MDM2 is Overexpressed and Regulated by the Eukaryotic Translation Initiation Factor 4E (eIF4E) in Human Squamous Cell Carcinoma of Esophagus

Abstract

We investigated the association between the increased eukaryotic translation initiation factor 4E (eIF4E) level and MDM2 overexpression in the esophageal cancer tissue and cells. This was a retrospective study of specimens from esophageal cancer patients treated over a 5-year period in a Taiwan university hospital. The predictor variable was eIF4E level in esophageal tumors and CE48T/VGH and TE6 esophageal carcinoma cell lines. The main outcome variable was MDM2 overexpression. Appropriate descriptive and univariate statistics were computed, and a P value of <0.05 was considered statistically significant. There were two study sample groups. Immunohistochemistry analyses of the first sample group (51 esophageal tumors) revealed that 19 specimens demonstrated MDM2 elevation and 20 specimens had eIF4E overexpression. eIF4E elevation was evidenced by accumulation of the protein in the cytoplasm. There was a significant association between the eIF4E and MDM2 expression (P < 0.001). Western blot analysis and semiquantitative reverse transcriptase-polymerase chain reaction of the second specimen group (20 pairs of tumors and normal tissues) revealed the co-elevation of MDM2 and eIF4E (P = 0.008). There was no increased mdm2 transcript in most of the specimens. Without significant alterations in the mdm2 mRNA level and subcellular distribution, MDM2 protein was upregulated in CE48T/VGH cultured cells expressing ectopic eIF4E. Conversely, reduction of eIF4E by specific siRNA enabled TE6 cells synthesizing reduced amounts of MDM2. Our findings indicate that MDM2 protein levels are strongly associated with and regulated by eIF4E in a posttranscriptional mechanism in esophageal cancer.