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1.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35163030

RESUMO

c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.


Assuntos
Antineoplásicos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Humanos , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/patologia
3.
Exp Mol Med ; 53(8): 1207-1217, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34385569

RESUMO

Compelling evidence has indicated the vital role of lysine-specific demethylase 4 A (KDM4A), hypoxia-inducible factor-1α (HIF1α) and the mechanistic target of rapamycin (mTOR) signaling pathway in nasopharyngeal carcinoma (NPC). Therefore, we aimed to investigate whether KDM4A affects NPC progression by regulating the HIF1α/DDIT4/mTOR signaling pathway. First, NPC and adjacent tissue samples were collected, and KDM4A protein expression was examined by immunohistochemistry. Then, the interactions among KDM4A, HIF1α and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1α and DDIT4 expression in NPC cells. The mechanism of KDM4A in NPC was evaluated both in vivo and in vitro via RT-qPCR, Western blot analysis, MTT assay, Transwell assay, flow cytometry and tumor formation experiments. KDM4A, HIF1α, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1α promoter region and thus inhibited the methylation of HIF1α to promote HIF1α expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1α, or DDIT4 or activation of the mTOR signaling pathway promoted SUNE1 cell proliferation, migration, and invasion but inhibited apoptosis. KDM4A silencing blocked the mTOR signaling pathway by inhibiting the HIF1α/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1α/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.


Assuntos
Carcinogênese/patologia , Movimento Celular , Histona Desmetilases com o Domínio Jumonji/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Adulto , Idoso , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Lisina/metabolismo , Masculino , Metilação , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Invasividade Neoplásica , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Regulação para Cima/genética , Adulto Jovem
4.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33924755

RESUMO

Human nasopharyngeal carcinoma (NPC) is a highly invasive cancer associated with proinflammation. Caspase-12 (Casp12), an inflammatory caspase, is implicated in the regulation of NF-κB-mediated cellular invasion via the modulation of the IκBα protein in NPC cells. However, the effect mechanisms of Casp12 need to be elucidated. NPC cells were transfected with the full length of human Casp12 cDNA (pC12) and the effect of human Casp12 (hCasp12) on the NF-κB activity was investigated. We found ectopic expression of hCasp12 increased the NF-κB activity accompanied by an increased p-IκBα expression and a decreased IκBα expression. Treatment of BMS, a specific IKK inhibitor, and pC12-transfected cells markedly decreased the NF-κB activity and ameliorated the expression level of IκBα reduced by hCasp12. Co-immunoprecipitation assays validated the physical interaction of hCasp12 with IKKα/ß, but not with NEMO. Furthermore, the NF-κB activity of ΔCasp12-Q (a mutated catalytic of hCasp12) transfected cells was concentration-dependently induced, but lower than that of hCasp12-transfected cells. Importantly, the hCasp12-mediated NF-kB activity was enhanced by TNFα stimulation. That indicated a role of the catalytic motif of hCasp12 in the regulation of the NF-κB activity. This study indicated hCasp12 activated the NF-κB pathway through the activation of IKK in human NPC cells.


Assuntos
Caspase 12/metabolismo , Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/enzimologia , Linhagem Celular Tumoral , Ativação Enzimática , Humanos
5.
Cell Mol Biol Lett ; 26(1): 9, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726680

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a tumor deriving from nasopharyngeal epithelium. Peptidyl-arginine deiminase 4 (PAD4) is a vital mediator of histone citrullination and plays an essential role in regulating disease process. Radiotherapy is an essential method to treat NPC. In this research, we explored the effect of PAD4 on NPC radiosensitivity. METHODS: We enrolled 50 NPC patients, established mice xenograft model, and purchased cell lines for this study. Statistical analysis and a series of experiments including RT-qPCR, clonogenic survival, EdU, Transwell, and wound healing assays were done. RESULTS: Our data manifested that PAD4 (mRNA and protein) presented a high expression in NPC tissues and cells. GSK484, an inhibitor of PAD4, could inhibit activity of PAD4 in NPC cell lines. PAD4 overexpression promoted the radioresistance, survival, migration, and invasion of NPC cells, whereas treatment of GSK484 exerted inhibitory effects on radioresistance and aggressive phenotype of NPC cells. Additionally, GSK484 could attenuate the effect of PAD4 of NPC cell progression. More importantly, we found that GSK484 significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation. CONCLUSIONS: PAD4 inhibitor GSK484 attenuated the radioresistance and cellular progression in NPC.


