Immunohistochemical Evaluation of NOTCH1 Signaling Pathway in Oral Squamous Cell Carcinoma: Clinical and Prognostic Significance

The aim of this study was to investigate the clinical and prognostic significance of the NOTCH1 pathway in oral squamous cell carcinoma (OSCC). To this end, the expression of NOTCH1 and two downstream targets, HES1 and p21, was evaluated by immunohistochemistry in 165 OSCC patient specimens. Clinicopathological associations and impact on survival were assessed. Possible mechanistic crosstalk with epithelial-mesenchymal transition (EMT) induction through combined E-cadherin and Vimentin markers, or mTORC1 activation by means of phospho-S6 expression were also investigated. NOTCH1 staining was detected in 56 (35%) tumors, nuclear HES1 in 131 (81%) and nuclear p21 in 116 (70%) tumors. p21 was strongly correlated with mTORC1 activation and HES1 expression was inversely associated with EMT status. NOTCH1 expression was positively associated with an advanced T stage, neck lymph node metastasis, advanced TNM stage, second primary cancer, and was significantly associated with shorter disease-specific survival (DSS). By contrast, HES1 and p21 expression showed significant associations with early clinical stages, and combined p21 and pS6 expression (p21+/p-S6+) distinguished good-prognosis patients. Multivariate Cox analysis further revealed NOTCH1 expression as a significant independent predictor of poor DSS. Mechanistically, we found a strong link between p21 and pS6 proteins, which could potentially serve as a good-prognosis classifier for OSCC patients.