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1.
Cancer Sci ; 111(1): 72-83, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31691433

RESUMO

Capn4, also known as CapnS1, is a member of the calpain family, which plays a crucial role in maintaining the activity and function of calpain. We previously reported that Capn4 also plays an essential role in the migration of nasopharyngeal carcinoma (NPC) cells through regulation of (MMP-2) by nuclear factor-kappa B activation. Epstein-Barr virus latent membrane protein 1 (LMP1) is closely related to the malignant functions of NPC; however, the relationship between LMP1 and Capn4 in NPC remain unclear. Immunohistochemical studies showed that the level of LMP1 and Capn4 expression was high in both primary and metastatic NPC tissues, with a significantly positive correlation. We further found that LMP1 was able to upregulate the Capn4 promoter in a dose-dependent way through the C-terminal activation region (CTAR)1 and CTAR2 domains to activate AP-1. Moreover, we also found that LMP1 activated AP-1 through ERK/JNK phosphorylation. These findings indicate that Capn4 coordination with LMP1 promotes actin rearrangement and, ultimately, cellular migration. These results show that Capn4 coordination with LMP1 enhances NPC migration by increasing actin rearrangement involving ERK/JNK/AP-1 signaling. Therapeutically, additional and more specific LMP1 and Capn4 targeted inhibitors could be exploited to treat NPC.


Assuntos
Calpaína/genética , Sistema de Sinalização das MAP Quinases/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Metástase Neoplásica/genética , Fator de Transcrição AP-1/genética , Proteínas da Matriz Viral/genética , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/patogenicidade , Humanos , NF-kappa B/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Metástase Neoplásica/patologia , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Regulação para Cima/genética
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(10): 1166-1172, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31801705

RESUMO

OBJECTIVE: To investigate the effect of down-regulation of miR-205-5p on 3-bromopyruvate-induced apoptosis in human nasopharyngeal carcinoma CNE2Z cells. METHODS: Nasopharyngeal carcinoma CNE2Z cells were transfected with miR- 205-5p-mimic or miR-205-5p-inhibitor, treated with 80 µmol/L 3-bromopyruvate alone, or exposed to both of the treatments. The proliferation of the treated cells was examined with MTT assay, and early apoptosis of the cells was detected using a mitochondrial membrane potential detection kit (JC-1). DAPI fluorescence staining was used to detect morphological changes of the cell nuclei and late cell apoptosis; Annexin V-FITC/PI double staining was employed to detect the cell apoptosis rate. Western blotting was used to detect the expressions of Bcl-2, Bax, Mcl-1 and Bak proteins. RESULTS: Exposure to 3-bromopyruvate significantly inhibited the proliferation of CNE2Z cells, and increasing the drug concentration and extending the treatment time produced stronger inhibitory effects. Treatment with 80 µmol/L 3-bromopyruvate for 24, 48 and 72 h resulted in inhibition rates of (45.7±1.21)%, (64.4±2.02)% and (78.3±1.55)% in non-transfected CNE2Z cells, respectively; the inhibition rates were (27.7±1.04)%, (34.8±2.10)% and (44.3±1.57)% in the cells transfected with miR-205-5p-mimic, and were (80.5 ± 0.94)%, (87.9 ± 0.50)% and (93.8 ± 1.16)% in cells transfected with miR-205-5p-inhibitor, respectively. The results of mitochondrial membrane potential detection showed that the relative proportion of red and green fluorescence decreased significantly in miR-205-5p-inhibitor-transfected cells with 3-bromopyruvate treatment. Combined treatment of the cells with 3-bromopyruvate and miR-205-5p-inhibitor transfection obviously increased nuclear fragmentation and nuclear pyknosis and significantly increased cell apoptotic rate as compared with the two treatments alone (P < 0.01), causing also decreased expressions of Bcl-2 and Mcl-1 proteins and increased expressions of Bax and Bak proteins. CONCLUSIONS: Inhibition of miR-205-5p enhances the proapototic effect of 3-bromopyruvate in CNE2Z cells possibly in relation to the down-regulation of Mcl-1 and Bcl-2 and the up-regulation of Bak and Bax proteins.


