Over-expression of 14-3-3zeta is an early event in oral cancer.

Background: The functional and clinical significance of 14-3-3 proteins in human cancers remain largely undetermined. Earlier, we have reported differential expression of 14-3-3zeta mRNA in oral squamous cell carcinoma (OSCC) by differential display.

Methods: The clinical relevance of 14-3-3zeta protein in oral tumorigenesis was determined by immunohistochemistry in paraffin embedded sections of oral pre-malignant lesions (OPLs), OSCCs and histologically normal oral tissues and corroborated by Western Blotting. Co-immunoprecipitation assays were carried out to determine its association with NFkappaB, beta-catenin and Bcl-2.

Results: Intense immunostaining of 14-3-3zeta protein was observed in 61/89 (69%) OPLs and 95/120 (79%) OSCCs. Immunohistochemistry showed significant increase in expression of 14-3-3zeta protein from normal mucosa to OPLs to OSCCs (ptrend < 0.001). Significant increase in expression of 14-3-3zeta protein was observed as early as in hyperplasia (p = 0.009), with further elevation in moderate and severe dysplasia, that was sustained in OSCCs. These findings were validated by Western blotting. Using Co-immunoprecipitation, we demonstrated that 14-3-3zeta protein binds to NFkappaB, beta-catenin and Bcl-2, suggesting its involvement in cellular signaling, leading to proliferation of oral cancer cells.

Conclusion: Our findings suggest that over-expression of 14-3-3zeta is an early event in oral tumorigenesis and may have an important role in its development and progression. Thus, 14-3-3zeta may serve as an important molecular target for designing novel therapy for oral cancer.