Assuntos
Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Proteína-Arginina Desiminase do Tipo 4/antagonistas & inibidores , Tolerância a Radiação/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/genética , Invasividade Neoplásica , Fenótipo , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/metabolismo
6.
Aging (Albany NY) ; 13(4): 5674-5685, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33589574

RESUMO

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment, which are characterized by pro-tumor M2 phenotype and correlate with poor survival of nasopharyngeal carcinoma (NPC). Heme oxygenase-1 (HO-1) plays a crucial role in macrophage polarization toward M2 phenotype, but its prognosis significance in NPC has been rarely determined. To gain insights into the HO-1 expression profile and to determine the clinical significance of HO-1 in NPC, we performed immunohistochemistry analyses in 126 NPC specimens. CD163, a highly specific marker of M2 macrophages, was used as a surrogate for the polarization state of TAMs. Our results showed that high expression of HO-1 and CD163 were detected in TAMs for 57.9% (73/126) and 61.9% (78/126) of the studied patients, and both of them were significantly associated with worse survival. Additionally, a significant correlation between the intensities of HO-1 and CD163 was identified, and HO-1 exhibited a superior ability in predicting survival compared with CD163. Our study revealed for the first time that overexpression of HO-1 characterized a poor-prognosis subtype in NPC. Individualized therapy targeting HO-1 might serve as a promising treatment modality for NPC.


Assuntos
Heme Oxigenase-1/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores Tumorais/metabolismo , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/mortalidade , Prognóstico , Receptores de Superfície Celular/metabolismo , Estudos Retrospectivos , Adulto Jovem
7.
Cancer Lett ; 504: 81-90, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33587980

RESUMO

Despite recent in advances in the management of nasopharyngeal carcinoma (NPC), development of targeted therapy remains challenging particularly in patients with recurrent or metastatic disease. To search for clinically relevant targets for the treatment of NPC, we carried out parallel genome-wide functional screens to identified essential genes that are required for NPC cells proliferation and cisplatin resistance. We identified lymphocyte-specific protein tyrosine kinase (LCK) as a key vulnerability of both proliferation and cisplatin resistance. Depletion of endogenous LCK or treatment of cells with LCK inhibitor induced tumor-specific cell death and synergized cisplatin sensitivity in EBV-positive C666-1 and EBV-negative SUNE1 cells. Further analyses demonstrated that LCK is regulating the proliferation and cisplatin resistance through activation of signal transducer and activator of transcription 5 (STAT5). Taken together, our study provides a molecular basis for targeting LCK and STAT5 signaling as potential druggable targets for the management of NPC.


Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Linfócitos/enzimologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Tirosina Quinases/genética , Interferência de RNA , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/patologia
8.
J BUON ; 25(5): 2395-2404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33277861

