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1.
Nat Commun ; 12(1): 117, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402692

RESUMO

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding 68Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Recidiva Local de Neoplasia/genética , Receptores de Somatostatina/genética , Proteínas da Matriz Viral/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/virologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/virologia , Octreotida/farmacologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/metabolismo , Transdução de Sinais , Análise de Sobrevida , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas da Matriz Viral/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(12): 1069-1075, 2020 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-33325359

RESUMO

Objective To analyze the immunocyte infiltration characteristics and clinical significance of gene expression profile in nasopharyngeal carcinoma (NPC). Methods Firstly, the gene expression profile data of NPC were downloaded from Gene Expression Omnibus (GEO), and the infiltration of 22 kinds of immune cells in NPC was analyzed by CIBERSORT's R software package. Secondly, differential genes were obtained by GEO2R and analyzed by R Studio regarding gene ontology (GO) function and Kyoto Encyclopedia of Genes and Gnomes (KEGG). Then, the network diagram of protein-protein interaction (PPI) was drawn by STRING database and the Degree algorithm of Cytoscape software was used to screen for key genes. Finally, the expression and clinical significance of key genes in NPC and the relationship between the key genes and immune cells were analyzed. Results The expression levels of M0 macrophages, M1 macrophages and γδ T cells in NPC increased, but the differences were not significant, while the expression levels of memory B cells and resting memory CD4+T cells decreased, and the difference was significant. There were positive correlations between monocytes and eosinophils (r=0.99), plasma cells and regulatory T cells (r=0.88), activated mast cells and dendritic cells (r=0.75) in NPC, while M1 macrophages were negatively correlated with memory B cells (r=-0.71) and activated memory CD4+T cells (r=-0.63). In addition, GO of differential genes in NPC was mainly enriched in the function related to ciliary movement, and KEGG was mainly enriched in the pathway related to cytochrome P450. CCDC39 was a key gene in NPC, which was highly expressed in NPC and beneficial to the prognosis of patients, but the low expression of memory B cells was not conducive to the prognosis of patients. Conclusion A large number of immune cells are distributed in the microenvironment of NPC, and the expression of different types of immune cells is different, but memory B cells have the most obvious effect on the prognosis of patients.


Assuntos
Neoplasias Nasofaríngeas , Transcriptoma , Biologia Computacional , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Microambiente Tumoral
3.
Sci Rep ; 10(1): 16328, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004943

RESUMO

Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.


Assuntos
Autofagia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Transplante de Neoplasias , Tolerância a Radiação , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologia
4.
Life Sci ; 263: 118620, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33096113

RESUMO

AIMS: The purpose of this study was to investigate the prognostic significance of tumor-infiltrating immune cells and microenvironment-relevant genes in nasopharyngeal carcinoma (NPC) and their correlations. MATERIALS AND METHODS: The "xCell" algorithm was used to calculate the enrichment scores for 33 immune cells in the samples of GSE12452, GSE40290, GSE53819, GSE68799, and GSE102349. The difference of immune cells between NPC group and non-cancerous group and the prognostic value of the immune cells were analyzed. Besides, based on the Microenvironment scores, the differentially expressed genes (DEGs) between the high- and low-score groups were screened to identify the microenvironment-relevant hub genes. Furthermore, the DEGs were used to establish a risk score model for predicting progression-free survival (PFS) via LASSO penalized Cox regression. KEY FINDINGS: The scores of B-cells and Memory B-cells of NPC were significantly lower than those of non-cancerous tissues, and they were positively associated with PFS. Moreover, 10 hub genes (PTPRC, CD19, CD79B, BTK, CD79A, SELL, MS4A1, CD38, CD52, and CD22) were identified and positively correlated with B-cells, Memory B-cells, and Microenvironment scores in GSE12452, GSE68799, and GSE102349. High expression levels of CD22, CD38, CD79B, MS4A1, SELL, and PTPRC were associated with longer PFS. Besides, a risk score model composed of DARC, IL33, IGHG1, and SLC6A8 was established with a good performance for PFS prediction. SIGNIFICANCE: These results enhance our understanding of the composition and prognostic significance of tumor-infiltrating immune cells in NPC lesions, and provide potential targets for prognostication and immunotherapy for NPC patients.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Microambiente Tumoral/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Prognóstico , Intervalo Livre de Progressão , Microambiente Tumoral/imunologia
5.
Int J Nanomedicine ; 15: 7569-7582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116488