Assuntos
Apoptose , MicroRNAs/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Piruvatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
3.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(10): 1191-1199, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31801714

RESUMO

OBJECTIVE: To analyze the effects of alterations in the expressions of methyltransferase SETD2 on protein expression profiles in human nasopharyngeal carcinoma (NPC) cells and enrich the differential signaling pathways. METHODS: The total protein was extracted from SETD2-knockout cell line CNE1SETD2-KO and the wild-type cell line CNE1WT, and the differentially expressed proteins were screened by tandem mass tag (TMT) labeled protein quantification technique and tandem mass spectrometry. GO analysis was used to annotate and enrich the differentially expressed proteins, and the KEGG database was used to enrich and analyze the pathways of the differential proteins. RESULTS: With a fold change (FC)≥1.2 and P < 0.05 as the screening standard, 2049 differentially expressed proteins were identified in CNE1SETD2-KO cells, among which 904 were up-regulated and 1145 were down-regulated. GO functional annotation results indicated that SETD2 knockout caused characteristic changes in multiple biological processes (cell processes and regulation, cell movement, metabolic processes, and biosynthesis of cellular components), molecular functions (catalytic activity and molecular binding, transcription factor activity), and cellular components (cell membrane, organelle, macromolecular complex). KEGG analysis showed that the differentially expressed proteins were involved in an array of signaling pathways closely related to tumors, including MAPK, PI3K-Akt, Ras, Rap1, mTOR, Hippo, HIF-1, Wnt, AMPK, FoxO, ErbB, P53 and JAK-STAT. CONCLUSIONS: SETD2 knockout significantly changes the protein expression characteristics of NPC cells and affects a number of signal pathways closely related to tumors. The results provide evidence for investigation of the pathogenesis and therapeutic target screening of NPC.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Proteômica , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Humanos
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 1014-1019, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878998

RESUMO

Objective To explore the effect of miR-129-1-3p on cisplatin sensitivity of chemo-resistant epithelial nasopharyngeal carcinoma HNE19/CDDP cells and the related mechanism. Methods Human nasopharyngeal carcinoma HNE1 cells and cisplatin-resistant HNE19/CDDP cells were cultured. Cisplatin resistance index of cisplatin-resistant HNE1/CDDP cells was tested by MTT assay. The levels of miR-129-1-3p and WEE1 mRNA in HNE1 and HNE19/CDDP cells were measured by real-time quantitative PCR. miR-129-1-3p mimics and unrelated sequence control (miR-129-1-3p NC) were transfected into HNE1/CDDP cells using LipofectamineTM 2000. The drug sensitivity (IC50) of these cells to cisplatin was determined by MTT assay. The protein expression level of WEE1 was determined by Western blot analysis. The 3'-UTR of WEE1 was cloned into luciferase reporter vector and its luciferase activity was detected to verify whether miR-129-1-3p targets WEE1. Results Resistance index of HNE1/CDDP cells to cisplatin was 5.29. The expression level of miR-129-1-3p in the HNE1 cells was significantly higher than that in the HNE1/CDDP cells. The mRNA expression level of WEE1 in the HNE1 cells was lower than that in the HNE1/CDDP cells. The level of miR-129-1-3p was negatively correlated with the level of WEE1 mRNA (r=-0.9784). The IC50 of cisplatin was significantly reduced in the HNE1/CDDP cells after transfected with miR-129-1-3p mimics. The protein expression level of WEE1 in the cells transfected with miR-129-1-3p mimics significantly decreased as compared with the control group and blank group. The miR-129-1-3p regulated the 3'-UTR of WEE1 and reduced the expression activity of luciferase. Conclusion miR-129-1-3p could reverse cisplatin resistance of HNE1/CDDP nasopharyngeal carcinoma cells via inhibiting WEE1 expression.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico
5.
Medicine (Baltimore) ; 98(51): e18036, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860954

RESUMO

Cullin 4A (CUL4A) is a protein of E3 ubiquitin ligase with many cellular processes. CUL4A could regulate cell cycle, development, apoptosis, and genome instability. This study aimed to analyze the expression of CUL4A in nasopharyngeal carcinoma (NPC) tissues and the associations of CUL4A expression with prognostic significance. A total of 115 NPC patients were collected to assess the protein expression of CUL4A by immunohistochemistry, so as to analyze the relationships between CUL4A expression and clinicopathological and prognostic parameters. All patients were followed-up until death or 5 years. The results showed that high expression of CUL4A was significantly associated with larger primary tumor size (P = .026), higher nodal status (P = .013), more distant metastasis (P = .020), and higher TNM stage (P = .005). Kaplan-Meier curves showed that patients with higher CUL4A expression had significantly shorter overall survival (OS) and progression-free survival (PFS) (both P < .001). In multivariate Cox analysis, CUL4A is an independent prognostic factor for OS (P = .016; hazard ratio [HR] = 2.770, 95% CI: 1.208-6.351) and PFS (P = .022; HR = 2.311, 95% CI: 1.126-4.743). In conclusion, high expression of CUL4A was associated with advanced disease status of NPC, and might serve as an independent prognostic factor.


