Expression and inactivation of glycogen synthase kinase 3 alpha/ beta and their association with the expression of cyclin D1 and p53 in oral squamous cell carcinoma progression

Background: The study aims to evaluate the expression and activity of glycogen synthase kinase 3 isoforms alpha/beta (GSK3 alpha/beta) and to assess their oncogenic potential through a correlation with the expression of cyclin D1 and p53 in oral cancer. Methods: The expression of total and phosphorylated GSK3 alpha/beta as well as cyclin D1 and p53 together with their interaction were assessed in human oral cancer tissue samples, apparently normal adjacent tissues, benign tumor samples, premalignant lesions and healthy normal tissues (total 179) using various methods, such as immunohistochemistry, Western blot assays, immunoprecipitation and RT-PCR analysis. Results: The expression of GSK3 beta was significantly higher relative to GSK3 alpha indicating the greater role of the beta isoform in oral cancer. Among various types of oral cancers, OSCC (of the lip and tongue) showed elevated expression of GSK3 alpha/beta, and the expression was correlated with disease progression. The increased expression of pS(21)GSK3 alpha and pS(9)GSK3 beta not only correlated positively with cyclin D1 and p53 expression in tongue cancer progression but a gradual shift of their expression from the cytoplasmic to the nuclear compartment and overall disease severity was also observed. The interaction of GSK3 beta-cyclin D1 and the positive correlation of pS(9)GSK3 beta and the transcription of cyclin D1 were observed. Conclusions: These results demonstrate that the inactivation of GSK3 beta is an important event in OSCC and can be used as a marker for assessing disease severity and may be exploited for therapeutic intervention.