RESUMEN
Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Citoesqueleto de Actina/metabolismo , Animales , Biomarcadores de Tumor/biosíntesis , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Genes Supresores de Tumor , Xenoinjertos , Humanos , Ratones , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Fenotipo , Proteínas Proto-Oncogénicas c-sis/antagonistas & inhibidores , Transducción de Señal , Transfección , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Proteínas Señalizadoras YAPRESUMEN
Major histocompatibility complex (MHC) class II regulatory genes play a paramount role in immune response that can exert a predominant influence on clinical outcome of Epstein-Barr virus infection consistently assumed as the main pathogenetic factor for nasopharyngeal carcinoma. To elucidate the relationship between allelic variants of MHC class II regulatory genes and susceptibility to nasopharyngeal carcinoma, a total of 28 polymorphic loci at MHC class II regulatory genes, involving CIITA, CREB1, RFX family genes (RFX5, RFXAP, and RFXANK), and NFY family genes (NFYA, NFYB, and NFYC), were genotyped by multiplex SNaPshot minisequencing in 137 patients with nasopharyngeal carcinoma and 107 healthy controls from the southern Chinese population. Allelic analysis disclosed that rs7404873, rs6498121, rs6498126, and rs56074043 shared correlations with nasopharyngeal carcinoma (Ptrend < 0.05). Further, rs6498126 on CIITA was independently associated with the risk of developing nasopharyngeal carcinoma (CC vs. GG, odds ratio: 7.386, 95% confidence interval: 1.934-28.207, Ptrend < 0.01). Conversely, rs7404873 on CIITA and rs56074043 on NFYB manifested epistatic interaction to decreased susceptibility of nasopharyngeal carcinoma (rs7404873, TT vs. GG, odds ratio: 0.256, 95% confidence interval: 0.088-0.740, Ptrend < 0.05; rs56074043, AA vs. AG, odds ratio: 0.341, 95% confidence interval: 0.129-0.900, Ptrend < 0.05). Additionally, bioinformatics analysis revealed that the three variants were transcriptional regulatory in function and might impact the expression of nearby genes. The findings suggested genetic variants on MHC class II regulatory genes contributed to nasopharyngeal carcinoma susceptibility and might provide new insights for screening high-risk population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Estudios de Casos y Controles , Terapia Combinada , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Ras association domain family member 6 (RASSF6) has been shown to act as a tumor suppressor and predictor of poor prognosis in renal cell carcinoma (RCC). However, little is known about the effects of RASSF6 on sorafenib resistance or the underlying mechanism. Here, we show that RASSF6 expression positively correlates with sorafenib sensitivity in RCC cells and human samples. Stable ectopic overexpression of RASSF6 in RCC cell lines reduces resistance to sorafenib in vitro and in vivo. At a molecular level, RASSF6 activates the JNK signaling pathway, which further contributes to Mcl-1 inhibition. Suppression of the JNK pathway can partially restore Mcl-1 expression and sorafenib resistance. Together, these findings suggest that RASSF6 inhibits sorafenib resistance by repressing Mcl-1 through the JNK-dependent pathway. RASSF6 may serve as a novel regulator for sorafenib therapy in RCC.
