RESUMEN
Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential in which distant metastasis is the main reason for treatment failure. Till present, the underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we identified S100 calcium-binding protein A14 (S100A14) as a functional regulator suppressing NPC metastasis by inhibiting the NF-kB signaling pathway and reversing the epithelial-mesenchymal transition (EMT). S100A14 was found to be downregulated in highly metastatic NPC cells and tissues. Immunohistochemical staining of 202 NPC samples revealed that lower S100A14 expression was significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS). S100A14 was also found as an independent prognostic factor for favorable survival. Gain- and loss-of-function studies confirmed that S100A14 suppressed the in vitro and in vivo motility of NPC cells. Mechanistically, S100A14 promoted the ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop that could be disrupted by the IRAK1 inhibitor T2457. Overall, our findings showed that the S100A14-IRAK1 feedback loop could be a promising therapeutic target for NPC metastasis.
Asunto(s)
Proteínas de Unión al Calcio/genética , Quinasas Asociadas a Receptores de Interleucina-1/genética , Neoplasias Pulmonares/genética , FN-kappa B/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Animales , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Retroalimentación Fisiológica , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones Desnudos , FN-kappa B/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Interferencia de ARN , Transducción de Señal/genética , Análisis de SupervivenciaRESUMEN
While emergency medical service (EMS) response time (ERT) is a major factor associated with the survival of patients with cardiovascular disease (CVD), relatively few studies have explored the factors associated with ERT. This study aimed to assess the current status of ERT and to identify the factors affecting ERT in patients with CVD in China. Between January 1, 2011 and December 31, 2015, EMS responses to CVD incidents in Guangzhou, China, were examined. The primary outcome was ERT, defined as the time from receipt of an emergency call to the arrival of paramedics on the scene. Factors associated with ERT were evaluated by multivariable logistic regression. A total of 44 383 CVD incidents were analysed. The median ERT was 12.58 min (interquartile range=9.98-15.67). Among the risk factors, distance (OR=13.73, 95% CI=11.76-16.04), level of hospital (OR=1.57, 95% CI=1.40-1.75), and site of the incident (OR=1.53, 95% CI=1.38-1.69) were the top three significant factors affecting the ERT. Our results suggest that greater attention should be given to factors affecting the ERT. It is essential to make continuous efforts to promote the development of effective interventions to reduce the response time.