RESUMEN
Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.
Asunto(s)
Neoplasias Nasofaríngeas , Animales , Ratones , Humanos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patología , Ratones Desnudos , Línea Celular Tumoral , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Luciferasas , Movimiento Celular , Invasividad Neoplásica , Metástasis de la NeoplasiaRESUMEN
Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.
Asunto(s)
Sistema de Señalización de MAP Quinasas/genética , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Metástasis de la Neoplasia/genética , Receptor ErbB-3/genética , Transducción de Señal/genética , beta-Lactamasas/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Receptores ErbB/genética , Femenino , Humanos , Ratones , Ratones Desnudos , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Metástasis de la Neoplasia/patología , Regiones Promotoras Genéticas/genéticaRESUMEN
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
Nasopharyngeal carcinoma (NPC) is relatively sensitive to ionizing radiation, and radiotherapy is the main treatment modality for non-metastatic NPC. Radiation therapy generates overproduction of reactive oxygen species (ROS), which can cause DNA damage and induce apoptosis in tumors, thereby killing the malignant cells. Although dietary antioxidant supplementation reduces oxidative stress and promotes tumor progression, the effects of antioxidants on the NPC cells upon radiation have not been reported. In the present study, we showed that antioxidants (ß-Carotene, NAC, GSH) played an anti-apoptotic role in response to radiation via decreasing ROS production and inhibiting MAPK pathway in NPC cells. Based on that, we conclude that the use of supplemental antioxidants during radiotherapy should be avoided because of the possibility of tumor protection and reduced treatment efficacy.