Combined Biomarker System Predicts Prognosis in Patients with Metastatic Oral Squamous Cell Carcinoma

SIMPLE SUMMARY: Metastasis poses a significant challenge in the advancement of oral squamous cell carcinoma, and it is closely associated with the epithelial–mesenchymal transition of tumor cells. In the current study, we investigated the expression profiles of connexin 43 and EMMPRIN, along with the known epithelial–mesenchymal transition markers E-cadherin and vimentin, using immunohistochemistry throughout the metastatic process. Additionally, we examined their prognostic impact both as a combined marker system and individually. The findings of this study reveal that a combined biomarker system can reliably predict overall and disease-free survival. Notably, alterations in EMMPRIN expression were found to have the highest prognostic impact, suggesting its potential as a therapeutic target for antimetastatic interventions. ABSTRACT: Background: Metastatic oral squamous cell carcinoma (OSCC) is associated with poor patient prognosis. Metastasis is a complex process involving various proteins, tumor cell alterations, including changes attributable to the epithelial-to-mesenchymal transition (EMT) process, and interactions with the tumor microenvironment (TME). In this study, we investigate a combined protein marker system consisting of connexin 43 (Cx43), EMMPRIN (CD147), E-cadherin, and vimentin, with a focus on their roles in the invasive metastatic progression of OSCC and their potential utility in predicting prognosis. Methods: We conducted an immunohistochemical analysis to assess the protein expression profiles of Cx43, EMMPRIN, E-cadherin, and vimentin using tissue samples obtained from 24 OSCC patients. The metastatic process was mapped through different regions of interest (ROIs), including adjacent healthy oral mucosa (OM), center of primary OSCC, invasive front (IF), and local cervical lymph node metastases (LNM). The primary clinical endpoints were disease-free survival (DFS) and overall survival (OS). Results: Substantial changes in the expression profiles of the different marker proteins were observed among the different ROIs, with all p-values < 0.05, signifying statistical significance. Multivariable Cox regression analysis results showed a significant effect of increased EMMPRIN expression toward the IF on DFS (p = 0.019) and OS (p = 0.023). Furthermore, the combined predictive analysis showed a significant predictive value of the marker system for DFS (p = 0.0017) and OS (p = 0.00044). Conclusions: The combined marker system exhibited a significant ability to predict patient prognosis. An increase in EMMPRIN expression toward the IF showed the strongest effect and could be an interesting new antimetastatic therapy approach.