RESUMO

Introduction: Nasopharyngeal carcinoma (NPC) is a common cancer in southern China and Taiwan, and radiation therapy combined with or without chemotherapy is its mainstay treatment. Although it is highly sensitive to radiotherapy, local recurrence and distant metastasis remain difficult unsolved problems. In recent years, graphene oxide (GO) has been found to be a promising novel anticancer drug carrier. Here, we present our designed functionalized GO, polyethylene glycol-coated GO (GO-PEG), as a drug carrier, which was loaded with erlotinib and showed promising anticancer effects on NPC cells. Methods: The effects of GO-PEG-erlotinib on the proliferation, migration, and invasion of NPC cells were investigated by WST-8 assay, wound healing assay, and invasion assay, respectively. RNA sequencing was conducted and analyzed to determine the molecular mechanisms by which GO-PEG-erlotinib affects NPC cells. Results: Our results showed that GO-PEG-erlotinib reduced NPC cell viability in a dose-dependent manner and also inhibited the migration and invasion of NPC cells. The RNA sequencing revealed several related molecular mechanisms. Conclusion: GO-PEG-erlotinib effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. GO-PEG-erlotinib may be a potential therapeutic agent for treating NPC in the future.


Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Cloridrato de Erlotinib/administração & dosagem , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Cloridrato de Erlotinib/farmacocinética , Cloridrato de Erlotinib/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Grafite/química , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Polietilenoglicóis/química
6.
Anticancer Res ; 40(10): 5503-5508, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988873

RESUMO

BACKGROUND/AIM: Accumulating evidence shows that caspase-8 (Cas-8) rs3834129 genotypes determine susceptibility to various cancers, but their association with nasopharyngeal carcinoma (NPC) has not been examined. We aimed at investigating the association of Cas-8 rs3834129 with NPC risk. MATERIALS AND METHODS: Cas-8 rs3834129 genotypes and their associations with NPC risk were investigated among 176 NPC patients and 352 non-cancer subjects by the PCR-RFLP method. Additionally, the interaction of Cas-8 rs3834129 genotypes with smoking was examined. RESULTS: The II, ID and DD frequencies were 56.8, 36.9 and 6.3% among NPC patients and 54.8, 38.1 and 7.1% among control subjects (ptrend=0.8830). Allelic frequency distribution analysis also indicated that the D allele is not a risk factor for NPC (p=0.6183). There was no interaction between Cas-8 rs3834129 and smoking and NPC risk (p=0.8305). CONCLUSION: Cas-8 rs3834129 genotypes play a minor role in the risk for NPC.


Assuntos
Caspase 8/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Carcinoma Nasofaríngeo/genética , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/epidemiologia , Carcinoma Nasofaríngeo/patologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Fatores de Risco , Fumar , Taiwan
7.
Am J Pathol ; 190(12): 2343-2354, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32971057

RESUMO

The long noncoding RNA DANCR (differentiation antagonizing non-protein coding RNA) displays aberrant expression in various cancers. However, its clinical value and functional mechanisms in nasopharyngeal carcinoma (NPC) remain poorly understood. We found that DANCR is dramatically up-regulated in human NPC, and that it is an indicator for poor survival prognosis. DANCR knockdown suppressed cell proliferation, colony formation in vitro, and tumorigenicity in vivo. Mechanistic analyses demonstrated that DANCR could bind to RNA-binding protein 3 (RBM3) protein and stabilize SOX2 mRNA, resulting in NPC cell proliferation. Our findings indicate that DANCR functions as an oncogene and a potential therapeutic target for NPC.


