de Vicente Juan Carlos, Lequerica-Fernández Paloma, Rivas Héctor Torres, Blanco-Lorenzo Verónica, López-Fernández Ana, Escalante-Narváez Samuel Andrés, Herrera I Nogués Sergi, Rodrigo Juan P, Álvarez-Teijeiro Saúl, García-Pedrero Juana M
Department of Oral and Maxillofacial Surgery, Hospital Universitario Central de Asturias (HUCA), C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, C/Carretera de Rubín, s/n, 33011 Oviedo, Asturias, Spain.
Int J Mol Sci. 2025 Sep 19;26(18):9167. doi: 10.3390/ijms26189167.
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.
本研究旨在探讨NOTCH1信号通路在口腔鳞状细胞癌（OSCC）中的临床及预后意义。为此，通过免疫组织化学方法评估了165例OSCC患者标本中NOTCH1及其两个下游靶点HES1和p21的表达情况。评估了临床病理相关性及对生存的影响。还研究了通过联合E-钙黏蛋白和波形蛋白标记物与上皮-间质转化（EMT）诱导之间可能的机制性相互作用，或通过磷酸化S6表达对mTORC1激活的影响。在56例（35%）肿瘤中检测到NOTCH1染色，131例（81%）肿瘤中检测到核HES1，116例（70%）肿瘤中检测到核p21。p21与mTORC1激活密切相关，HES1表达与EMT状态呈负相关。NOTCH1表达与晚期T分期、颈部淋巴结转移、晚期TNM分期、第二原发癌呈正相关，且与较短的疾病特异性生存（DSS）显著相关。相比之下，HES1和p21表达与早期临床分期显著相关，联合p21和pS6表达（p21+/p-S6+）可区分预后良好的患者。多变量Cox分析进一步显示NOTCH1表达是DSS不良的显著独立预测因素。从机制上讲，我们发现p21和pS6蛋白之间存在紧密联系，这可能潜在地作为OSCC患者预后良好的分类指标。
