MDM-2 oncoprotein overexpression in laryngeal squamous cell carcinoma: association with wild-type p53 accumulation

Mod Pathol. 1997 Aug;10(8):785-92.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Blotting, Southern
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • DNA / analysis
  • Female
  • Humans
  • Immunohistochemistry
  • Laryngeal Neoplasms / genetics
  • Laryngeal Neoplasms / metabolism*
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • DNA
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2