Background Oral squamous-cell carcinoma (OSCC) is the most common oral malignancy with a dismal prognosis. Exploring markers predict tumor behavior, help in diagnosis, and therapy is crucial. Actinin alpha 1 (ACTN1) is known to be a prognostic biomarker in acute myeloid leukemia. It also plays a role in many tumors. The epithelial–mesenchymal transition has been suggested as one of the mechanisms of action for ACTN1. The role of ACTN1 in OSCC is still unclear. This study aimed at evaluating the role of ACTN1 in OSCC. Materials and methods This study was performed on 68 OSCC cases and 68 normal-tissue samples. Immunohistochemical staining of ACTN1 and E-cadherin was done and evaluated. Correlation to clinicopathologic parameters and survival was statistically analyzed. Results ACTN1 expression was high in 47 (69.1%) cases. E-cadherin expression was high in 27 (39.7%) cases with a significant inverse correlation between both expressions. Cases with high ACTN1/low E-cadherin expressions were significantly associated with tumor grade, stage, presence of tumor buds, lymph-node metastasis, recurrence, and distant metastasis. They also show statistically significant shorter overall survival and disease-free survival. Conclusion ACTN1 is a promising prognostic marker that correlates with tumor staging, node metastasis, and poor survival. It might also serve as a therapeutic target in OSCC. Its role in epithelial–mesenchymal transition is strongly suggested by this study.
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