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1.
J Transl Med ; 19(1): 387, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503528

RESUMO

OBJECTIVE: The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated. METHODS: The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed. RESULTS: In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells. CONCLUSION: These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC.


Assuntos
MicroRNAs , Neoplasias Nasofaríngeas , Linhagem Celular Tumoral , Movimento Celular/genética , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , MicroRNAs/genética , Proteína Homeobox Nanog/genética , Neoplasias Nasofaríngeas/genética , Recidiva Local de Neoplasia , Células-Tronco Neoplásicas
2.
Theranostics ; 11(16): 8112-8128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335983

RESUMO

The coiled-coil domain containing protein members have been well documented for their roles in many diseases including cancers. However, the function of the coiled-coil domain containing 65 (CCDC65) remains unknown in tumorigenesis including gastric cancer. Methods: CCDC65 expression and its correlation with clinical features and prognosis of gastric cancer were analyzed in tissue. The biological role and molecular basis of CCDC65 were performed via in vitro and in vivo assays and a various of experimental methods including co-immunoprecipitation (Co-IP), GST-pull down and ubiquitination analysis et al. Finally, whether metformin affects the pathogenesis of gastric cancer by regulating CCDC65 and its-mediated signaling was investigated. Results: Here, we found that downregulated CCDC65 level was showed as an unfavourable factor in gastric cancer patients. Subsequently, CCDC65 or its domain (a.a. 130-484) was identified as a significant suppressor in GC growth and metastasis in vitro and in vivo. Molecular basis showed that CCDC65 bound to ENO1, an oncogenic factor has been widely reported to promote the tumor pathogenesis, by its domain (a.a. 130-484) and further promoted ubiquitylation and degradation of ENO1 by recruiting E3 ubiquitin ligase FBXW7. The downregulated ENO1 decreased the binding with AKT1 and further inactivated AKT1, which led to the loss of cell proliferation and EMT signal. Finally, we observed that metformin, a new anti-cancer drug, can significantly induce CCDC65 to suppress ENO1-AKT1 complex-mediated cell proliferation and EMT signals and finally suppresses the malignant phenotypes of gastric cancer cells. Conclusion: These results firstly highlight a critical role of CCDC65 in suppressing ENO1-AKT1 pathway to reduce the progression of gastric cancer and reveals a new molecular mechanism for metformin in suppressing gastric cancer. Our present study provides a new insight into the mechanism and therapy for gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , China , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas/genética , Humanos , Masculino , Metformina/metabolismo , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oncogenes , Prognóstico , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
3.
Mol Ther Nucleic Acids ; 22: 557-571, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33230457

RESUMO

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation in vitro and in vivo. Mechanism analysis indicated that miR-4721 directly targetes GSK3ß and reduces its expression, which therefore elevates ß-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3ß are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3ß, which thus activates the WNT/ß-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future.

4.
Int J Cancer ; 146(2): 496-509, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125123

RESUMO

The biological role of vacuolar protein sorting 33B (VPS33B) has not been examined in colorectal cancer (CRC). We report that VPS33B was downregulated in dextran sulfate sodium/azoxymethane (DSS/AOM) -induced CRC mice models and nicotine-treated CRC cells via the PI3K/AKT/c-Jun pathway. Reduced VPS33B is an unfavorable factor promoting poor prognosis in human CRC patients. VPS33B overexpression suppressed CRC proliferation, intrahepatic metastasis and chemoresistance of cisplatin (DDP) in vivo and in vitro through modulating the epidermal growth factor receptor (EGFR)/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and the downstream cell cycle or EMT-related factors. Furthermore, NESG1 as a newly identified tumor suppressor interacted with VPS33B via colocalization in the cytoplasm, and it was stimulated by VPS33B through the downregulation of RAS/ERK/c-Jun-mediated transcription. NESG1 also activated VPS33B expression via the RAS/ERK/c-Jun pathway. Suppression of NESG1 increased cell growth, migration and invasion via the reversion of the VPS33B-modulating signal in VPS33B-overexpressed cells. Taken together, VPS33B as a tumor suppressor is easily dysregulated by chemical carcinogens and it interacts with NESG1 to modulate the EGFR/RAS/ERK/c-Myc/p53/miR-133a-3p feedback loop and thus suppress the malignant phenotype of CRC.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes Supressores de Tumor/efeitos dos fármacos , Nicotina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas de Transporte Vesicular/genética , Animais , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HT29 , Humanos , Camundongos , Transdução de Sinais/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética
5.
Artigo em Inglês | MEDLINE | ID: mdl-31754475

RESUMO

In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3ß/ß-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3ß, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3ß protein. Increased GSK3ß expression stimulated the ß-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3ß/ß-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.

