Clinical significance of 14-3-3 zeta in human esophageal cancer.

We recently found 14-3-3 zeta to be overexpressed in esophageal squamous cell carcinomas (ESCCs) by differential display. In the present study we determined the clinical significance of 14-3-3 zeta in esophageal tumorigenesis. Immunohistochemical analysis was carried out in 61 ESCCs, 33 dysplasia samples, 14 hyperplasia samples and 7 matched histologically normal esophageal tissues and correlated with clinicopathological parameters. Cytoplasmic expression of 14-3-3 zeta protein was observed in 95% of ESCCs; 63% of tumors also showed nuclear localization. All hyperplastic and dysplastic tissues distant from ESCCs as well as dysplastic endoscopic biopsies showed cytoplasmic immunopositivity for 14-3-3 zeta, while nuclear localization was observed in 58% of dysplasia and 36% of hyperplasia samples. Matched distant histologically normal epithelia either showed basal cytoplasmic expression of 14-3-3 zeta or no detectable nuclear expression of the protein. Interestingly, immunopositivity observed in normal esophageal tissues and early hyperplasia was confined to cytoplasm only, though significant nuclear expression was detected in dysplasia and ESCC. Immunoblotting and RT-PCR analyses further confirmed 14-3-3 zeta expression in dysplasia and ESCC. To our knowledge, this is the first report demonstrating overexpression of 14-3-3 zeta in esophageal hyperplasia, dysplasia and squamous cell carcinoma, suggesting that alteration in its expression occurs in early stages and is associated with esophageal tumorigenesis.

Alterations in MDM2 expression in esophageal squamous cell carcinoma: relationship with p53 status.

In view of the significance of MDM2 as a regulator as well as critical target of wild type p53, this study was undertaken to determine the alteration in MDM2 expression in esophageal squamons cell carcinoma (ESCC) and its relationship to clinicopathological parameters as well as p53gene and protein status. Immunohistochemical analysis of MDM2 and p53 proteins on paraffin embedded sections from 64 surgically resected ESCCs and matched histologically normal tissues showed overexpression of MDM2 protein in 23/64 (36%) ESCCs, while the histopathologically normal esophageal tissues did not show detectable level of MDM2 immunoreactivity. Interestingly, MDM2 /p53 + phenotype was observed in 37/64 (58%) cases. None of the cases with p53 mis-sense mutations (12/30, 40%) showed detectable level of MDM2 protein. Missense p53 mutations were significantly associated with discordant p53 + /MDM2 immunophenotype (p= 0.004). The most intriguing feature of the study was accumulation of MDM2 in the absence of detectable p53 in 11% of and overexpression of MDM2 and p53 in 25% of ESCCs, suggesting a p53-independent role for MDM2 in a subset of tumors. These results underscore the involvement of MDM2 in p53-dependent and -independent pathways in the pathogenesis of esophageal cancer in the Indian population.