Assuntos
Proteínas Culina/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/mortalidade , Adulto , Idoso , China , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Hospitais Universitários , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida
6.
Medicine (Baltimore) ; 98(47): e17831, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764777

RESUMO

The RTN4 gene plays a role in the development and progression of cancer. This case-control study aimed to investigate the association between the RTN4 gene polymorphism and its plasma level with the risk of nasopharyngeal carcinoma (NPC) in a Chinese population.RTN4 gene polymorphisms (rs2920891, rs17046583, rs117465650, rs10496040, and rs2588519) in 220 patients with NPC and 300 healthy controls were analyzed using Snapshot single-nucleotide polymorphism genotyping assays. The plasma level of RTN4 was measured using the enzyme-linked immunosorbent assay.The allele frequencies of RTN4 gene polymorphisms showed no significant difference between the patients and controls (P > .05). Nevertheless, the rs2920891 polymorphism in a dominant model (A/C+C/C) and codominant model (A/C) was significantly associated with the susceptibility to NPC (P = .017, odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.08-2.21 and P = .034, OR = 1.64, 95% CI = 1.13-2.38, respectively). The plasma level of RTN4 was significantly higher in patients with NPC in comparison with the controls (P < .001). Furthermore, we observed that patients with NPC carrying the rs2920891 A/C+C/C genotype had a higher RTN4 level than those carrying the A/A genotype (P < .001).Our findings indicated that the rs2920891 polymorphism may be associated with increased susceptibility to NPC, possibly by increasing plasma RTN4.


Assuntos
Carcinoma Nasofaríngeo/sangue , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/sangue , Neoplasias Nasofaríngeas/genética , Proteínas Nogo/sangue , Proteínas Nogo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade
7.
Medicine (Baltimore) ; 98(48): e17997, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770211

RESUMO

As for the lack of simple and effective diagnostic methods at the early of the nasopharyngeal carcinoma (NPC), the mortality rate of NPC still remains high. Therefore, it is meaningful to explore the precise molecular mechanisms involved in the proliferation, carcinogenesis, and recurrence of NPC and thus find an effective diagnostic way and make a better therapeutic strategy.Three gene expression data sets (GSE64634, GSE53819, and GSE12452) were downloaded from Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DEGs were performed in Database for Annotation, Visualization and Integrated Discovery. The Search Tool for the Retrieval of Interacting Genes database was used to evaluate the interactions of DEGs and to construct a protein-protein interaction network using Cytoscape software. Hub genes were validated with the cBioPortal database.The overlap among the 3 data sets contained 306 genes were identified to be differentially expressed between NPC and non-NPC samples. A total of 13 genes (DNAAF1, PARPBP, TTC18, GSTA3, RCN1, MUC5AC, POU2AF1, FAM83B, SLC22A16, SPEF2, ERICH3, CCDC81, and IL33) were identified as hub genes with degrees ≥10.The present study was attempted to identify and functionally analyze the DEGs that may be involved in the carcinogenesis or progression of NPC by using comprehensive bioinformatics analyses and unveiled a series of hub genes and pathways. A total of 306 DEGs and 13 hub genes were identified and may be regarded as diagnostic biomarkers for NPC. However, more experimental studies are needed to carried out elucidate the biologic function of these genes results for NPC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Biologia Computacional , Bases de Dados Genéticas , Ontologia Genética , Humanos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética
8.
BMC Cancer ; 19(1): 843, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31455274

