Ltd. All rights reserved.