RESUMO

PURPOSE: To identify new effective prognostic indicators for patients with nasopharyngeal carcinoma (NPC). METHODS: The immunohistochemical staining method was used to detect cyclooxygenase-2 (COX-2) protein in tumor tissues of 100 patients before and after chemoradiation. All the patients had stage III poorly differentiated NPC. RESULTS: The positive expression of COX-2 was decreased before and after chemotherapy. The expression levels of COX-2 in patients before treatment was associated with T stage (p<0.05). The changes in the positive expression of COX-2 following treatment was also associated with T stage (p<0.05). The clinical response rate (CR+PR) exhibited significant differences (p<0.05) in patients with negative, weakly positive, partially positive, and strongly positive COX-2 expression before treatment. The clinical response rate (CR+PR) exhibited significant differences (p<0.05) compared with the patients who were negative or weakly positive. The COX-2 positive expression level of patients with NPC before treatment was closely associated with the survival time and survival rate of the patients (p<0.05). The changes of COX-2 positive expression were associated with the survival time and survival rate (p<0.05) in patients with NPC following treatment. T stage, COX-2 expression before treatment and changes in COX-2 expression after treatment were independent factors affecting NPC prognosis (p<0.05). CONCLUSION: Changes in COX-2 expression levels before and after treatment may be a useful indicator for assessing the prognosis of NPC after chemoradiotherapy.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/terapia , Quimiorradioterapia , Ciclo-Oxigenase 2/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Masculino , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
9.
Aging (Albany NY) ; 12(20): 20380-20395, 2020 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-33068388

RESUMO

Many articles have reported that Rab1A was overexpressed in a variety of human cancers and involved in tumor progression and metastasis. However, the biological function and molecular mechanism of Rab1A in nasopharyngeal carcinoma (NPC) remained unknown until now. Here we found that Rab1A overexpression is a common event and was positively associated with distant metastasis and poor prognosis of NPC patients. Functionally, Rab1A depletion inhibited the migration and EMT phenotype of NPC cells, whereas Rab1A overexpression led to the opposite effect. Furthermore, we reveal an important role for Rab1A protein in the induction of radioresistance via regulating homologous recombination (HR) signaling pathway. Mechanistically, Rab1A activated Wnt/ß-catenin signaling by inhibiting the activity of GSK-3ß via phosphorylation at Ser9. Then Wnt/ß-catenin signaling induced NPC cells radioresistance and metastasis through nuclear translocation of ß-catenin and transcription upregulation of HR pathway-related and EMT-related genes expression. In general, this study shows that Rab1A may serve as a potential biomarker for predicting prognosis in NPC patients. Targeting Rab1A and Wnt/ß-catenin signaling may hold promise to overcome NPC radioresistance.


Assuntos
Movimento Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Tolerância a Radiação , Via de Sinalização Wnt , beta Catenina/metabolismo , Proteínas rab1 de Ligação ao GTP/metabolismo , Adulto , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Fosforilação , Proteínas rab1 de Ligação ao GTP/genética
10.
Cancer Med ; 9(19): 7268-7278, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32780562

RESUMO

Radioresistance was the main reason for local recurrence and metastasis of nasopharyngeal carcinoma. Tetrandrine is reported as an antitumor drug via inducing cell cycle arrest and apoptosis. In this study, the radiosensitization effects of maximum noncytotoxic doses of tetrandrine in nasopharyngeal carcinoma were analyzed both in vitro and in vivo, using MTT assay, western blot, TUNEL, and HE staining. It was found that the maximum dose of tetrandrine inhibited the phosphorylation of ERK and MEK induced by irradiation, and significantly enhanced irradiation-induced cell growth inhibition in nasopharyngeal carcinoma cells CNE1, CNE2, and C666-1. The ERK activator and overexpression of ERK reversed the radiosensitization effect of tetrandrine. About 50 mg/kg of tetrandrine which was used as the maximum noncytotoxic dose of tetrandrine in vivo, enhanced the radiosensitivity of the xenograft tumor and increased the apoptosis rate of the xenograft tumor cells caused by irradiation, while did not raise the side effect of the treatment. Moreover, tetrandrine increased autophagy in nasopharyngeal carcinoma cells. These results suggested that the maximum noncytotoxic dose of tetrandrine sensitized nasopharyngeal carcinoma to irradiation by inhibiting MEK/ERK pathway and inducing autophagy.