Assuntos
Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXB1/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Proteínas de Ligação a RNA/metabolismo
8.
Medicine (Baltimore) ; 99(32): e21505, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769887

RESUMO

The purpose of this study was to investigate novel biomarkers and potential mechanisms in nasopharyngeal carcinoma (NPC) patients with metastasis.Two microarray datasets (GSE103611 and GSE36682) were obtained from GEO database, differentially expressed genes (DEGs) and differentially expressed miRNA (DEMs) were identified, Gene ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted with DEGs and DEMs targeted genes. Protein-protein interactions (PPI) network of the DEGs and DEMs targeted genes were constructed, furthermore, Connectivity Map (CMap) database was applied to select the potential drugs with therapeutic effects.Overall, we identified 396 upregulated and 19 downregulated DEGs. Additionally, we identified 1 upregulated DEM, miR-135b, and a downregulated DEM, miR-574-5p. Functional enrichment analysis indicated that both DEGs and DEMs targeted genes participated in biological process (BP) of regulation of transcription from RNA polymerase II promoter, DNA-templated positive regulation of transcription, and Epstein-Barr virus infection signaling pathway. Besides, upregulated EP300 gene was a hub node both in DEGs and DEMs target genes. CMap database analysis indicated that sanguinarine, verteporfin, and chrysin are potential drugs for prevention and treatment of NPC metastasis.In summary, the common hub gene, biological process and pathway identified in the study provided a novel insight into the potential mechanism of NPC metastasis. Furthermore, we identified several possible small molecule compounds for treatment of NPC metastasis.


Assuntos
MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Biomarcadores Tumorais/genética , Bases de Dados Genéticas , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica/genética , Mapas de Interação de Proteínas , Transdução de Sinais/genética , Regulação para Cima/genética
9.
Artigo em Chinês | MEDLINE | ID: mdl-32842368

RESUMO

Objective: To explore the relationship between NOX4 and radiosensitivity of nasopharyngeal carcinoma cells. Methods: Western blot was used to test the expression of NOX4 in nasopharyngeal carcinoma cells (CNE1, CNE2 and HONE1) and normal nasopharyngeal epithelial cells (NP69). The lentiviral vectors for RNA interference and overexpression of NOX4 gene were constructed and nasopharyngeal carcinoma cells were transfected. After treatment with radiation or/and PI3K/AKT inhibitor LY294002, the expressions of related proteins in cells were tested by Western blot, and the cell proliferation was detected by CCK-8 assay and the cell apoptosis was determined by flow cytometry. GraphPad Prism 5 was used for statistical analysis, and P<0.05 was statistically significant. Results: The expressions of NOX4 in nasopharyngeal carcinoma cells were higher than those in normal nasopharyngeal epithelial cells. Compared with the siNC group, the siNOX4 group of nasopharyngeal carcinoma cell had lower proliferation capacity [72 h absorbance (A) value:1.16 vs. 0.75] and higher apoptosis rate (2.9% vs. 10.0%). In contrast,compared with the vector group, the NOX4 group of nasopharyngeal carcinoma cell had higher proliferation capacity [72 h absorbance (A) value: 1.01 vs. 1.32] and lower apoptotic rate (1.7% vs. 1.1%).Treatment with LY294002 for nasopharyngeal carcinoma cells of NOX4 overexpression,compared with the NOX4 group, the proliferation ability of nasopharyngeal carcinoma cells in the NOX4+LY294002 group was reduced (72 h absorbance (A) value: 1.32 vs. 0.77), while the apoptotic rate was increased (1.1% vs. 3.1%).Treatment with radiotherapy, compared with the siNC/Vector group, the proliferation ability of nasopharyngeal carcinoma cells in the siNOX4 group was reduced (72 h absorbance (A) value: 0.72 vs. 0.33), and the apoptotic rate was increased (7.8% vs. 17.3%). However, in the NOX4 group, the proliferation of nasopharyngeal carcinoma cells was enhanced (72 h absorbance (A) value:0.65 vs. 0.78), and the apoptotic rate was reduced (8.1% vs. 3.8%). Compared with the NOX4+radiation group, the proliferation ability of nasopharyngeal carcinoma cells in the NOX4+radiation+LY294002 group was reduced (72 h absorbance (A) value: 0.79 vs. 0.56), while the apoptotic rate was increased (3.8% vs. 8.1%). Conclusion: NOX4 can inhibit radiosensitivity of nasopharyngeal carcinoma cells possibly by activating PI3K/AKT pathway.


