MDM-2 oncoprotein overexpression in laryngeal squamous cell carcinoma: association with wild-type p53 accumulation.
The MDM-2 gene encodes for a nuclear phosphoprotein that binds p53 and inhibits its ability to activate transcription by concealing the p53 activation domain. It has been suggested that MDM-2 overexpression might represent an alternative mechanism by which p53-mediated pathways are inactivated in human tumors. MDM-2 overexpression can be detected by immunohistochemical analysis as a result of gene amplification and/or increased mRNA expression. We studied MDM-2 gene amplification and protein overexpression in 46 and 50 cases, respectively, of laryngeal squamous cell carcinomas previously analyzed for p53 gene alterations. Not one of the cases showed MDM-2 gene amplification, whereas MDM-2 nuclear immunoreactivity was found in 17 tumors (34%). In 10 of these, coexpression of p53 protein was detectable in the absence of gene mutations in exons 5 through 9 (P = .03). Likewise, MDM-2 was also overexpressed in 18 (46%) of 39 morphologically normal mucosa samples, 15 (50%) of 30 preneoplastic lesions, and 9 (40%) of 22 cases of severe dysplasia. Finally, we found no significant correlations between MDM-2 expression (neither per se nor in association with wild-type or mutated p53), and the evaluated clinicopathologic parameters of histologic grade, lymph node status, or clinical stage. Our results suggest that MDM-2 gene amplification might not occur in laryngeal carcinomas and that MDM-2 protein overexpression might represent an alternative mechanism by which p53 is inactivated in the early stages of laryngeal cancer tumorigenesis.
Pruneri
G
G
II Servizio di Anatomia Patologica, Università di Milano, Italy.
Pignataro
L
L
Carboni
N
N
Luminari
S
S
Capaccio
P
P
Neri
A
A
Buffa
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015139:Blotting, Southern; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007822:Laryngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2