Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 214
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Fish Shellfish Immunol ; 93: 406-415, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31369857

RESUMO

Mandarin fish (Siniperca chuatsi) is a universally farmed fish species in China and has a large farming scale and economic value. With the high-density cultural mode in mandarin fish, viral diseases, such as infectious spleen and kidney necrosis virus (ISKNV) and Siniperca chuatsi rhabdovirus (SCRV), have increased loss, which has seriously restricted the development of aquaculture. Y-Box binding protein 1 (YB-1) is a member of cold shock protein family that regulates multiple cellular processes. The roles of mammalian YB-1 protein in environmental stress and innate immunity have been studied well, but its roles in teleost fishes remain unknown. In the present study, the characteristic of S. chuatsi YB-1 (scYB-1) and its roles in cold stress and virus infection were investigated. The scYB-1 obtained an 1541 bp cDNA that contains a 903 bp open reading frame encoding a protein of 300 amino acids. Tissue distribution results showed that the scYB-1 is a ubiquitously expressed gene found among tissues from mandarin fish. Overexpression of scYB-1 can increase the expression levels of cold shock-responsive genes, such as scHsc70a, scHsc70b, and scp53. Furthermore, the role of scYB-1 in innate immunity was also investigated in mandarin fish fry (MFF-1) cells. The expression level of scYB-1 was significant change in response to poly (I:C), poly (dG:dC), PMA, ISKNV, or SCRV stimulation. The overexpression of scYB-1 can significantly increase the expression levels of NF-κB-responsive genes, including scIL-8, scTNF-α, and scIFN-h. The NF-κB-luciferase report assay results showed that the relative expression of luciferin was significantly increased in the cells overexpressed with scYB-1 compared with those in cells overexpressed with control plasmid. These results indicate that scYB-1 can induce the NF-κB signaling pathway in MFF-1 cells. Overexpressed scYB-1 can downregulate the expression of ISKNV viral major capsid protein (mcp) gene but upregulates the expression of SCRV mcp gene. Moreover, knockdown of scYB-1 using siRNA can upregulate the expression of ISKNV mcp gene but downregulates the expression of SCRV mcp gene. These results indicate that scYB-1 suppresses ISKNV infection while enhancing SCRV infection. The above observations suggest that scYB-1 is involved in cold stress and virus infection. Our study will provide an insight into the roles of teleost fish YB-1 protein in stress response and innate immunity.


Assuntos
Doenças dos Peixes/imunologia , Peixes/genética , Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/veterinária , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Iridoviridae/fisiologia , Filogenia , Poli I-C/farmacologia , Polidesoxirribonucleotídeos/farmacologia , Rhabdoviridae/fisiologia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Alinhamento de Sequência/veterinária , Acetato de Tetradecanoilforbol/farmacologia , Proteína 1 de Ligação a Y-Box/química
2.
Int J Mol Med ; 44(4): 1484-1494, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432139

RESUMO

Virotherapy using oncolytic viruses is an upcoming therapy strategy for cancer treatment. A variety of preclinical and clinical trials have indicated that adenoviruses may be used as potent agents in the treatment of a variety of cancers, and also for the treatment of brain tumors. In these studies, it has also been shown that oncovirotherapy is safe in terms of toxicity and side effects. In addition, previous studies have presented evidence for a significant role of oncovirotherapy in the activation of anti­tumor immune responses. With regard to oncolytic adenoviruses, we have demonstrated previously that the multifunctional protein Y­box binding protein­1 (YB­1) is a potent factor that was used to develop an YB­1­dependent oncolytic adenovirus (XVir­N­31). XVir­N­31 provides the opportunity for tumor­selective replication and exhibited marked oncolytic properties in a mouse glioma tumor model using therapy­resistant brain tumor initiating cells (BTICs). In a number of, but not all, patients with glioma, YB­1 is primarily located in the nucleus; this promotes XVir­N­31­replication and subsequently tumor cell lysis. However, in certain BTICs, only a small amount of YB­1 has been identified to be nuclear, and therefore virus replication is suboptimal. YB­1 in BTICs was demonstrated to be translocated into the nucleus following irradiation, which was accompanied by an enhancement in XVir­N­31 production. R28 glioma spheres implanted in living organotypic human brain slices exhibited a significantly delayed growth rate when pre­irradiated prior to XVir­N­31­infection as compared with single treatment methods. Consistent with the in vitro data, R28 glioma­bearing mice exhibited a prolonged mean and median survival following single tumor irradiation prior to intratumoral XVir­N­31 injection, compared with the single treatment methods. In conclusion, the present study demonstrated that in an experimental glioma model, tumor irradiation strengthened the effect of an XVir­N­31­based oncovirotherapy.