Assuntos
Autofagia/efeitos da radiação , Benzilisoquinolinas/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Radiossensibilizantes/farmacologia , Animais , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/patologia , Fosforilação , Transdução de Sinais , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Laryngol Otol ; 134(4): 338-343, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32172705

RESUMO

OBJECTIVES: The conclusive prognostic significance of cyclo-oxygenase-2 has been determined in various cancers but not in nasopharyngeal carcinoma. Therefore, this study aimed to evaluate the relationship of cyclo-oxygenase-2 expression with the survival outcome and treatment response of nasopharyngeal carcinoma patients via a systematic meta-analysis approach. METHODS: A meta-analysis was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses ('PRISMA') checklist. The primary clinical characteristics of patients, and hazard ratios with 95 per cent confidence intervals of overall survival data, were tabulated from eligible studies. The relationship of cyclo-oxygenase-2 expression with survival outcome (expressed as hazard ratio) and treatment response (expressed as odds ratio) in nasopharyngeal carcinoma patients was analysed, and explained with the aid of forest plot charts. RESULTS AND CONCLUSION: The pooled hazard ratio for overall survival was 2.02 (95 per cent confidence interval = 1.65-2.47). This indicates that the over-expression of cyclo-oxygenase-2 is significantly associated with the poor survival of nasopharyngeal carcinoma patients. The pooled odds ratio of 0.98 (95 per cent confidence interval = 0.27-3.49) reveals that over-expression of cyclo-oxygenase-2 was not significantly related to the treatment outcome.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/patologia , Tratamento Farmacológico/métodos , Feminino , Humanos , Masculino , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/terapia , Prognóstico , Radioterapia/métodos , Análise de Sobrevida , Resultado do Tratamento
12.
Biomed Pharmacother ; 118: 109120, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302419

RESUMO

PROBLEM AND OBJECT: 5-fluorouracil (5-FU) is a pyrimidine-like antimetabolite. It has been widely used in human cancer therapies; however, the drug sensitivity can be very low and the survival outcome can be very poor dependent on tumor types and individual heterogeneity. This research was aimed to study the effects of matrix metalloproteinase 1 (MMP1) gene on nasopharyngeal carcinoma (NPC) cell proliferation, viability, invasiveness, apoptosis, and sensitivity to 5-FU. METHODS: Bioinformatics method was used to screen out the differentiated expressed genes in nasopharyngeal carcinomas compared with normal nasopharyngeal epithelial tissues. qRT-PCR was used to determine the expression of MMP1 mRNA, and western blot was used to determine the protein expression of MMP1, thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD). Colony foci formation assay, CCK8 assay, and BrdU incorporation assay were used to study the cell proliferation. Transwell invasion assay was carried out to determine cell invasion. Flow cytometry and caspase 3/7 activation assay were used to detect cell apoptosis. RESULTS: MMP1 gene was the most significantly upregulated gene in nasopharyngeal carcinomas according to the bioinformatics analysis. And the upregulation of MMP1 gene was confirmed in both NPC tissues and cell lines using RT-QPCR and western blot technique. When 5-FU was not a player, the forced overexpression of MMP1 gene led to enhanced growth and invasion of CNE1 and HNE1 cell lines, whereas MMP1 gene knockdown resulted in the opposite outcome. When 5-FU was added, MMP1 gene knockdown led to significantly suppressed cell proliferation and enhanced cell apoptosis. Also, MMP1 gene knockdown caused significantly lower level of TS and DPD enzymes. CONCLUSION: Not only the knockdown of MMP1 gene led to suppressed proliferation and invasion but also increased the sensitivity to 5-FU of CNE1 and HNE1 cells. Our results provided convincing evidence that MMP1 gene knockdown could offer a favorable sensitivity approach for NPC with 5-FU treatment.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Metaloproteinase 1 da Matriz/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Silenciamento de Genes , Humanos , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/enzimologia , Regulação para Cima
13.
J Cell Physiol ; 234(11): 20915-20924, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31012106

