RESUMEN
Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.
Asunto(s)
Proteínas de Unión al Calcio , Carcinoma de Células Escamosas , Movimiento Celular , Mitocondrias , Neoplasias de la Boca , Subtipo EP4 de Receptores de Prostaglandina E , Animales , Humanos , Ratones , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Calmodulina/metabolismo , Calmodulina/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Mitocondrias/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/genética , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismoRESUMEN
BACKGROUND: The aim of this study was to evaluate the prognostic factors and treatment outcomes of advanced maxillary gingival squamous cell carcinoma (SCC) treated with intra-arterial infusion chemotherapy concurrent with radiotherapy. METHODS: A total of 46 patients were reviewed retrospectively in this study. The treatment schedule comprised intra-arterial chemotherapy (total, 60 mg/m2 docetaxel and 150 mg/m2 cisplatin) and three-dimensional computed tomography based, daily conventional radiotherapy (total, 60 Gy/30 fr) for 6 weeks. RESULTS: The median follow-up period was 40 months (range, 3-110 months). The 3-year overall survival and locoregional control rates for all patients were 64.3% and 84.3%, respectively. The OS rate of the patients with N0-1 was significantly higher than that of the patients with N ≥ 2 (P < .05). No grade 5 toxicities were observed. CONCLUSIONS: Intra-arterial infusion chemotherapy concurrent with radiotherapy was effective for advanced maxillary gingival SCC.