SMAD4 Expression and Its Association With Treatment Resistance and Clinical Outcomes in Oral Squamous Cell Carcinoma Treated With Preoperative Chemoradiotherapy.

BACKGROUND: Small mothers against decapentaplegic homologue 4 (SMAD4) plays an important role in transforming growth factor (TGF)-β signaling and is associated with various cancers. However, little is known about SMAD4 expression in oral squamous cell carcinoma (OSCC). AIM: To investigate the clinical and biological significance of SMAD4 expression in OSCC. METHODS AND RESULTS: Immunohistochemical analysis was performed to detect SMAD4 expression in 90 OSCC specimens obtained from patients who underwent preoperative chemoradiotherapy and surgery (phase II study). We also investigated the correlation between SMAD4 expression and various clinicopathological features. In vitro experiments were performed to assess the effects of SMAD4 expression on chemosensitivity and changes in apoptosis-related molecules. Notably, low SMAD4 expression was significantly correlated with an increased risk of lymph node metastasis, poor response to chemoradiotherapy, and adverse prognosis in patients with OSCC who underwent preoperative 5-FU-based chemoradiotherapy. Additionally, SMAD4 downregulation in OSCC cells decreased sensitivity to cisplatin and 5-fluorouracil and was associated with an increase in cIAP2 expression. CONCLUSION: The reduced expression of SMAD4 has been linked to both chemotherapy resistance and prognosis in OSCC. However, it may not function as an independent prognostic biomarker. Further research is necessary to determine whether these findings can be generalized to the broader OSCC population.