RESUMO

Metastasis of the cancer cells to the regional lymph nodes parts of the body remains an important cause of treatment failure in nasopharyngeal carcinoma (NPC) patients. Epigallocatechin-3-gallate (EGCG), the most important ingredient in the green tea, has been reported to possess antioxidant and anticancer activities. However, the effects of EGCG on NPC cell metastasis are still unclear. In the present study, we examined the in vitro antimetastatic properties of EGCG on human NPC cells, NPC-39, HONE-1 and NPC-BM. The results revealed that EGCG considerably inhibited the migration abilities of three NPC cells. The matrix metalloproteinases-2 (MMP-2) activity and expression were also significantly inhibited by EGCG treatment. Furthermore, EGCG suppressed the phosphorylation of the Src signaling pathway. Moreover, blocking the Src pathway also inhibits MMP-2 expression and migration in the NPC cells. In conclusion, this study revealed that EGCG could inhibit the metastatic activity of human NPC cells by downregulating the protein expression of MMP-2 through modulation of the Src signaling pathway, suggesting that EGCG may be a potential candidate for chemoprevention of NPC.


Assuntos
Catequina/análogos & derivados , Movimento Celular/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Catequina/química , Catequina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
14.
J Cell Biochem ; 120(3): 3547-3558, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30295336

RESUMO

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in southern China and Southeast Asia, but the molecular mechanism of its pathogenesis is poorly understood. Our previous work demonstrated that NEK2 is overexpressed in multiple cancers. However, how NEK2 involves in NPC development remains to be elucidated. In this study, we firstly identified NEK2, located at +1q32-q33, a late event in NPC pathogenesis, overexpressed in the stage III-IV and paired sequential recurrent patients with NPC by immunohistochemistry. Furthermore, Kaplan-Meier analysis indicated high NEK2 conferred an inferior overall survival in NPC. In addition, cisplatin experiments with cell counting kit-8, colony formation, and a xenograft mice model of NPC demonstrated that NEK2 contributed to proliferation and cisplatin resistance in vitro and in vivo. On the contrary, downregulation of NEK2 by short hairpin RNA inhibited NPC cell growth and increased the sensitivity of cisplatin treatment in vitro. Thus, increased expression of NEK2 protein could not be predicted for poor survival but used as a novel biomarker for recurrence of NPC. Targeting NEK2 has the potential to eradicate the cisplatin-based chemotherapy resistant NPC cells.


Assuntos
Cisplatino/administração & dosagem , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quinases Relacionadas a NIMA/biossíntese , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Linhagem Celular Tumoral , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/mortalidade , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Biomed Pharmacother ; 111: 262-269, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30590314

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common cancers in areas of Southeast Asia, such as Taiwan, and North Africa. The treatments of NPC, including radiotherapy and chemotherapy, were effective, but they also caused some severe side effects. Erianin, a natural product derived from Dendrobium, was proved to have anti-cancer effect in hepatoma, melanoma, non-small-cell lung carcinoma, myelogenous leukemia, breast cancer, and osteosarcoma. HYPOTHESIS/PURPOSE: According to previous research, we hypothesized that erianin inhibits cancer cell growth through apoptotic mechanisms. This study aimed to determine whether Erianin has an anti-NPC effect and what mechanisms were involved. METHODS AND RESULTS: The result showed that erianin significantly increased activation of apoptosis in NPC cell lines (NPC-039 and NPC-BM) and arrest the cell cycle obviously through mitochondrial membrane alternation, death receptors activation, and caspase-3, -8, -9 activation. Phosphorylated ERK1/2 was also decreased in erianin-treated NPC cell with dose-dependent manner, and the result was thought to promote apoptosis. Furthermore, the increased rate of apoptotic cells with erianin plus it's inhibitors (U) was also revealed in this study. CONCLUSION: In conclusion, this is the first research to identify the anti-NPC effect of erianin via the apoptosis mechanism. Erianin was a promising natural agent against nasopharyngeal carcinoma.