RESUMO

BACKGROUND: Recent studies reported that blood-based microRNAs (miRNAs) could detect cancers and predict prognosis have opened a new field of utilizing circulating miRNAs as cancer biomarkers. In this pilot study, we conducted for the first time, to our knowledge, the evaluation of the applicability of salivary miRNAs as novel biomarkers for nasopharyngeal carcinoma (NPC) detection. METHODS: Microarray miRNA expression profiling was performed on saliva samples from 22 newly diagnosed NPC patients and 25 healthy controls, and 12 significantly down-regulated miRNAs were selected for quantitative real-time-PCR (qRT-PCR) validation and further analysis. Their target genes enriched by gene ontology and pathway analysis were used to construct regulatory and interaction networks. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy. RESULTS: Twelve dysregulated miRNAs screened by microarray that showed the same expression patterns with qRT-PCR analysis. Through bioinformatics analysis, the most prominent hub gene probably regulated by the 12 down-regulated miRNAs is found to be TP53. The ROC including the 12 miRNAs separated NPC patients from healthy controls with very high accuracy (areas under the receiver operating characteristic curve [AUC] = 0.999, sensitivity = 100.00%, specificity = 96.00%). Furthermore, if only six significantly dysregulated miRNAs were selected for the ROC analysis, the accuracy is still impressive (AUC = 0.941, sensitivity = 95.45%, specificity = 80.00%). CONCLUSIONS: This study highlights the potential for salivary miRNAs as biomarkers for the detection of NPC. Meanwhile, differentially expressed miRNAs in saliva might play critical roles in NPC by regulating their target genes, which associated with some significant pathways, such as p53 signaling pathway.


Assuntos
Biomarcadores Tumorais , MicroRNA Circulante , MicroRNAs/genética , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Saliva/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/metabolismo , Curva ROC
9.
PLoS Genet ; 15(8): e1008325, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31430288

RESUMO

The role of long non-coding RNA (lncRNA) in the progression of Nasopharyngeal carcinoma (NPC) has not been fully elucidated. The study was designed to explore the functional role of NKILA, a newly identified lncRNA, in the progression of NPC. We performed a lncRNA expression profile microarray using four NPC and paired para-cancerous tissues. NKILA was identified as a potential functional lncRNA by this lncRNA expression profile. We used 107 paraffin-embedded NPC tissues with different TNM stages to detect the expression of NKILA and analyzed the survival data by Log-rank test and Cox regression. The role of NKILA and its underlying mechanisms in the progression of NPC were evaluated by a series of experiments in vitro and vivo by silencing or expressing NKILA. Compared with control tissues, NKILA expression was identified to be decreased in NPC tissues. Low NKILA expression was correlated with unfavorable clinicopathological features and predicted poor survival outcome in NPC patients. After adjusting for potential confounders, low expression of NKILA was confirmed to be an independent prognostic factor correlated with poor survival outcomes. Furthermore, we found that NKILA overexpression in high-metastatic-potential NPC cells repressed motile behavior and impaired the metastatic capacity in vitro and in vivo. In contrast, RNAi-mediated NKILA depletion increased the invasive motility of cells with lower metastatic potential. Further experiments demonstrated that NKILA regulated the metastasis of NPC through the NF-κB pathway. Taken together, NKILA plays vital roles in the pathogenesis of NPC. The unique histological characteristics of NPC indicate that local inflammation plays a vital role in carcinogenesis of nasopharyngeal carcinoma.


Assuntos
Carcinogênese/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Nasofaringe/patologia , Prognóstico , RNA Longo não Codificante/genética
10.
Br J Radiol ; 92(1102): 20190107, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31322911

RESUMO

Many of the principles established in adults with undifferentiated nasopharyngeal carcinoma (NPC) apply to children, adolescents and young adults. However, NPC in young patients should be distinguished from the adult form by several points. This review focuses mainly on differences between adult and pediatric NPC. The role of biology and genetics in pediatric NPC is discussed. Systemic treatment modalities including type of chemotherapy induction, timing of treatment, role of immunotherapy as adjuvant treatment, or in relapsing/ metastatic diseases are reported. Radiation modalities (doses, techniques…) in children are also reviewed. Long-term effects including secondary cancers are finally be discussed in this young NPC population.


