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MDM-2 oncoprotein overexpression in laryngeal squamous cell carcinoma: association with wild-type p53 accumulation
G Pruneri1, L Pignataro, N Carboni
1II Servizio di Anatomia Patologica, Università di Milano, Italy.
Abstract:
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.
Insights
MDM-2 gene amplification is not observed in laryngeal squamous cell carcinomas. However, MDM-2 protein overexpression occurs frequently, suggesting a role in early laryngeal cancer development by inactivating p53 pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The MDM-2 gene product inhibits the tumor suppressor protein p53.
- MDM-2 overexpression is a potential mechanism for p53 pathway inactivation in tumors.
- MDM-2 overexpression can result from gene amplification or increased mRNA expression.
Purpose of the Study:
- To investigate MDM-2 gene amplification and protein overexpression in laryngeal squamous cell carcinomas.
- To assess the correlation between MDM-2 alterations, p53 status, and clinicopathological features.
- To determine if MDM-2 overexpression plays a role in early laryngeal tumorigenesis.
Main Methods:
- Analysis of MDM-2 gene amplification and protein overexpression using immunohistochemistry.
- Study included 46-50 cases of laryngeal squamous cell carcinomas.
- p53 gene alterations in exons 5-9 were previously analyzed.
Main Results:
- No MDM-2 gene amplification was detected in any laryngeal carcinoma cases.
- MDM-2 nuclear immunoreactivity (overexpression) was found in 34% of tumors.
- MDM-2 overexpression was also observed in normal mucosa, preneoplastic lesions, and severe dysplasia, often coexisting with wild-type p53.
Conclusions:
- MDM-2 gene amplification is unlikely to be involved in laryngeal carcinoma development.
- MDM-2 protein overexpression is a frequent event in laryngeal lesions, including early stages.
- MDM-2 overexpression may inactivate p53, contributing to the early stages of laryngeal cancer tumorigenesis.