Assuntos
NADPH Oxidase 4 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Tolerância a Radiação/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Epiteliais/fisiologia , Humanos , NADPH Oxidase 4/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética
10.
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
11.
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
12.
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
13.
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
14.
Medicine (Baltimore) ; 99(24): e20682, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541515

RESUMO

Nasopharyngeal carcinoma (NPC) is the most common malignant tumor with a remarkable racial and geographical distribution including people in southern China, South East Asia, and the Middle East/North Africa. DNA methylation is an important manifestation of epigenetic modification, has been studied over several decades, and by regulating and controlling the expression of cancer-related genesits, abnormal DNA methylation can influence in a variety of human malignancy tumors.Until now, there is no analysis focus on differentially methylated, differential expressed genes (MDEGs) study, so we make a joint analysis for both gene methylation profiling microarray and gene expression profiling microarray in NPC. Two gene expression datasets (GSE64634 and GSE12452) and gene methylation profiling data set (GSE62336) were downloaded from GEO and analyzed using the online tool GEO2R to identify MDEGs. Gene ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differentially methylated genes were performed. The STRING database was used to evaluate the interactions of MDEGs and to construct a protein-protein interaction (PPI) network using Cytoscape software. Hub genes were validated with the cBioPortal database.The overlap among the 3 datasets contained 135 hypermethylation genes and 541 hypomethylation genes between NPC and non-NPC samples. A total of 4 genes (TROAP, PCOLCE2, HOXA4, and C1QB) in Hyper-LGs and 14 genes (DYNC1H1, LNX1, RAB37, ALDH3A1, SLC24A4, CP, CEP250, ANK2, DNAI2, MUC13, ACACB, GABRP, STX7, and TTC9) in Hypo-HGs were identified as hub genes.The study of DNA methylation and gene expression provides us a strong support as well as new comprehensive information of MDEGs to the revelation of nasopharyngeal carcinoma's complex pathogenesis. However, further studies are needed to elucidate the biological function of these genes in NPC in the future.


Assuntos
Metilação de DNA , Perfilação da Expressão Gênica , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Análise em Microsséries , Prognóstico
15.
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
16.
Sci Rep ; 10(1): 9690, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546739

RESUMO

In the era of intensity-modulated radiotherapy (IMRT), it is important to analyse the prognostic value of deficient mismatch repair (dMMR) in nasopharyngeal carcinoma (NPC). In this study, in pretreatment biopsies of 69 patients with stage II-IVa NPC, the expression levels of MMR proteins, including MLH1, MSH2, MSH6 and PMS2, were assessed by immunohistochemistry (IHC). The median follow-up time was 37.5 months (3.1-87.4 months). 50.7% of cases (35/69) showed preserved expression of all 4 MMR proteins, which was interpreted as proficient mismatch repair (pMMR). Only 1.5% of cases (1/69) lost expression of all 4 MMR proteins, 26.1% of cases (18/69) have PMS2 loss alone and 21.7% of cases (15/69) lost expression of both PMS2 and MLH1. Thus, 49.3% of cases (34/69) lost expression of one or more MMR proteins, which was interpreted as dMMR. There was no significant difference (P > 0.05) in terms of sex, age, clinical stage, T category, N category or therapy regimens between the dMMR and pMMR groups. The multivariate Cox regression analysis revealed that dMMR was an independent significant prognostic factor for distant metastasis-free survival (DMFS) (dMMR vs pMMR: P = 0.01, HR = 0.25, 95% CI: 0.09~0.75). Therefore, NPC patients with dMMR had significantly superior DMFS compared with patients with pMMR. It can be expected that dMMR will become a new independent prognostic factor for NPC.