Assuntos
Apoptose/efeitos dos fármacos , Bibenzilas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/enzimologia , Apoptose/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Fenol
16.
Cell Mol Biol (Noisy-le-grand) ; 64(13): 21-25, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30403591

RESUMO

To investigate the effects of microRNA-122 (miR-122) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) HONE-1 cells, and its correlation with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Human NPC cell line (HONE-1) was transfected with miR-122 inhibitor (anti-miR-122 group), negative controls (vector control group) via lipofectamines, and HONE-1 cell lines undergoing no transfection were selected (non-transfection group). The expression of miR-122, cell proliferation, apoptosis, and expressions of PI3K/AKT pathway and downstream target proteins in the three groups were determined using fluorescence quantitative polymerase chain reaction (qPCR), cell counting kit-8 (CCK8), immunofluorescence (IF) and Western blotting, respectively. The expression of miR-122 in the anti-miR-122 group was significantly lower than corresponding expressions in the non-transfection and vector control groups after 48h of transfection (p <0.05). The proliferation of cells in the anti-miR-122 group was significantly reduced with time after transfection (p <0.05). After 48h of transfection, the extent of apoptosis in the anti-miR-122 group (47.11 ± 1.95%) was significantly higher than that in normal control (7.37 ± 0.82%) and vector control group (8.54 ± 0.96%; p <0.05). There were no significant differences in the expressions of PI3K, AKT, mTOR protein, and the downstream signal proteins (p70S6K and 4E-BP1) in the three groups (p >0.05). However, the expressions of phosphorylated forms of these proteins were significantly lower in the anti-miR-122 group than in the non-transfection and vector control groups (p <0.05). IF results revealed that there were no significant differences in the fluorescence intensity value of PI3K and Akt among the three groups of patients (p>0.05). Inhibition of the expression of miR-122 in NPC suppresses the proliferation, and promotes their apoptosis through the PI3K/AKT signal transduction pathway.


Assuntos
Apoptose , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Carcinoma Nasofaríngeo/enzimologia
17.
Eur Rev Med Pharmacol Sci ; 22(19): 6342-6349, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30338802

RESUMO

OBJECTIVE: To investigate the effects of miR-30e-5p on the proliferation, invasion and migration of nasopharyngeal carcinoma (NPC) cells, as well as its underlying mechanism. PATIENTS AND METHODS: We detected the expressions of miR-30e-5p in NPC tissues, adjacent normal tissues, NPC cells (5-8F cells) and control cells (293T cells) by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The target gene of miR-30e-5p was predicted by online software and ubiquitin-specific peptidase 22 (USP22) was screened out. Luciferase reporter gene assay was performed after NPC cells were co-transfected miR-30e-5p mimics or miR-30e-5p inhibitor and mutant-type or wild-type USP22, respectively. Expressions of miR-30e-5p and USP22 in 5-8F cells were detected by qRT-PCR and Western blotting. The proliferation of 5-8F cells was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, and the invasion and migration abilities were detected by transwell assay. The activation of the epithelial-mesenchymal transition (EMT) was analyzed by detecting expressions of EMT-associated proteins (E-cadherin and Vimentin) in NPC cells. RESULTS: Expression level of miR-30e-5p was remarkably reduced, while USP22 expression was elevated in NPC tissues and cells compared with the controls. Molecular mechanism analysis con-firmed that miR-30e-5p could negatively regulate mRNA and protein levels of USP22 by binding to its specific sequence of 3'UTR. Subsequent experiments showed that USP22 knockdown resulting from up-regulation of miR-30e-5p could inhibit proliferation, invasion, migration, and EMT in 5-8F cells. CONCLUSIONS: MiR-30e-5p was lowly expressed in NPC by targeting USP22, suggesting that miR-30e-5p could be used as a potential therapeutic target for NPC.