Assuntos
Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Adolescente , Fatores Etários , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Criança , Herpesvirus Humano 4/genética , Humanos , Quimioterapia de Indução , Interferon beta/uso terapêutico , Quimioterapia de Manutenção , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virologia , Estadiamento de Neoplasias/métodos , Radioterapia/efeitos adversos , Radioterapia/métodos , Adulto Jovem
11.
Artif Cells Nanomed Biotechnol ; 47(1): 3043-3052, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31334669

RESUMO

We planned to dig the significant role of long noncoding RNA HAGLROS in nasopharyngeal carcinoma (NPC) and the latent mechanism. The levels of HAGLROS in NPC tissues and cells were determined, followed by correlation analysis of HAGLROS level and clinicopathological features of patients suffered with NPC. The impacts of HAGLROS dysregulation on NPC cell viability, apoptosis, and the expression of apoptotic proteins and autophagy-related symbols were investigated. Moreover, we explored whether HAGLROS modulated the expression of autophagy-related gene 14 (ATG14) by competitively sponging miR-100, and then regulated the briskness of PI3K/AKT/mTOR signals in NPC development. HAGLROS level in NPC tissues and cell was very high. High level of HAGLROS indicated a short overall survival in NPC patients. Depressing of HAGLROS lessened NPC cell viability, enhanced apoptosis and reduced autophagy. Besides, HAGLROS negative controlled miR-100 and consequently targeted ATG14 expression, thus modulating NPC cell viability, apoptosis, and autophagy. Besides, dysregulation of HAGLROS/miR-100/ATG14 axis was correlated to the briskness of PI3K/AKT/mTOR signals in NPC cells. Our results indicate that of the augment of HAGLROS contributes to NPC development via modulating miR-100/ATG14 axis-mediated PI3K/AKT/mTOR signals. Our study will offer a comprehensive basis for better illustrating the pathogenesis of NPC. Highlights HAGLROS expression was upregulated in NPC tissues and cells. High expression of HAGLROS indicated a short overall survival in NPC patients. Silencing of HAGLROS promoted apoptosis and inhibited autophagy of NPC cells. HAGLROS regulated ATG14 expression in NPC cells via sponging miR-100. HAGLROS/miR-100/ATG14 axis regulated NPC development via PI3K/AKT/mTOR pathway.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Relacionadas à Autofagia/genética , MicroRNAs/genética , Carcinoma Nasofaríngeo/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Serina-Treonina Quinases TOR/metabolismo , Apoptose/genética , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Transdução de Sinais/genética
12.
Biomed Res Int ; 2019: 7457013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31321241

RESUMO

Introduction: The role of podoplanin (PDPN) in nasopharyngeal carcinoma (NPC) is still unknown. The aims of this study were to investigate the expression and role of PDPN in NPC cells. Materials and Methods: Immunofluorescence staining and functional tests were used to determine the effects of PDPN knockdown by siRNA in TW01 NPC cells. Microarray analysis was conducted to identify genes regulated by PDPN. The molecular mechanism of PDPN on NPC cells was further determined by Ingenuity Pathways Analysis (IPA). Results: PDPN was expressed in most TW01 NPC cells. PDPN knockdown by siRNA decreased NPC cell proliferation, migration, and invasion. The microarray data showed 63 upregulated genes and 12 downregulated genes following PDPN knockdown. The top 5 most upregulated genes analyzed by IPA were IFI27, IFI44L, IFI6, OAS1, and TRIM22, and the most relevant pathway was the interferon signaling pathway. Conclusions: To the best of our knowledge, this is the first report to show that knocking down PDPN leads to suppression of NPC cell proliferation, migration, and invasion. Our results suggest that PDPN may serve as a potential chemotherapeutic target for NPC treatment in the future.


Assuntos
Biomarcadores Tumorais/genética , Proliferação de Células/genética , Glicoproteínas de Membrana/genética , Carcinoma Nasofaríngeo/genética , 2',5'-Oligoadenilato Sintetase/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Proteínas de Membrana/genética , Análise em Microsséries , Antígenos de Histocompatibilidade Menor/genética , Proteínas Mitocondriais/genética , Carcinoma Nasofaríngeo/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas Repressoras/genética , Transdução de Sinais/genética , Proteínas com Motivo Tripartido/genética , Proteínas Supressoras de Tumor/genética
13.
Neoplasma ; 66(6): 939-945, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31307201

