Investigating GSK-3β as a Potential Prognostic Marker for Metastasis in Head and Neck Squamous Cell Carcinoma: A Preliminary Study on the Crossroads of GABAergic and Wnt Signaling

Abstract

The purpose of this study was to determine whether glycogen synthase kinase-3β (GSK-3β) mediates the link between γ-aminobutyric-acid (GABA) signaling and Wnt/β-catenin activation in the progression of head and neck squamous cell carcinoma (HNSCC) and to evaluate whether tumor GSK-3β expression can predict cervical nodal metastasis.Forty patients diagnosed with primary HNSCC supplied paired specimens of normal, dysplastic, and tumor tissues. Immunohistochemistry was performed for GABA-BR1/2, β-catenin, and GSK-3β. Nonparametric tests, Spearman's correlation, and multivariable logistic regression (adjusted for age, sex, T-stage, and site) were utilized to investigate clinicopathological associations. Receiver operating characteristic analysis was applied to evaluate the predictive performance for metastasis.The expression of GABA-BR1/2 and nuclear β-catenin increased progressively from normal mucosa to dysplasia to carcinoma (all p < 0.001). A tumor GSK-3β score ≥ 6 independently predicted nodal metastasis after adjusting for standard clinicopathological variables (adjusted odds ratio = 8.8, 95% confidence interval: 1.9-39.6; p = 0.005), with an area under the curve (AUC) of 0.84. While promising, this AUC should be interpreted cautiously due to the small sample size. Multivariate analysis confirmed functional interactions between the GABAergic and Wnt pathways.GSK-3β appears to integrate GABAergic and Wnt/β-catenin signaling and may serve as a robust, independent biomarker of metastatic risk in HNSCC. Although preliminary, these findings support the potential clinical value of GSK-3β and warrant validation in larger, multicenter cohorts before considering its incorporation into risk stratification models or targeted therapeutic strategies.