Assuntos
Movimento Celular , Proliferação de Células , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Neoplasias Nasofaríngeas/enzimologia , Tioléster Hidrolases/metabolismo , Regiões 3' não Traduzidas , Sítios de Ligação , Linhagem Celular Tumoral , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica , Tioléster Hidrolases/genética , Ubiquitina Tiolesterase
18.
Biomed Pharmacother ; 108: 1-6, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30212707

RESUMO

RIPK4 (receptor interacting serine/threonine kinase 4) has been reported to be aberrantly expressed in several cancer types. However, its expression pattern and functions in nasopharyngeal carcinoma (NPC) have never been reported. In this study, we have shown that the expression of RIPK4 was up-regulated in NPC tissues. RIPK4 promoted the growth and anchorage-independent growth of NPC cells, and down-regulation of RIPK4 inhibited the growth of NPC cells both in the plate-based culture and on the soft agar. Moreover, RIPK4 promoted the expression of VEGF in the NPC cells and induced the tube formation of HUVEC, and Axitinib (the inhibitor for VEGF receptor) inhibited the tumorigenesis driven by RIPK4. In the molecular mechanism study, RIPK4 was found to enhance the interaction between IKKα and IKKß, and activated NF-kB signaling. Taken together, our study demonstrated the oncogenic roles of RIPK4 in NPC and suggested that RIPK4 might be a therapeutic target.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Masculino , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/irrigação sanguínea , Carcinoma Nasofaríngeo/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Ensaio Tumoral de Célula-Tronco , Regulação para Cima/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Cancer Med ; 7(9): 4755-4764, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30105829

RESUMO

The radioresistance of nasopharyngeal carcinoma (NPC) may be related to cancer stem cells (CSCs), and the characteristics of CSCs may be maintained by telomerase activity. In this study, we explored the CSC-like characteristics and telomerase activity of the NPC radioresistant cell line CNE-2R. This work provides a foundation for future studies on stem cell-targeted therapies by targeting the radioresistance of NPC. The expression of stem cell-related genes/proteins and the hTERT gene/protein in CNE-2R and its parent radiosensitive cell line CNE-2 were detected using qPCR/Western Blot. Label-retaining cells (LRCs) were detected through immunocytochemistry, and telomerase activity was detected using a PCR-ELISA kit. CD133 expression was detected with flow cytometry. CNE-2R-CD133+ and CNE-2R-CD133- cells were separated with magnetic-activated cell sorting. The proliferation and tumorigenesis capacities of CNE-2R-CD133+, CNE-2R-CD133-, and CNE-2R cells were compared with a CCK-8 assay, sphere formation assay, and an in vivo experiment. Our results showed that the expression of stem cell-related genes and the hTERT gene in CNE-2R cells was higher than those in CNE-2 cells. Similarly, the expression of stem cell-related proteins and the hTERT protein in CNE-2R cells was markedly higher than those in CNE-2 cells. The proportion of LRCs in CNE-2R and CNE-2 cells was (3.10 ± 0.63%) vs (0.40 ± 0.35%; P < 0.001), respectively. Telomerase activity in CNE-2R cells was remarkably higher than that in CNE-2 cells. Flow cytometry suggested that the CD133 positive rates in CNE-2R and CNE-2 cells were (2.49 ± 0.56%) vs (0.76 ± 0.25%; P = 0.008), respectively. Meanwhile, the proliferation capacity, tumorigenesis capacity, and telomerase activity of CNE-2R-CD133+ cells were notably higher than those of CNE-2R-CD133- and CNE-2R cells. Collectively, CNE-2R displayed CSC-like characteristics; our results also showed that CNE-2R cells, especially the sorted CSCs, had high telomerase activity levels.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Carcinoma Nasofaríngeo/enzimologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Telomerase/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Células-Tronco Neoplásicas/patologia , Proteoma , Proteômica/métodos , Telomerase/genética
20.
J Pathol ; 244(4): 394-407, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29230817

RESUMO

Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , RNA Viral/genética , Regiões 3' não Traduzidas , Animais , Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Sítios de Ligação , Linhagem Celular Tumoral , Dano ao DNA , Repressão Enzimática , Infecções por Vírus Epstein-Barr/diagnóstico , Feminino , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Interações Hospedeiro-Patógeno , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/enzimologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Transcriptoma , Latência Viral
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