RESUMO

Nasopharyngeal carcinoma (NPC) is one common head and neck malignancy with leading cause of cancer-related death. Long noncoding RNAs (lncRNAs) have been reported to play essential roles in progression, prognosis and treatment of NPC. However, the exact role of lncRNA zinc finger antisense 1 (ZFAS1) in NPC progression and its potential mechanism remain largely unknown.The expressions of ZFAS1 and microRNA-135a (miR-135a) were measured in NPC tissues or cells by quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between ZFAS1 and miR-135a was explored by luciferase reporter assay and RNA immunoprecipitation (RIP). Cell proliferation, apoptosis, migration and invasion were analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5 -diphenyl-2-H-tetrazolium bromide (MTT) assay, flow cytometry or trans-well assay, respectively. Our data showed the expression of ZFAS1 was up-regulated and miR-135a was down-regulated in NPC tissues and cells. miR-135a was bound to ZFAS1 in NPC cells. Moreover, knockdown of ZFAS1 or addition of miR-135a inhibited cell proliferation, migration and invasion but promoted apoptosis in NPC cells. Besides, down-regulation of miR-135a reversed abrogation of ZFAS1-mediated inhibition of proliferation, migration and invasion and increase of apoptosis in NPC cells. Our data suggested Inhibition of ZFAS1 protected against proliferation, migration and invasion but contributed to apoptosis by sponging miR-135a in NPC cells, providing a novel avenue for NPC treatment.


Assuntos
MicroRNAs , Carcinoma Nasofaríngeo , RNA Longo não Codificante , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/fisiopatologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
14.
Oncogene ; 38(32): 6065-6081, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31273338

RESUMO

Long non-coding RNA (lncRNA) plays an important role in malignant tumor occurrence, development, and chemoresistance, but the mechanism of how they affect nasopharyngeal cancer (NPC) paclitaxel chemosensitivity is unclear. In this study, lncRNA array of CNE-1 and HNE-2 paclitaxel-resistant cells and their parental strains revealed that the paclitaxel-resistant strains had significantly lower MRVI1-AS1 (murine retrovirus integration site 1 homolog antisense RNA 1) expression than the parental strains, and that MRVI1-AS1 overexpression in vitro and in vivo increased paclitaxel chemosensitivity. Further, MRVI1-AS1 upregulated ATF3 (activating transcription factor 3) by simultaneously inhibiting miR-513a-5p (microRNA-513a-5p) and miR-27b-3p expression levels to increase NPC paclitaxel chemosensitivity. Chromatin immunoprecipitation and quantitative real-time PCR showed that ATF3 could feed-back MRVI1-AS1 regulation positively. Furthermore, MRVI1-AS1 and ATF3 could form a positive feedback loop, which promoted the expression of RASSF1 (Ras association domain family member 1), a Hippo-TAZ (tafazzin) signaling pathway regulatory factor, thereby inhibiting TAZ expression. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay and flow cytometry showed that the decreased TAZ increased NPC cell paclitaxel chemosensitivity. Overall, the results indicate that the MRVI1-AS1/ATF3 signaling pathway can increase NPC paclitaxel chemosensitivity by modulating the Hippo-TAZ signaling pathway. Therefore, targeting the loop may be a new NPC treatment strategy.


Assuntos
Fator 3 Ativador da Transcrição/genética , Proteínas de Membrana/genética , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Paclitaxel/uso terapêutico , Fosfoproteínas/genética , RNA Antissenso/fisiologia , Células A549 , Fator 3 Ativador da Transcrição/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Células MCF-7 , Proteínas de Membrana/antagonistas & inibidores , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Fosfoproteínas/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
Mol Carcinog ; 58(10): 1886-1896, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31270884

RESUMO

Notch pathway is a highly conserved cell signaling system that plays very important roles in controlling multiple cell differentiation processes during embryonic and adult life. Multiple lines of evidence support the oncogenic role of Notch signaling in several human solid cancers; however, the pleiotropic effects and molecular mechanisms of Notch signaling inhibition on nasopharyngeal carcinoma (NPC) remain unclear. In this study, we evaluated Notch1 expression in NPC cell lines (CNE1, CNE2, SUNE1, HONE1, and HK1) by real-time quantitative PCR and Western blot analysis, and we found that CNE1 and CNE2 cells expressed a higher level of Notch1 compared with HONE1, SUNE1, and HK1 cells. Then Notch1 expression was specifically knocked down in CNE1 and CNE2 cells by Notch1 short hairpin RNA (shRNA). In Notch1 knockdown cells, cell proliferation, migration, and invasion were significantly inhibited. The epithelial-mesenchymal transition of tumor cells was reversed in Notch1-shRNA-transfected cells, accompanied by epithelioid-like morphology changes, increased protein levels of E-cadherin, and decreased expression of vimentin. In addition, knockdown of Notch1 markedly inhibited the expression of urokinase plasminogen activator (uPA) and its receptor uPAR, and chemokines C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 16, indicating that these factors are downstream targets of Notch1. Furthermore, deleting uPA expression had similar effects as Notch1. Finally, knockdown of Notch1 significantly diminished CNE1 cell growth in a murine model concomitant with inhibition of cell proliferation and induction of apoptosis. These results suggest that Notch1 may become a novel therapeutic target for the clinical treatment of NPC.