6.
EBioMedicine ; 48: 386-404, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31594754

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related tumor. The role of EBV-encoding miR-BART22 is still unclear in NPC. This study aimed to identify the detailed mechanisms by which EBV-miR-BART22 functions as a tumor-promoting factor and evaluate the action of cinobufotalin in treating EBV-miR-BART22-overexpressing NPC cells. METHODS: Using real-time PCR, western blotting, immunohistochemistry, and In situ hybridization, we detected the expression of miR-BART22 and MAP2K4 in tissues and cells, as well as evaluated their clinical relevance in NPC patients. The effects of miR-BART22 on cell metastasis, stemness and DDP chemoresistance were examined by sphere formation assay, side population analysis, transwell, boyden, in vivo xenograft tumor mouse model et al. Western blotting, immunofluorescence staining, luciferase reporter assay, ChIP, EMSA and Co-IP assay et al. were performed to explore the detailed molecular mechanism of EBV-miR-BART22 in NPC. Finally, we estimated the effects and molecular basis of Cinobufotalin on EBV-miR-BART22-overexpressing NPC cells in vitro and in vivo assays. FINDINGS: We observed that EBV-miR-BART22 not only promoted tumor stemness and metastasis, but also enhanced the resistance to Cisplatin (DDP) in vitro and in vivo. Mechanistic analysis indicated that EBV-miR-BART22 directly targeted the MAP2K4 and upregulated non-muscle myosin heavy chain IIA (MYH9) expression by PI3K/AKT/c-Jun-induced transcription. Further, MYH9 interacted with glycogen synthase 3ß(GSK3ß) protein and induced its ubiquitin degradation by activating PI3K/AKT/c-Jun-induced ubiquitin transcription and the latter combined with increased TRAF6 E3 ligase, which further bound to GSK3ß protein. Reductions in the GSK3ß protein thus promoted ß-catenin expression and nuclear translocation, which induced tumor stemness and the epithelial-to-mesenchymal transition (EMT) signals. Furthermore, we observed that cinobufotalin, a new chemically synthesized compound, significantly suppressed EBV-miR-BART22-induced DDP chemoresistance by upregulating MAP2K4 to suppress MYH9/GSK3ß/ß-catenin and its downstream tumor stemness and EMT signals in NPC. Finally, clinical data revealed that increased miR-BART22 and reduced MAP2K4 expression caused the poor prognoses of NPC patients. INTERPRETATION: Our study provides a novel mechanism that cinobufotalin reversed the DDP chemoresistance and EMT induced by EBV-miR-BART22 in NPC.


Assuntos
Bufanolídeos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Herpesvirus Humano 4/genética , MicroRNAs/genética , RNA Viral , Linhagem Celular Tumoral , Glicogênio Sintase/metabolismo , Humanos , MAP Quinase Quinase 4/genética , Cadeias Pesadas de Miosina/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , beta Catenina/metabolismo
7.
Signal Transduct Target Ther ; 4(1): 48, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33199698

RESUMO

In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3ß/ß-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3ß, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3ß protein. Increased GSK3ß expression stimulated the ß-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3ß/ß-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.

8.
J Mech Behav Biomed Mater ; 72: 182-191, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28499166

RESUMO

Binary Zn-Cu alloy system is developed as potential biodegradable materials for cardiovascular implant application. The microstructure, tensile properties, in vitro corrosion behavior, cytotoxicity and antibacterial property of as-extruded Zn-xCu (x=1, 2, 3, and 4wt%) alloys are investigated systematically. It shows that as Cu content increases more CuZn5 phase precipitates. After extrusion, the CuZn5 phases are broken and the grains of Zn-xCu alloys are refined. Tensile test shows that Cu addition could significantly improve the mechanical properties of Zn-xCu alloys. Particularly, the elongation of the Zn-4Cu reaches 50.6±2.8%, which could facilitate the micro-tubes processing for stent fabrication. The micro-tubes of 3mm in outer diameter and 0.2mm in thickness as well as vascular stents have been fabricated successfully using the Zn-Cu binary alloy. The degradation rates of Zn-xCu alloys in c-SBF solution are quite low, which vary from 22.1±4.7 to 33.0±1.0µmyear-1. With increasing Cu concentration, the corrosion rates of the Zn-xCu alloys generally exhibit a little increase compared with pure Zn, which show no significant difference among Zn-xCu alloys. In vitro test shows that Zn-xCu alloys exhibit acceptable cytotoxicity to human endothelial cells and the antibacterial property (S. aureus) is perfect when Cu concentration is higher than 2wt%. Therefore, the newly developed Zn-xCu binary alloys could be promising candidates for biodegradable cardiovascular implant application due to their excellent combination of strength and ductility, low degradation rates, acceptable cytotoxicity and good antibacterial property.


Assuntos
Implantes Absorvíveis , Ligas/química , Materiais Biocompatíveis/química , Células Endoteliais/citologia , Stents , Linhagem Celular , Cobre/química , Corrosão , Humanos , Teste de Materiais , Staphylococcus aureus , Difração de Raios X , Zinco/química
9.
Mater Sci Eng C Mater Biol Appl ; 69: 407-13, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27612729

RESUMO

Zn-based alloys have been viewed as new potential materials for biodegradable implants, such as cardiovascular stents, mainly in consideration of their lower corrosion rate when compared with that of Mg alloys. In this study we developed a new Zinc-4wt.%Copper (Zn-4Cu) alloy as a biodegradable material. Hot extrusion was applied to Zn-4Cu to refine the microstructure and consequently improve its mechanical properties and corrosion resistance. After extrusion, dendritic CuZn5 phases were broken and distributed along the extrusion direction. The grains were refined obviously due to dynamical recrystallization. The yield strength (YS), ultimate tensile strength (UTS) and elongation of the as-extruded alloy are 250±10MPa, 270±10MPa and 51±2%, respectively. The corrosion rate of the as-extruded alloy in Hank's solution is about 9.41(±1.34)µmyear(-1). In vitro evaluation shows that Zn-4Cu presents acceptable toxicity to human endothelial cells, and could effectively inhibit bacteria adhesion and biofilm formation. The present study indicates that the as-extruded Zn-4Cu alloy exhibits excellent strength and ductility, uniform and slow degradation, good biocompatibility and significant antibacterial effect, which make it an excellent candidate material for biodegradable implants, especially for cardiovascular stents application.


Assuntos
Ligas/química , Materiais Biocompatíveis/química , Cobre/química , Stents , Zinco/química , Implantes Absorvíveis , Ligas/farmacologia , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Biofilmes/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Corrosão , Humanos , Staphylococcus aureus/fisiologia , Resistência à Tração
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