Assuntos
Reparo de Erro de Pareamento de DNA , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Radioterapia de Intensidade Modulada , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Estadiamento de Neoplasias , Prognóstico , Adulto Jovem
17.
BMC Cancer ; 20(1): 376, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370736

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC), with distinct geographical distribution, has gathered public attention. Despite that radiotherapy and chemotherapy are applied to treat NPC, cell metastasis still cannot be avoided. Numerous works have elucidated that lncRNAs are essential players in the development of multiple cancers. LncRNA SNHG7 has been reported as a contributing factor in the occurrence of certain cancers, but its mechanism in NPC deserves further investigation. The purpose of the study is to figure out the role and molecular regulation mechanism of SNHG7 in NPC. METHODS: The role of SNHG7 in NPC was verified by CCK-8, colony formation, EdU staining, western blot and capase-3 assays. The interactions between SNHG7/ELAVL1 and miR-514a-5p were confirmed by RNA pull down, RT-qPCR, RIP and luciferase reporter assays. RESULTS: SNHG7 was upregulated in NPC cells, and absence of SNHG7 suppressed cell proliferation as well as promoted cell apoptosis in NPC. Furthermore, SNHG7 was confirmed to bind with miR-514a-5p and negatively modulate miR-514a-5p expression. Besides, miR-514a-5p was found to be able to bind with ELAVL1 and negatively regulate ELAVL1 mRNA and protein expressions. In the end, rescue assays demonstrated that the miR-514a-5p deficiency restored the NPC progression inhibited by SNHG7 silence, and ELAVL1 partly counteracted the restoration caused by miR-514a-5p inhibitor in HNE1 cells. CONCLUSIONS: LncRNA SNHG7 promotes the proliferation and migration of nasopharyngeal carcinoma by miR-514a-5p/ ELAVL1 axis.


Assuntos
Proteína Semelhante a ELAV 1/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteína Semelhante a ELAV 1/genética , Humanos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Regulação para Cima
18.
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
19.
PLoS One ; 15(4): e0230524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271791

RESUMO

BACKGROUND: Aberrant methylation of DNA plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC). In the current study, we aimed to integrate three cohorts profile datasets to identify abnormally methylated-differentially expressed genes and pathways associated with NPC. METHODS: Data of gene expression microarrays (GSE53819, GSE412452) and gene methylation microarrays (GSE52068) obtained from the GEO database. Aberrantly methylated differentially expressed genes (DEGs) were obtained by GEO2R. The David database was utilized to perform enrichment and functional analysis regarding selected genes. To create a protein-protein interaction (PPI), STRING and Cytoscape software were utilized. The MCODE was used for module analysis of the PPI network. RESULTS: In total, 181 hypomethylation-high expression genes were identified, which were enriched in the biological mechanisms involved in the differentiation of endodermal cell, mitotic nuclear division, mitotic cell cycle process, chromosome segregation and cell cycle phase transition, etc. Pathway enrichment showed ECM-receptor interaction, PI3K-Akt signaling pathway, Focal adhesion, Protein digestion and absorption and Amoebiasis, etc. The top 3 hub genes of PPI network were FANCI, POSTN, and IFIH1. Additionally, 210 hypermethylation-low expression genes were identified, and our data revealed enrichment in biological processes including axoneme assembly, micro tubular formation, assembly of axonemal dynein complex, cilium movement and cilium organization, etc. Pathway analysis indicated enrichment in B cell receptor signaling pathway, Hematopoietic cell lineage, Leukocyte transendothelial migration, Complement and coagulation cascades and Fc gamma R-mediated phagocytosis, etc. The ZMYND10, PACRG and POU2AF1 were identified as the top three hub genes of PPI network. After validation in TCGA and GEPIA database, most hub genes remained significant. Patients with high expression of POSTN found to have shorter overall survival, while in patients with high expression of ZMYND10 and POU2AF1 longer overall survival was identified. CONCLUSIONS: The data revealed novel aberrantly methylated-differentially expressed genes and pathways in NPC by bioinformatics analysis, potentially providing novel insights for the molecular mechanisms governing NPC progression. Hub genes including FANCI, POSTN, IFIH1, ZMYND10, PACRG and POU2AF1 might serve as novel biomarkers for precision diagnosis and providing medical treatment for patient with NPC.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA/genética , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Progressão da Doença , Epigênese Genética/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Marcadores Genéticos/genética , Humanos , Análise em Microsséries/métodos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , Transdução de Sinais/genética , Transcriptoma
20.
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
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