Assuntos
Quimiocina CCL2/genética , Quimiocina CXCL16/genética , Carcinoma Nasofaríngeo/genética , Receptor Notch1/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Animais , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , Carcinoma Nasofaríngeo/patologia , Metástase Neoplásica , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Receptor Notch1/antagonistas & inibidores , Transdução de Sinais
16.
Mol Med Rep ; 20(2): 1672-1682, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257481

RESUMO

MicroRNA­30a (miR­30a) was previously reported to serve as a tumor suppressor able to inhibit the development and progression of certain types of cancer. A number of previous studies demonstrated that zinc finger E­box binding homeobox 2 (ZEB2) may be regulated by miR­30a in clear cell renal cell carcinoma and breast cancer. However, the function of miR­30a in human nasopharyngeal carcinoma (NPC) remains unclear. The present study aimed to investigate the association between miR­30a and ZEB2 in NPC. Therefore, the expression levels of miR­30a and ZEB2 were measured in human NPC cells and tissues from patients with NPC, and the present results suggested that the expression level of miR­30a was significantly decreased in NPC tissues compared with paracancerous tissues. The direct interaction between miR­30a and the untranslated region of ZEB2 was examined using the dual­luciferase reporter assay, and ZEB2 was identified as a direct target of miR­30a. Additionally, the effects of miR­30a and ZEB2 overexpression on cell proliferation, migration, invasion and apoptosis were additionally investigated. Functional experiments identified that overexpression of miR­30a increased apoptosis and suppressed cell proliferation, cell migration and cell invasion by directly targeting ZEB2. Collectively, the present study suggested that miR­30a may serve an important role in the progression of NPC and may represent a novel target for the treatment of patients with NPC.


Assuntos
MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Adulto , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade
17.
Biomed Res Int ; 2019: 7246491, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309112

RESUMO

Our previous studies showed that ZBTB7A played an important role in promoting nasopharyngeal carcinoma (NPC) progression. However, molecular mechanisms of different levels of ZBTB7A are still unclear. It is necessary to search molecular markers which are closely connected with ZBTB7A. We selected NPC sublines CNE2 with stably transfecting empty plasmid (negative control, NC) and short hair RNA (shRNA) plasmid targeting ZBTB7A as research objectives. Microarray was used to screen differentially expressed long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) via shRNA-CNE2 versus NC-CNE2. Quantitative PCR (qPCR) was used to validate lncRNAs and mRNAs from the sublines, chronic rhinitis, and NPC tissues. Bioinformatics was used to analyze regulatory pathways which were connected with ZBTB7A. The 1501 lncRNAs (long noncoding RNAs) and 1275 differentially expressed mRNAs were upregulated or downregulated over 2-fold. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the upregulated or downregulated carbohydrate and lipid metabolisms probably involved in carcinogenicity of shRNA-CNE2 (P-value cut-off was 0.05). In order to find the molecular mechanisms of ZBTB7A, we validated 12 differentially expressed lncRNAs and their nearby mRNAs by qPCR. Most of the differentially expressed mRNAs are closely connected with carbohydrate and lipid metabolisms in multiply cancers. Furthermore, part of them were validated in NPC and rhinitis tissues by qPCR. As a result, NR_047538, ENST00000442852, and fatty acid synthase (FASN) were closely associated with NPC. ZBTB7A had a positive association with NR_047538 and negative associations with ENST00000442852 and FASN. The results probably provide novel candidate biomarkers for NPC progression with different levels of ZBTB7A.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Humanos , Regulação para Cima/genética
18.
Arch Oral Biol ; 106: 104478, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319350

