Background: Epithelial–mesenchymal transition (EMT) enables tumor cell invasion and metastasis. Many studies have demonstrated the critical role of EMT in lymph node metastasis in oral squamous cell carcinoma (OSCC). During EMT, epithelial cancer cells lose intercellular adhesion and apical–basal polarity and acquire mesenchymal properties such as motility and invasiveness. A significant feature of EMT is cadherin switching, involving the downregulation of E-cadherin and upregulation of N-cadherin. The TGF-β/SMAD pathway can also induce EMT. We aimed to evaluate EMT markers as predictors of lymph node metastasis in OSCC. Methods: We performed genetic profiling of 159 primary OSCCs from TCGA and analyzed the expression of EMT markers, including cadherin switch genes (CDH1, CDH2), and TGF-β/SMAD pathway genes. Samples were divided into advanced (stage III–IV) and early (stage I–II) stage groups. Differential expression analysis was performed, as well as an independent validation study containing fresh OSCC samples. Results: TGF-β/SMAD pathway genes such as SMAD6 were upregulated in advanced stage tumors. N-cadherin and SNAIL2 were overexpressed in node-positive tumors. Keratins were downregulated in these groups. Conclusion: Our findings demonstrate that EMT marker expression correlates with lymph node metastasis in OSCC. Developing therapies targeting regulators such as N-cadherin may prevent metastasis and improve outcomes.

Background: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with a poor prognosis. Surgical removal of the primary tumor and regional lymph nodes (LNs) remains the fundamental treatment for OSCC, although 40% of patients are negative for LN metastasis. The epithelial–mesenchymal transition (EMT) plays a crucial role in OSCC progression by enabling epithelial cells to acquire mesenchymal traits, thereby facilitating migration and metastasis. Smad4, a tumor suppressor protein, is known to mediate EMT and is associated with poor prognosis and metastasis; however, its precise pro-metastatic role in OSCC via EMT remains unclear. Aims: We hypothesize that EMT and Smad4 could serve as practical diagnostic tools for personalized OSCC treatment. Methods: In this study, we analyzed 23 OSCC samples from Tzafon Medical Center, comparing the expression of Smad4 and EMT markers with clinical and histopathological data. Additionally, an OSCC cell model with and without Smad4 mutation was used to investigate tumor phenotypes, including proliferation and invasion, in relation to EMT markers. Results and Conclusion: Our findings reveal a strong correlation between EMT markers, Smad4 expression, and OSCC pathological staging, with the cell model further confirming the link between Smad4 and EMT markers. The combined influence of Smad4 and EMT markers on OSCC progression highlights their potential as diagnostic tools and as guides for personalized treatment strategies.