Assuntos
Adenoviridae/genética , Neoplasias Encefálicas/terapia , Vetores Genéticos/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Radiação Ionizante , Animais , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Feminino , Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Terapia Genética , Vetores Genéticos/administração & dosagem , Humanos , Camundongos , Transgenes , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/genética
3.
Nat Cell Biol ; 21(8): 978-990, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31358969

RESUMO

Although 5-methylcytosine (m5C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the single-nucleotide resolution landscape of messenger RNA m5C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m5C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m5C 'reader' recognizing m5C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m5C methylation site in the HDGF 3' untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m5C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.


Assuntos
5-Metilcitosina/metabolismo , Regulação da Expressão Gênica/genética , Metiltransferases/genética , Neoplasias da Bexiga Urinária/genética , Proteína 1 de Ligação a Y-Box/genética , Animais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Humanos , Camundongos , RNA Mensageiro/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
4.
J Biosci ; 44(2)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180040

RESUMO

Human Y-box binding protein-1 (YBX1) is a member of highly conserved cold-shock domain protein family, which is involved in transcriptional as well as translational regulation of many genes. Nuclear localization of YBX1 has been observed in various cancer types and it's overexpression has been linked to adverse clinical outcome and poor therapy response, but no diagnostic or therapeutic correlation has been established so far. This study aimed to identify differentially expressed novel genes among the interactors of YBX1 in different cancer types. Analysis of RNA-Seq data for colorectal, lung, prostate and stomach adenocarcinoma identified 39 unique genes, which are differentially expressed in the four adenocarcinoma types. Gene-enrichment analysis for the differentially expressed genes from individual adenocarcinoma with focus on unique genes resulted in a total of 57 gene sets specific to each adenocarcinoma. Gene ontology for commonly expressed genes suggested the pathways and possible mechanisms through which they affect each adenocarcinoma type considered in the study. Gene regulatory network constructed for the common genes and network topology was analyzed for the central nodes. Here 12 genes were found to play important roles in the network formation; among them, two genes FOXM1 and TOP2A were found to be in central network formation, which makes them a common target for therapeutics. Furthermore, five common differentially expressed genes in all adenocarcinomas were also identified.


Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias da Próstata/genética , Neoplasias Gástricas/genética , Proteína 1 de Ligação a Y-Box/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Feminino , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Anotação de Sequência Molecular , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica , Mapeamento de Interação de Proteínas , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Proteína 1 de Ligação a Y-Box/metabolismo
5.
Parasit Vectors ; 12(1): 279, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151477

RESUMO

BACKGROUND: Activation of hepatic stellate cells is the dominant pathogenic event during the process of liver fibrosis. Bone morphogenic protein (BMP)-7 has recently been identified as an anti-fibrotic factor and leads to phosphorylation of Smad1/5/8 in activated hepatic stellate cells. Its expression can be upregulated by the transcriptional activator, Y-Box protein-1 (YB1). Previous studies have found that the recombinant Schistosoma japonicum protein p40 (rSjp40) can inhibit the activation of hepatic stellate cells, and based on this evidence we attempted to investigate whether or not BMP-7 is involved in rSjp40's inhibition. METHODS: A human hepatic stellate cell line, the LX-2 cell line, was cultured and treated with rSjp40. The role of BMP-7 was analyzed by Western blot. RESULTS: Our findings testified that knockdown of BMP-7 impaired rSjp40-induced downregulation of α-SMA and phosphorylation of Smad1/5/8 in LX-2 cells. Furthermore, rSjp40 upregulated expression of BMP-7 at both mRNA and protein levels depending on YB1. Interestingly, YB1 was translocated from the cytoplasm to the nucleus upon treatment of rSjp40. CONCLUSIONS: These results suggest that rSjp40 inhibits the activation of hepatic stellate cells by promoting nuclear translocation of YB1 and inducing BMP-7/Smad1/5/8 pathway, which provide a new clue to guide ongoing research into the anti-fibrosis of rSjp40.


Assuntos
Antígenos de Helmintos/metabolismo , Proteína Morfogenética Óssea 7/metabolismo , Proteínas de Helminto/metabolismo , Células Estreladas do Fígado/parasitologia , Transdução de Sinais , Proteínas Smad/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Humanos , Cirrose Hepática/patologia , Fosforilação , Transporte Proteico , Interferência de RNA , Proteínas Recombinantes/farmacologia , Schistosoma japonicum , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Proteína Smad8/metabolismo , Proteína 1 de Ligação a Y-Box/genética
6.
Arch Pharm Res ; 42(6): 519-530, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31004257

RESUMO

Lysophosphatidic acid (LPA) has been known to induce epithelial-mesenchymal transition (EMT) to stimulate cancer cell invasion, and resveratrol (3,5,4'-trans-trihydroxystilbene; REV) suppresses the invasion and metastasis of various cancers. The current study aimed to identify the underlying mechanism by which LPA aggravates breast cancer cell invasion and the reversal of this phenomenon. Immunoblotting and quantitative RT-PCR analysis revealed that LPA induces amphiregulin (AREG) expression. Silencing of Y-box binding protein 1 (YB-1) or enhancer of zeste homolog 2 (EZH2) expression efficiently inhibited LPA-induced AREG expression. In addition, transfection of the cells with YB-1 siRNA abrogated LPA-induced EZH2 and AREG expression, leading to attenuation of breast cancer cell invasion. Furthermore, we observed that both REV and 5-fluorouracil (5-Fu) significantly reduce LPA-induced YB-1 phosphorylation and subsequent breast cancer invasion. Importantly, combined treatment of REV with 5-Fu showed more significant inhibition of LPA-induced breast cancer invasion compared to single treatment. Therefore, our data demonstrate that the YB-1/EZH2 signaling axis mediates LPA-induced AREG expression and breast cancer cell invasion and its inhibition by REV and 5-Fu, providing potential therapeutic targets and inhibition of breast cancer.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Lisofosfolipídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Anfirregulina/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Invasividade Neoplásica/patologia , Fosforilação/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo
7.
Oncol Rep ; 41(5): 2889-2896, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864697

RESUMO

Y­box­binding protein 1 (YB­1) is a DNA/RNA­-binding protein and an important transcription and translation factor in carcinogenesis. However, the biological function and molecular correlation of YB­1 in colorectal cancer are not fully understood. The aim of the present study was to determine the significance of YB­1 expression and its biological role in colorectal cancer. Cell proliferation, migration and apoptosis were examined upon knockdown of YB­1 expression in different colon cancer cell lines that had different genetic backgrounds. Since the properties of different colon cancer cell lines with specific RAS/RAF gene mutations downstream epidermal growth factor receptor (EGFR) may differ from wild­type colorectal cancer, it is critical to study the role of YB­1 with respect to the mutational status of RAS. The results indicated that the suppression of YB­1 decreased cell proliferation (P<0.05) and migration (P<0.05) regardless of the status of RAS/RAF in the HT29, HCT116 and CaCo2 cell lines. In contrast, YB­1 knockdown altered the expression of apoptosis­related genes and the expression of EGFR was detected in the cell lines expressing wild­type RAS/RAF but not in those expressing mutated RAS/RAF. These results indicated that YB­1 plays an important role in cell proliferation, migration, apoptosis and EGFR expression in colorectal cancer. Furthermore, apoptosis and EGFR expression may be affected by the mutational status of RAS/RAF and controlled through YB­1.


Assuntos
Neoplasias do Colo/patologia , Proteína 1 de Ligação a Y-Box/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Receptores ErbB/metabolismo , GTP Fosfo-Hidrolases/genética , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Proteína 1 de Ligação a Y-Box/genética
8.
Cancer Lett ; 452: 119-131, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-30905819

RESUMO

Y-box binding protein-1 (YB-1), an important transcription and translation regulator protein, is known to increase cancer cell invasiveness and spreading. Here, we report its role in breast cancer, particularly in mediating cell invasion in triple-negative breast cancer (TNBC). YB-1 stable knockdown (shYB-1) significantly reduced the invasive potential of MDA-MB-231 TNBC cells in 2D and 3D (spheroid) cultures. Whole proteome mass spectrometry analysis showed an enrichment of cell adhesion and cell to matrix interaction proteins, notably, matrix metalloproteinase-1 (MMP1) and beta-catenin (CTNNB1), which are known to play critical roles in cancer metastasis. shYB-1 cells exhibited substantial downregulation of MMP1 and CTNNB1 mRNA and protein expression, with reduced MMP1 enzyme activity. YB-1 was also observed to bind to the promoter of MMP1 and overexpression of MMP1 plasmid in shYB-1 cells increased cell invasion. Finally, analysis of tumour samples from the Gene Expression-Based Outcome for Breast Cancer Online (GOBO) database revealed that high gene expressions of YBX1, MMP1 and CTNNB1 predict for a significantly lower 10-year distant metastasis free survival. Altogether, this study shows that YB-1 mediates breast cancer invasion and metastasis via regulation of MMP1 and beta-catenin.


Assuntos
Metaloproteinase 1 da Matriz/biossíntese , Neoplasias de Mama Triplo Negativas/patologia , Proteína 1 de Ligação a Y-Box/genética , beta Catenina/biossíntese , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metaloproteinase 1 da Matriz/genética , Invasividade Neoplásica/genética , Regiões Promotoras Genéticas/genética , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno/genética , Esferoides Celulares , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Células Tumorais Cultivadas , beta Catenina/genética
9.
Drug Des Devel Ther ; 13: 317-326, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30679904

RESUMO

Background: Y-box-binding protein-1 (YB-1) is aberrantly expressed in a variety of cancers. However, the biological functional role of YB-1 in glioma is not yet clear. Methods: The expression of MDM2 and YB-1 was analyzed by real time PCR. Overexpression and knockdown of YB-1 in glioma cells were created by transfection of pcDNA-YB-1 and siRNA against YB-1, respectively. Cell viability was performed by CCK8 assay. Results: Our findings showed that glioma tissues had higher expressions of YB-1 than that in cancer-free tissues in 54 glioma patients, which were also positively correlated with Murine MDM2 expression. Overexpression of YB-1 or MDM2 renders a drug resistance feature in glioma cell exposed to temozolomide (TMZ), by directly targeting p53. Genetic or chemical inhibition of MDM2 significantly blocked YB-1-modulated response of glioma cells to TMZ. Moreover, inhibition of YB-1 or MDM2 reduced glioma cells metastasis and mortality in mice. Conclusion: YB-1 facilitates the resistance of glioma cells to TMZ by direct activation of MDM2/p53 signaling and represents a promising molecular target for glioma treatment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioma/patologia , Humanos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Relação Estrutura-Atividade , Temozolomida/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/genética
10.
Nucleic Acids Res ; 47(6): 3127-3141, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30605522

RESUMO

The structural rearrangements accompanying mRNA during translation in mammalian cells remain poorly understood. Here, we discovered that YB-1 (YBX1), a major partner of mRNAs in the cytoplasm, forms a linear nucleoprotein filament with mRNA, when part of the YB-1 unstructured C-terminus has been truncated. YB-1 possesses a cold-shock domain (CSD), a remnant of bacterial cold shock proteins that have the ability to stimulate translation under the low temperatures through an RNA chaperone activity. The structure of the nucleoprotein filament indicates that the CSD of YB-1 preserved its chaperone activity also in eukaryotes and shows that mRNA is channeled between consecutive CSDs. The energy benefit needed for the formation of stable nucleoprotein filament relies on an electrostatic zipper mediated by positively charged amino acid residues in the YB-1 C-terminus. Thus, YB-1 displays a structural plasticity to unfold structured mRNAs into extended linear filaments. We anticipate that our findings will shed the light on the scanning of mRNAs by ribosomes during the initiation and elongation steps of mRNA translation.


Assuntos
Nucleoproteínas/química , Proteínas de Ligação a RNA/ultraestrutura , Proteína 1 de Ligação a Y-Box/ultraestrutura , Sequência de Aminoácidos/genética , Citoesqueleto/genética , Citoesqueleto/ultraestrutura , Escherichia coli/genética , Humanos , Nucleoproteínas/genética , Nucleoproteínas/ultraestrutura , Ligação Proteica/genética , Biossíntese de Proteínas/genética , Dobramento de Proteína , RNA Mensageiro/química , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Ribossomos/química , Ribossomos/genética , Proteína 1 de Ligação a Y-Box/química , Proteína 1 de Ligação a Y-Box/genética
11.
Cancer Sci ; 110(1): 166-179, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30426615

RESUMO

Chordomas are rare bone tumors with a poor prognosis and no approved targeted therapy. Y-box binding protein-1 (YBX1) promotes tumor growth, invasion and drug resistance. However, the role of YBX1 in chordoma is unclear. In this study, we examined the expression of YBX1 using immunohistochemistry and found that YBX1 was significantly upregulated in 32 chordoma tissues compared to distant normal tissues. In addition, YBX1 upregulation was associated with surrounding tissue invasion, recurrence and poor prognosis. Biological function studies demonstrated that YBX1 promoted cell proliferation and invasion, accelerated G1/S phase transition, and inhibited apoptosis. Further investigation revealed that YBX1 enhanced epidermal growth factor receptor (EGFR) transcription by directly binding to its promoter in chordoma cells. YBX1 regulated protein expression of p-EGFR, p-AKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma.


Assuntos
Carcinogênese/metabolismo , Cordoma/metabolismo , Receptores ErbB/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Coluna Vertebral/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Adolescente , Adulto , Idoso , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Cordoma/genética , Cordoma/terapia , Progressão da Doença , Receptores ErbB/genética , Feminino , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/genética , Interferência de RNA , Terapêutica com RNAi/métodos , Transdução de Sinais/genética , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/terapia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Proteína 1 de Ligação a Y-Box/genética , Adulto Jovem
12.
Cancer Lett ; 442: 222-232, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419346

RESUMO

In the present study, two circular RNA (circRNA) expression profiles in paired gastric cancer (GC) tissues from the GEO database were examined. We identified a novel circRNA, has_circ_0001461, which we termed circFAT1(e2). We verified that circFAT1(e2) was significantly downregulated in GC tissues and cell lines and was correlated with overall survival of GC patients. Fluorescence in situ hybridization (FISH) analysis showed that circFAT1(e2) was distributed in the cytoplasm of GC cells, as well as in the nucleus. Functional assays indicated that overexpression of circFAT1(e2) inhibited GC cell proliferation, migration and invasion. Then, we investigated whether circFAT1(e2) acts as a sponge of microRNA-549g(miR-548g) and regulates the expression of tumor suppressor RUNX1 in GC cells. Moreover, we found that nucleus-located circFAT1(e2) could directly interact with Y-box binding protein-1 (YBX1) and inhibit its function. In conclusion, circFAT1(e2) may play a role as a tumor suppressor in GC cells by regulating the miR-548g/RUNX1 axis in the cytoplasm and targeting YBX1 in the nucleus.


Assuntos
MicroRNAs/metabolismo , RNA/metabolismo , Neoplasias Gástricas/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Bases de Dados Genéticas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , RNA/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Carga Tumoral , Proteína 1 de Ligação a Y-Box/genética
13.
Mol Cancer ; 17(1): 167, 2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30470227

RESUMO

Vasculogenic mimicry (VM) gives rise to tumor neovascularization that is critical for tumor growth and metastasis. Long non-coding RNAs (lncRNAs) have been implicated in diverse and fundamental biological processes. LINC00312 is associated with lung adenocarcinoma. In this study, we found that LINC00312 induced migration, invasion and VM of lung cancer cells by direct binding to the transcription factor Y-Box Binding Protein 1 (YBX1). Moreover, we demonstrated that YBX1 is associated with different fragments within 0-2410 nt 5'region of LINC00312. In addition, LINC00312 is associated with VM in 124 lung adenocarcinoma clinical specimens. The results suggest that LINC00312 is a promising therapeutic and diagnostic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/irrigação sanguínea , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Proteína 1 de Ligação a Y-Box/genética , Adenocarcinoma de Pulmão/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia
14.
Int J Oncol ; 53(6): 2579-2589, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30221675

RESUMO

Y-box binding protein-1 (YB-1) facilitates cancer chemoresistance through the upregulation of ATP-binding cassette (ABC) transporters associated with multidrug resistance, which is one of the primary obstacles in cancer treatment. Since aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is also implicated in chemoresistance in numerous human malignancies, the interaction between YB-1 and JAK/STAT signaling was explored underlying the chemoresistance of NUGC3 gastric cancer cells. It was demonstrated that YB-1 translocated into the nuclei of NUGC3 cells exposed to doxorubicin hydrochloride, suggesting its important role in chemoresistance. Consistently, knockdown of YB-1 significantly decreased the chemoresistance of cells to doxorubicin hydrochloride and epirubicin hydrochloride, as evidenced by a decrease in cell viability. Notably, JAK inhibitor AG490 treatment further decreased the cell viability caused by YB-1 inhibition and doxorubicin hydrochloride. It was also observed that YB-1 transcriptionally regulated the ABCC3 transporter, whereas STAT3 modulated ABCC2 transporter levels. These findings suggest that YB-1 and STAT3 act together to facilitate chemoresistance via modulating the expression of different ABC transporters in NUGC3 cells. Notably, siYB-1 did not exhibit any significant effect on STAT3 expression. Similarly, siSTAT3 failed to alter YB-1 expression, suggesting that the two may not regulate each other in a mutual manner. However, double knockdown of YB-1 and STAT3 led to a synergistic inhibition of cell invasion in NUGC3 cells. Nonetheless, the combined treatment of YB-1 antagonists with STAT3 inhibitors may serve as an effective therapy in gastric cancer.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Transporte Proteico/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Tirfostinas/farmacologia , Proteína 1 de Ligação a Y-Box/genética
15.
RNA ; 24(12): 1706-1720, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30139801

RESUMO

Cytoplasmic localization, stability, and translation of mRNAs are controlled by their dynamic association of numerous mRNA-binding (mRNP) proteins, including cold shock domain (CSD)-containing proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), and serine/arginine-rich (SR) proteins. Here, we demonstrate that the most abundant human mRNP protein, the CSD-containing Y-box-binding protein 1 (YBX1), the closely related YBX3 protein, and other mRNP proteins, such as SRSF1, SRSF2, SRSF3, hnRNP A1, and H, specifically and efficiently interact with overlapping sets of mitochondrial tRNAs (mt tRNAs). In vitro reconstitution and in vivo binding experiments show that YBX1 recognizes the D- and/or T-stem-loop regions of mt tRNAs through relying on the RNA-binding capacity of its CSD. Cell fractionation and in vivo RNA-protein cross-linking experiments demonstrate that YBX1 and YBX3 interact with mt tRNAs in the cytosol outside of mitochondria. Cell fractionation and fluorescence in situ hybridization experiments provide evidence that mitochondrial autophagy promotes the release of mt tRNAs from the mitochondria into the cytoplasm. Association of mRNP proteins with mt tRNAs is highly dynamic; it is rapidly increased upon transcription inhibition and decreased during apoptosis. Although the cytoplasmic function of mt tRNAs remains elusive, their dynamic interactions with key mRNA-binding proteins may influence cytoplasmic mRNA stability and/or translation.


Assuntos
Citosol/química , Mitocôndrias/química , RNA de Transferência/química , Ribonucleoproteínas/química , Autofagia/genética , Ribonucleoproteína Nuclear Heterogênea A1/química , Ribonucleoproteína Nuclear Heterogênea A1/genética , Humanos , Hibridização in Situ Fluorescente , Mitocôndrias/genética , RNA Mensageiro/química , RNA Mensageiro/genética , RNA de Transferência/genética , Ribonucleoproteínas/genética , Fatores de Processamento de Serina-Arginina/química , Fatores de Processamento de Serina-Arginina/genética , Proteína 1 de Ligação a Y-Box/química , Proteína 1 de Ligação a Y-Box/genética
16.
Development ; 145(19)2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30135188

RESUMO

Maternal mRNAs and proteins dictate early embryonic development before zygotic genome activation. In the absence of transcription, elaborate control of maternal mRNA translation is of particular importance for oocyte maturation and early embryogenesis. By analyzing zebrafish ybx1 mutants with a null allele, we demonstrate an essential role of maternal ybx1 in repressing global translation in oocytes and embryos. Loss of maternal Ybx1 leads to impaired oocyte maturation and egg activation. Maternal ybx1 (Mybx1) mutant embryos fail to undergo normal cleavage and the maternal-to-zygotic transition (MZT). Morpholino knockdown of ybx1 also results in MZT loss and epiboly failure, suggesting the postfertilization requirement of Ybx1. In addition, elevated global translation level and the unfolded protein response were found in Ybx1-depleted embryos. Supplementing translational repression by eIF4E inhibition markedly rescues the Mybx1 phenotype. Mechanistically, Ybx1 in embryos may associate with processing body components and repress translation when tethered to target mRNAs. Collectively, our results identify maternal Ybx1 as a global translational repressor required for oocyte maturation and early embryogenesis.


Assuntos
Diferenciação Celular , Oócitos/citologia , Oócitos/metabolismo , Biossíntese de Proteínas , Proteína 1 de Ligação a Y-Box/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Zigoto/metabolismo , Animais , Sequência de Bases , Proliferação de Células , Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Feminino , Fertilização , Regulação da Expressão Gênica no Desenvolvimento , Pleiotropia Genética , Modelos Biológicos , Mutação/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a Y-Box/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
17.
Oncogene ; 37(44): 5811-5828, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29970904

RESUMO

The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/fisiologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Fator 1 Induzível por Hipóxia/genética , Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/secundário , RNA Longo não Codificante/metabolismo , