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1.
Environ Toxicol ; 35(12): 1299-1307, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32652857

RESUMO

Recent evidences show that acylglycerol kinase (AGK) expression is related to the occurrence and development of various human cancers. However, its roles in nasopharyngeal carcinoma (NPC) progression are still unclear. This work aims to explore the roles of AGK in NPC cell stemness. It was shown that AGK expression was higher in NPC tissues compared to the adjacent tissues. Online dataset analysis revealed that AGK expression was negatively correlated with the overall survival of NPC patients. Gain and loss of functional experiments demonstrated that AGK positively regulated the stemness of NPC cells, as evident by the change of the tumor sphere-formation ability, ALDH1 activity and expression of stemness critical regulators. KEGG analysis were performed to determine the potential pathways of AGK involved in NPC cell stemness and showed that the PI3K/Akt pathway exhibited the most correlation with AGK expression. Further mechanistic studies confirmed that AGK promoted the stemness of NPC cells through activating the PI3K/Akt pathway, and thus enhancing ß-catenin accumulation in nucleus. This study demonstrates a novel AGK/PI3K/Akt/ß-catenin axis involving in NPC cell stemness.


Assuntos
Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , beta Catenina/metabolismo , Adulto , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/genética , Humanos , Masculino , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Células-Tronco Neoplásicas/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Transporte Proteico
2.
Oncogene ; 39(34): 5616-5632, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32661324

RESUMO

Increasing evidence indicates that long non-coding RNAs (lncRNAs) play vital roles in the tumorigenesis and progression of cancers. However, the functions and regulatory mechanisms of lncRNAs in nasopharyngeal carcinoma (NPC) are still largely unknown. Our previous lncRNA expression profiles identified that LINC01503 was overexpressed in NPC. Here, we verified that LINC01503 was highly expressed in NPC and correlated with poor prognosis. LINC01503 promoted NPC cell proliferation, migration, and invasion in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, LINC01503 recruited splicing factor proline-and glutamine-rich (SFPQ) to activate Fos like 1 (FOSL1) transcription, and ectopic expression of FOSL1 reversed the suppressive effect of LINC01503 knockdown on NPC progression. Moreover, androgen receptor (AR)-mediated transcription activation was responsible for the overexpression of LINC01503, and AR ligand-dependent cell growth, migration, and invasion in NPC cells. Taken together, our findings reveal that AR-induced LINC01503 can promote NPC progression through the SFPQ-FOSL1 axis, which represents a novel prognostic biomarker and therapeutic target for NPC patients.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fator de Processamento Associado a PTB/genética , Proteínas Proto-Oncogênicas c-fos/genética , RNA Longo não Codificante/genética , Receptores Androgênicos/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/terapia , Fator de Processamento Associado a PTB/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Interferência de RNA , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
Oncogene ; 39(30): 5307-5322, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555330

RESUMO

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.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Neoplasias Pulmonares/genética , NF-kappa B/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos Nus , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Análise de Sobrevida
4.
Anticancer Res ; 40(6): 3255-3264, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487620

RESUMO

BACKGROUND/AIM: Rta, a transactivator of Epstein-Barr virus, is associated with progression of nasopharyngel carcinoma (NPC); however, its mechanism of contribution to the pathogenesis of NPC remains unclear. Interleukin-6 (IL-6), a tumor promoter, is detected in NPC. This in vitro study examined whether and how Rta promotes NPC progression by up-regulating IL-6. MATERIALS AND METHODS: Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, ELISA, immunoblotting assays, reporter gene assays, and transwell migration assays were performed. RESULTS: In NPC cells, Rta up-regulated IL-6 expression at the mRNA and protein levels, and the Rta's C-terminus was essential for promoter activation and expression of IL-6. The induction of IL-6 by Rta also required activation of extracellular signal-regulated kinase 1/2 and activator protein-1. Furthermore, IL-6 secreted from Rta-expressing NPC cells promoted migration of Rta-negative NPC cells by activating IL-6 receptor/Janus kinase/signal transducer and activator of transcription 3 pathway. CONCLUSION: Rta contributes to progression of NPC cells through induction of IL-6 in vitro.


Assuntos
Proteínas Imediatamente Precoces/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neoplasias/metabolismo , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Proteínas Imediatamente Precoces/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Neoplasias/genética , Neoplasias/patologia , Neoplasias/virologia , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Transativadores/genética , Fator de Transcrição AP-1/metabolismo , Transfecção , Regulação para Cima
5.
J Cancer Res Ther ; 16(2): 309-319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474518

RESUMO

Objective: Regulatory T cells (Tregs) are critical factors that impair antitumor immunity. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is one of the most pathogenic factors in nasopharyngeal carcinoma (NPC). However, the role of EBV-encoded LMP1 in regulating Treg generation in NPC remains unclear. Materials and Methods: The in vitro stability of activated Tregs (aTregs) influenced by LMP1 was analyzed by flow cytometry. The inhibitory effects of LMP1-HONE1 antigen-induced aTregs on tumor-associated antigen (TAA)-specific T cells were analyzed in vitro and in vivo. Finally, the expression of LMP1, Foxp3, and enhancer of zeste homolog 2 (EZH2) were analyzed in samples from 86 NPC patients by immunohistochemistry and immunofluorescence. Results: LMP1 upregulated the expression of EZH2, which increased the stability of aTregs in vitro. EZH2 inhibitor, DZnep, depleted LMP1-HONE1 antigen-induced aTregs in vitro and led to potent TAA-specific T cell antitumor immunity in vivo. In NPC tissues, LMP1 expression level was positively correlated with the number of EZH2+ Tregs, which was positively correlated with clinical stage and overall survival. Conclusions: EZH2 is essential for maintaining the stability and inhibitory functions of aTregs that are induced by EBV-encoded LMP1 in NPC.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Carcinoma Nasofaríngeo/imunologia , Linfócitos T Reguladores/imunologia , Proteínas da Matriz Viral/metabolismo , Animais , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Imunidade Celular , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Taxa de Sobrevida , Linfócitos T Reguladores/metabolismo , Proteínas da Matriz Viral/imunologia
6.
Braz J Med Biol Res ; 53(7): e9029, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520206

RESUMO

This study examined the expression and potential mechanism of microRNA (miRNA)-424-5p in nasopharyngeal carcinoma (NPC). NPC tissues were collected from 40 patients who were enrolled in the study, and skin samples were collected from 26 healthy subjects during plastic surgery as controls. We performed various in vitro assays using miR-424-5p to examine its function in primary NPC-1 cells. Bioinformatics was employed to analyze potential target genes and signaling pathways of miR-424-5p. We found that miR-424-5p expression in NPC tissues is downregulated and negatively correlated with lymph node metastasis and clinical staging. Expression of miR-424-5p in NPC cells was also downregulated, and transfection with miR-424-5p mimics inhibited proliferation, migration, and invasion of NPC-1 cells. Bioinformatics identified the AKT3 gene as a potential target of miR-424-5p and dual luciferase assays confirmed this finding. Upregulation of AKT3 expression rescued the inhibitory effect of miR-424-5p on the proliferation, migration, and invasion. Our results suggest that miR-424-5p inhibited the proliferation, migration, and invasion of NPC cells by decreasing AKT3 expression.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adulto , Idoso , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
7.
Ann Otol Rhinol Laryngol ; 129(10): 1011-1019, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32468823

RESUMO

OBJECTIVES: Tunisia is in the endemic area of nasopharyngeal carcinoma. Epstein-Barr virus (EBV) based assays have been commonly used as standard markers for screening and monitoring the disease. So, it is very important to find novel factors for the early diagnostic and prognostic evaluation of this cancer. The aim of the study was to evaluate the expression of IGF-1R (Insulin Growth Factor Receptor 1), LMP 1 (Latent Membrane Protein 1) and EBERs (EBV encoded RNAs) in order to determine their correlation with clinicopathologic parameters and survival rates in patients with nasopharyngeal carcinoma (NPC). We also looked for the relationship between these biomarkers. METHODS: IGF-1R and LMP1 expression was performed by means of immunohistochemical method and EBERs were detected using in situ hybridization of paraffin embedded tumor tissues of 94 patients with nasopharyngeal carcinoma and 45 non-cancerous nasopharyngeal mucosa samples. RESULTS: Our findings demonstrated that IGF-1R was over expressed in 47.87% of NPC patients and only in 2.22% of controls. Positive LMP1 expression was detected in 56.38% of NPC patients and all NPC patients were positive for the EBV-encoded RNAs staining. A statistically significant positive correlation was observed between IGF-1R expression and the tumor size (P < .001). Kaplan-Meier survival curves showed that NPC patients with a strong IGF-1R expression level have shorter median and 5-year Overall Survival than those with weak expression rates (100.15 vs 102.68 months, P = .08). In addition, median and 5-year Disease-Free Survival was significantly lower in the LMP1 positive NPC patients than in the LMP1 negative ones (53.38 vs 93.37 months, P = .03). Moreover, LMP1 expression correlated strongly with IGF-1R expression (P = .018). The relationship between these two biomarkers could influence patient survival. CONCLUSION: IGF1-R and LMP1 could be valuable prognostic markers in Tunisian NPC patients.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , RNA Viral/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteínas da Matriz Viral/metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Nasofaringe/metabolismo , Prognóstico , Mucosa Respiratória/metabolismo , Taxa de Sobrevida , Tunísia , Adulto Jovem
8.
Environ Toxicol ; 35(10): 1082-1090, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449842

RESUMO

Nasopharyngeal carcinoma (NPC) arises from the epithelium of the nasopharyngeal mucosa. Elderly people above the age of 65 years are more susceptible to NPC. Nasopharyngectomy is the renowned treatment procedure to NPC; however, it is too risky due to its complicated surgical procedure. Other treatment methods also reported with serious side effects such brain injury; hence, the alternative anticancer drug without any side effects was needed. Fucoxanthin is a carotenoid derived from marine algae with the numerous pharmacological functions. This study aims to examine the inhibitory potential in NPC cell proliferation via apoptosis and autophagy. The cytotoxicity of fucoxanthin on C666-1 cells was observed by the MTT assay. The expression of autophagy-linked proteins was assessed with immunoblotting analysis. The expression of autophagy protein LC3 was estimated using immunocytochemical analysis in C666-1 and GFP-LC3 transfected cells. Furthermore, the fucoxanthin-treated C666-1 cells were analyzed with TUNEL assay. The apoptotic level in the fucoxanthin-treated C666-1 cells was evaluated using acridine orange staining. Fucoxanthin significantly increased the expression of autophagy-linked proteins which is clearly depicted in the immunoblotting analysis and immunocytochemical analysis of GFP-tagged LC3 protein. The results of TUNEL assay of fucoxanthin-treated C666-1 in the presence autophagy inhibitors demonstrated the induction of autophagy by fucoxanthin. Acridine orange staining results of C666-1 confirmed fucoxanthin decreases the expression of autophagy-linked proteins during stressed condition thereby causes apoptosis. Our overall results authentically conclude that fucoxanthin induces autophagy and apoptosis in NPC cell line, and it can be ideal agent to treat nasopharyngeal cancer in future with further investigations.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Xantofilas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Masculino , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo
9.
Sci Rep ; 10(1): 6115, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273550

RESUMO

Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we identify for the first time a role for monoamine oxidase A (MAOA) in NPC. MAOA is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines. Depending on the cancer type, MAOA can either have a tumour-promoting or tumour-suppressive role. We show that MAOA is down-regulated in primary NPC tissues and its down-regulation enhances the migration of NPC cells. In addition, we found that EBV infection can down-regulate MAOA expression in both pre-malignant and malignant nasopharyngeal epithelial (NPE) cells. We further demonstrate that MAOA is down-regulated as a result of IL-6/IL-6R/STAT3 signalling and epigenetic mechanisms, effects that might be attributed to EBV infection in NPE cells. Taken together, our data point to a central role for EBV in mediating the tumour suppressive effects of MAOA and that loss of MAOA could be an important step in the pathogenesis of NPC.


Assuntos
Monoaminoxidase/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Epigênese Genética , Células Epiteliais/metabolismo , Herpesvirus Humano 4/patogenicidade , Humanos , Interleucina-6/metabolismo , Monoaminoxidase/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
10.
Technol Cancer Res Treat ; 19: 1533033820917959, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32281513

RESUMO

The objective of this article is to study the effect of inhibiting phosphatase and tensin homolog deleted chromatosome 10 gene on phosphoinositide 3-kinase/protein kinase B (Akt)/Forkhead homeobox O3a signaling pathway in human nasopharyngeal carcinoma HK-1 cells. Nasopharyngeal carcinoma HK-1 cell lines were divided into PTEN gene interference group (siPTEN), nonspecific small interfering RNA group (siNC), empty vector group (Vector), and no transfection control group (Normal). The mRNA and protein expression levels of PTEN, PI3K, p-Akt, and FoxO3a were detected by real-time fluorescence quantitative polymerase chain reaction and Western blot. Immunofluorescence was used to detect the subcellular localization of PTEN, PI3K, p-Akt, and FoxO3a in HK-1 cells. The proliferation of HK-1 cells was detected by MTT assay, and the apoptosis of HK-1 cells was detected by flow cytometry. Compared with the siNC group, the expression levels of PTEN, FoxO3a messenger RNA, and protein in the siPTEN group were significantly decreased (P < .05), while the expression levels of PI3K, p-Akt messenger RNA, and protein were significantly increased (P < .05). The growth rate of HK-1 cells in the siPTEN group was significantly higher than the siNC group (P < .05), while the apoptosis rate was significantly lower than that of the siNC group (P < .05). Small interfering RNA can inhibit the expression of PTEN in HK-1 cells, and PTEN can participate in the development of NPC by affecting PI3K/Akt/FoxO3a signaling pathway.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Proteína Forkhead Box O3/metabolismo , Neoplasias Nasofaríngeas/patologia , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Apoptose/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteína Forkhead Box O3/genética , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/biossíntese , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
11.
Genes Cells ; 25(7): 466-474, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32281175

RESUMO

Nasopharyngeal carcinoma (NPC) is a malignant tumor in nasopharynx tissues and lacks effective treatment strategies. Dysregulation of distal-less homeobox 4 (DLX4) participates in the development of tumors. Understanding the regulatory mechanism of DLX4 in NPC progression may address this issue. Here, we first identified an up-regulation of DLX4 in NPC cell lines compared to normal epithelial cells. Data from colony formation and transwell assays showed that knockdown of DLX4 inhibited cell proliferation and invasion of NPC, respectively. Moreover, DLX4 knockdown blocked the cell cycle of NPC at G1 phase, suggesting the antitumor effect of DLX4 knockdown on NPC. The downstream target of DLX4 was identified as Y-box binding protein 1 (YB-1), whose expression was increased by over-expression of DLX4, while decreased by knockdown of DLX4. The binding capacity between DLX4 and YB-1 was verified by chromatin immunoprecipitation (ChIP), and the result showed that DLX4 could not directly bind to the promoter of YB-1. Mechanically, YB-1 over-expression reversed the effects of DLX4 knockdown on cell proliferation, cell cycle arrest and cell invasion of NPC. In conclusion, our findings indicated that DLX4 promoted NPC progression via up-regulation of YB-1, which would shed light on therapeutic schedule in NPC.


Assuntos
Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Homeodomínio/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Regiões Promotoras Genéticas , Ligação Proteica , RNA Interferente Pequeno , Fatores de Transcrição/genética , Regulação para Cima , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo
12.
Cancer Sci ; 111(6): 1991-2003, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32232887

RESUMO

Alternative polyadenylation (APA), which induces shortening of the 3'-UTR, is emerging as an important feature in cancer development and progression. Nevertheless, the effects and mechanisms of APA-induced 3'-UTR shortening in nasopharyngeal carcinoma (NPC) remain largely unclear. Fibronectin type III domain containing 3B (FNDC3B) tended to use proximal polyadenylation site and produce shorter 3'-UTR according to our previous sequencing study. Herein, we found that FNDC3B with shorter 3'-UTR could escape from miRNA-mediated gene repression, and caused its increased expression in NPC. Knocking down of FNDC3B inhibited NPC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Overexpression of FNDC3B, especially those with shorter 3'-UTR, promoted NPC progression. Furthermore, the mechanism study revealed that FNDC3B could bind to and stabilize myosin heavy chain 9 (MYH9) to activate the Wnt/ß-catenin signaling pathway. In addition, MYH9 could reverse the inhibitory effects of FNDC3B knockdown in NPC. Altogether, our results suggested that the 3'-UTR shortening of FNDC3B mRNA mediated its overexpression in NPC and promoted NPC progression by targeting MYH9. This newly identified FNDC3B-MYH9-Wnt/ß-catenin axis could represent potential targets for individualized treatment in NPC.


Assuntos
Fibronectinas/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Cadeias Pesadas de Miosina/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Regiões 3' não Traduzidas , Animais , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Fibronectinas/genética , Xenoenxertos , Humanos , Camundongos , MicroRNAs , Cadeias Pesadas de Miosina/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Via de Sinalização Wnt/fisiologia
13.
Cancer Biother Radiopharm ; 35(3): 208-213, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32202926

RESUMO

Background: Nasopharyngeal carcinoma (NPC) is leading form of cancer occurring in a few well-defined regions, including southern China. NPC possess a unique and intricate etiology that remains to be elucidated. Herein, we determine expression patterns of CCNB2 and NKX3-1 and identify their roles in NPC. Materials and Methods: Gene-expression profiles of NPC in the Gene Expression Omnibus (GEO) were analyzed. Cell viability, invasion, apoptosis, cell cycle entry and mitochondrial membrane potential (MMP) were evaluated in the presence of NKX3-1 or in the absence of CCNB2. Results: In all, 187 upregulated genes and 683 downregulated genes were obtained by analyzing GSE13597. NKX3-1, the downregulated gene, and CCNB2, the upregulated one, were further confirmed by in vitro studies. Overexpression of NKX3-1 was shown to inhibit NPC cell viability and invasion. Knockdown of CCNB2 was demonstrated to reduce cell cycle entry and MMP but induce apoptosis in NPC cells. Conclusions: Taken together, the key finding obtained from the study supports CCNB2 and NKX3-1 as two promising therapeutic candidates for NPC. Molecular mechanisms that control CCNB2 or NKX3-1 disturbance require further investigation and clarification.


Assuntos
Ciclina B2/genética , Proteínas de Homeodomínio/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fatores de Transcrição/genética , Ciclina B2/biossíntese , Regulação para Baixo , Técnicas de Inativação de Genes , Proteínas de Homeodomínio/biossíntese , Humanos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Fatores de Transcrição/biossíntese , Transcriptoma , Regulação para Cima
14.
PLoS One ; 15(3): e0230449, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191754

RESUMO

Tumor microenvironment have been implicated in many kind of cancers to hold an important role in determining treatment success especially with immunotherapy. In nasopharyngeal cancer, the prognostic role of this immune cells within tumor microenvironment is still doubtful. We conducted a study that included 25 nasopharyngeal cancer biopsy specimens to seek a more direct relationship between tumor infiltrating immune cells and tumor progression. Apart from that, we also checked the PD-L1 protein through immunohistochemistry. The PD-L1 was positively expressed in all our 25 samples with nasopharyngeal cancer WHO type 3 histology. Majority samples have >50% PD-L1 expression in tumor cells. We also found that denser local tumor infiltrating immune cells population have relatively much smaller local tumor volume. The inverse applied, with the mean local tumor volumes were 181.92 cm3 ± 81.45 cm3, 117.13 cm3 ± 88.72 cm3, and 55.13 cm3 ± 25.06 cm3 for mild, moderate, and heavy immune cells infiltration respectively (p = 0.013). Therefore, we concluded that tumor infiltrating immune cells play an important role in tumor progression, hence evaluating this simple and predictive factor may provide us with some valuable prognostic information.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Microambiente Tumoral , Feminino , Humanos , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/imunologia , Carga Tumoral
15.
PLoS One ; 15(3): e0229272, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119704

RESUMO

BACKGROUND AND AIMS: Radiotherapy is one of the major remedies for the treatment of cancer, including nasopharyngeal carcinoma (NPC). Radioresistance occurs very often in target cells that is a large drawback in cancer treated with radiotherapy. Livin involves the over-growth of cancer cells. This study aims to investigate the role of livin in the radioresistance formation in NPC cells. METHODS: NPC cell lines were exposed to small doses of irradiation to establish a cell model of radioresistance, in which the role of livin in the development of radioresistance was evaluated. RESULTS: The expression of livin was observed in NPC cells, which was significantly increased after exposing to small doses of irradiation. A negative correlation was detected between livin and Fas expression in NPC cells. Livin formed a complex with heat shock factor-1 (HSF1, the transcription factor of Fas) in NPC cells after irradiation, which sped up ubiquitination of HSF1. Livin was involved in suppressing Fas expression in NPC cells with radioresistance. Exposure to livin inhibitors prevented radioresistance development and overcame the established radioresistance in NPC cells. CONCLUSIONS: Livin expression in NPC cells plays a critical role in the development of radioresistance. Depletion of livin increases the sensitiveness of NPC cells to irradiation. Target therapy against livin may have the translational potential for the treatment of NPC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação , Regulação para Cima , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Fatores de Transcrição de Choque Térmico/metabolismo , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Proteínas de Neoplasias/antagonistas & inibidores , Peptídeos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Transdução de Sinais , Ubiquitinação , Regulação para Cima/efeitos dos fármacos , Receptor fas/metabolismo
16.
World J Surg Oncol ; 18(1): 29, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013999

RESUMO

BACKGROUND: The dysregulation of microRNAs (miRNAs) has been found in diseases and cancers, including microRNA-192 (miR-192). This study was designed to investigate the role of miR-192 in nasopharyngeal carcinoma (NPC) progression. METHODS: The expression levels of miR-192 and some genes were assessed by qRT-PCR and Western blot. The function of miR-192 was investigated through MTT, Transwell, and dual-luciferase reporter assays. RESULTS: The expression of miR-192 was increased in NPC tissues, and high miR-192 expression predicted poor prognosis in NPC patients. Functionally, upregulation of miR-192 promoted NPC cell migration, invasion, and growth. Furthermore, miR-192 activated EMT and PI3K/AKT pathway to regulate NPC progression. In addition, miR-192 directly targeted RB1 and suppressed its expression in NPC. Moreover, overexpression of RB1 weakened the promoted effect of miR-192 in NPC. CONCLUSION: miR-192 promoted cell viability and metastasis in NPC through suppressing RB1 expression and activating PI3K/AKT pathway.


Assuntos
Biomarcadores Tumorais/metabolismo , MicroRNAs/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Fosfatidilinositol 3-Quinases/genética , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas de Ligação a Retinoblastoma/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/genética
17.
Biochem Biophys Res Commun ; 524(4): 816-824, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32044038

RESUMO

Nasopharyngeal carcinoma (NPC) is a malignant tumor from head and neck with characteristics in remarkable geographic and racial distribution worldwide, which has the important features of vigorous proliferation and inflammatory cells infiltration. By analyzing the expression profile data of NPC, we found that the E2F-related gene sets were highly enriched in NPC tissues. E2F transcription factor family is an important cycle regulator, which can promote the malignant proliferation and tumorigenesis. Here, we showed that E2Fs accelerated malignant phenotypes of NPC cells. RNA sequencing revealed that E2Fs can significantly up-regulate the inflammatory pathways in NPC cells. E2F1, as a transcription factor, can active the transcription activity of IL-6 promoter, and modulate macrophage function through a microenvironment manner. Thus, this study characterized a significant role of E2Fs in inflammation and tumorigenesis of NPC, which provided a promising anti-tumor target in NPC, since E2Fs are highly expressed and activated in NPC.


Assuntos
Carcinogênese/genética , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F3/genética , Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Animais , Apoptose/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Estudos de Coortes , Fator de Transcrição E2F1/antagonistas & inibidores , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F3/antagonistas & inibidores , Fator de Transcrição E2F3/metabolismo , Humanos , Inflamação , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Células THP-1 , Carga Tumoral , Microambiente Tumoral/genética
18.
Biomed Pharmacother ; 122: 109763, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918288

RESUMO

Emerging evidence suggests that cinobufagin, an active ingredient in Venenum Bufonis, inhibits cell proliferation in several tumor cells. However, the anti-tumor effect of cinobufagin on nasopharyngeal carcinoma and the underlying molecular mechanisms are still unclear. In this study, we found that cinobufagin significantly inhibits the proliferation of nasopharyngeal carcinoma HK-1 cells. Further analyses demonstrated that cinobufagin induces cell cycle arrest at the S phase in HK-1 cells through downregulating the levels of CDK2 and cyclin E. Moreover, cinobufagin significantly downregulates the protein level of Bcl-2 and upregulates the levels of Bax, subsequently increasing the levels of cytoplasmic cytochrome c, Apaf-1, cleaved PARP1, cleaved caspase-3, and cleaved caspase-9, leading to HK-1 apoptosis. Furthermore, we found that cinobufagin significantly increases ROS levels and decreases the mitochondrial membrane potential in HK-1 cells. Collectively, these data imply that cinobufagin induces cell cycle arrest at the S phase and induces apoptosis through increasing ROS levels, thereby inhibiting cell proliferation in HK-1 cells. Therefore, cinobufagin is a promising bioactive agent that may contribute to the development of treatment strategies of nasopharyngeal carcinoma.


Assuntos
Apoptose/efeitos dos fármacos , Bufanolídeos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Fase S/efeitos dos fármacos , Antineoplásicos/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Int J Mol Med ; 45(3): 836-846, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31985027

RESUMO

Circular RNAs have been reported to play a vital role in the development and progression of various types of cancer. However, the underlying molecular role of circular RNA CTDP1 (circCTDP1) in the tumorigenesis of nasopharyngeal carcinoma (NPC) remains unknown. In the present study, circCTDP1 expression was found to be markedly upregulated in NPC tissues and cell lines (SUNE1, SUNE2 and 6­10B cell lines). Knockdown of circCTDP1 resulted in inhibition of proliferation, migration and invasion, and promoted apoptosis of NPC cells. Moreover, circCTDP1 directly interacted with microRNA (miR)­320b based on bioinformatics prediction and dual luciferase assay, and transfection with an miR­320b inhibitor reversed the effects of circCTDP1 knockdown on NPC cells. Furthermore, circCTDP1/miR­320b promoted NPC progression by regulating the expression of homeobox A10 (HOXA10). In addition, it was demonstrated that HOXA10 may exert its oncogenic role in NPC by regulating the expression of transforming growth factor ß2 (TGFß2). Taken together, these results revealed a novel regulatory mechanism, which may provide an improved understanding of NPC tumorigenesis and be useful in the development of potential targets for NPC therapy.


Assuntos
Proteínas Homeobox A10/metabolismo , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Adulto , Idoso , Animais , Western Blotting , Linhagem Celular , Movimento Celular/genética , Movimento Celular/fisiologia , Biologia Computacional , Progressão da Doença , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Proteínas Homeobox A10/genética , Humanos , Técnicas In Vitro , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Circular/genética , RNA Longo não Codificante/genética , Ratos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta2/genética , Cicatrização/genética , Cicatrização/fisiologia
20.
Eur Rev Med Pharmacol Sci ; 24(1): 181-188, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31957831

RESUMO

OBJECTIVE: This study aims to detect microRNA-326 expression in nasopharyngeal carcinoma (NPC) tissues and cell lines and to explore the potential mechanism of microRNA-326 inhibiting the proliferative capacity and invasiveness of NPC cells. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed to examine microRNA-326 expression in 40 cases of NPC tissue samples and cell lines. Meanwhile, microRNA-326 mimics were transfected into NPC cells to up-regulate microRNA-326 level. Next, the influence of microRNA-326 mimics on the proliferation and invasiveness of NPC cells was observed by Cell Counting Kit-8 (CCK-8) assay and transwell assay, respectively. Bioinformatics analysis was applied to search for target genes which may have direct effects on microRNA-326. An EST1 luciferase reporter vector containing microRNA-326 binding site was constructed and the binding relation between ETS1 and microRNA-326 was detected by Dual-Luciferase reporting assay. Lastly, the underlying mechanism of microRNA-326 and ETS1 in NPC was further verified via cell reverse experiments. RESULTS: Compared with control group, microRNA-326 expression was found remarkably decreased both in NPC tissue specimens and cell lines. The low expression of microRNA-326 could predict poor prognosis of patients with NPC. In vitro cell experiments revealed that overexpression of microRNA-326 remarkably inhibited the proliferative capacity and invasiveness of NPC cells. Bioinformatics analysis and Dual-Luciferase assay results suggested that microRNA-326 may bind to ETS1. Cell reverse assay indicated that inhibiting ETS1 expression partially reversed the changes in cell biological behavior induced by the down-regulation of microRNA-326 in CNE1 and 5-8F cell lines. CONCLUSIONS: Overexpression of microRNA-326 in NPC cells could remarkably inhibit the proliferative capacity and invasiveness of NPC cells. In addition, microRNA-326 may participate in the development of NPC by inhibiting ETS1 expression.


Assuntos
MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proliferação de Células/genética , Células Cultivadas , Humanos , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteína Proto-Oncogênica c-ets-1/genética
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