RESUMO

OBJECTIVE: This study aimed to identify candidate genes as potential biomarkers in nasopharyngeal carcinoma (NPC) by bioinformatical analysis. METHODS: Three microarray datasets: GSE32906, GSE15170, GSE53819 were download from public database and analyzed to identify the differentially expressed genes (DEGs) between NPC and normal samples. Functional and pathway enrichment analysis of the DEGs were performed. Protein-protein interaction network and gene-transcription factor regulatory network of DEGs were constructed. And the expression of hub genes in NPC was also validated based on the public database. RESULTS: A total of 16 up-regulated and 27 down-regulated genes were screened out from the microarray datasets. Functional and pathway enrichment analysis showed that DEGs were mostly enriched in positive regulation of angiogenesis, mesenchymal cell proliferation, cell surface and DNA binding, ECM-receptor interaction pathway, PI3K-Akt signaling pathway, and pathways in cancer. Five hub genes JUN, VEGFA, FOXM1, MYB, and WNT5A were identified from the protein-protein interaction network. Subsequently, the hub gene-transcription factor regulatory network revealed that STAT3, MYC, SOX2, RUNX2 present key relations with hub genes. The expression of these five hub genes were also validated to be differentially expressed among NPC and normal samples. CONCLUSIONS: The current study indicated that the hub DEGs JUN, VEGFA, FOXM1, MYB, and WNT5A we identified might be potential therapeutic biomarkers of NPC.


Assuntos
Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Biologia Computacional , Proteína Forkhead Box M1/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-myb/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteína Wnt-5a/genética
19.
J Exp Clin Cancer Res ; 38(1): 300, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291971

RESUMO

BACKGROUND: Cancer is fundamentally a deregulation of cell growth and proliferation. Cancer cells often have perturbed metabolism that leads to the alteration of metabolic intermediates. Dehydrogenase/reductase member 2 (DHRS2) belongs to short-chain alcohol dehydrogenase/reductase (SDR) superfamily, which is functionally involved in a number of intermediary metabolic processes and in the metabolism of lipid signaling molecules. DHRS2 displays closely association with the inhibition of cell proliferation, migration and quiescence in cancers. METHODS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4- sulfophenyl)-2H-tetrazolium (MTS), 5-ethynyl-2'-deoxyuridine (EdU) and colony formation assays were applied to evaluate the proliferative ability of nasopharyngeal carcinoma (NPC) cells. We performed lipid metabolite profiling using gas chromatography coupled with mass spectrometry (GC/MS) to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA sequencing technique combined with differentially expressed genes analysis was applied to identify the expression of genes responsible for the anti-tumor effect of trichothecin (TCN), a natural sesquiterpenoid compound isolated from an endophytic fungus. RESULTS: Our current findings reveal that DHRS2 affects lipid metabolite profiling to induce cell cycle arrest and growth inhibition in NPC cells. Furthermore, we demonstrate that TCN is able to induce growth inhibition of NPC in vitro and in vivo by up-regulating DHRS2. CONCLUSIONS: Our report suggests that activating DHRS2 to reprogram lipid homeostasis may be a target for the development of targeted therapies against NPC. Moreover, TCN could be exploited for therapeutic gain against NPC by targeting DHRS2 and it may also be developed as a tool to enhance understanding the biological function of DHRS2.


Assuntos
Carbonil Redutase (NADPH)/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Animais , Carbonil Redutase (NADPH)/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Carcinoma Nasofaríngeo/metabolismo , Tricotecenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Biochem ; 166(5): 433-440, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350893

RESUMO

Nasopharyngeal carcinoma (NPC) is an important type of head and neck malignant cancer with geographical distribution. MicroRNA-449b-5p (miR-449b-5p) is related to the development of various cancers, while its function in NPC remains unknown. The present study aimed to investigate the role and target gene of miR-449b-5p in NPC. Expressions of miR-449b-5p in NPC cell lines and clinical tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was determined by MTT and colony formation assays. Migration and invasion abilities after different treatment were evaluated by wound healing and Transwell assays, respectively. Dual-luciferase reporter assay was performed to explore the relationship between miR-449b-5p and tumour protein D52 (TPD52). TPD52 expression was determined by qRT-PCR and western blot assay. miR-449b-5p was significantly downregulated in NPC cell lines and clinical tissues than the matched control. Overexpression of miR-449b-5p inhibited proliferation, migration and invasion of NPC cells. Dual-luciferase reporter assay indicated that miR-449b-5p directly targeted TPD52. Furthermore, shRNA-mediated downregulation of TPD52 rectified the promotion of cell migration and invasion by miR-449b-5p inhibition. In conclusion, the present study suggests that miR-449b-5p, as a novel tumour-suppressive miRNA against NPC, inhibits proliferation, migration and invasion of NPC cells via inhibiting TPD52 expression.


Assuntos
Movimento Celular/genética , Genes Supressores de Tumor , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia
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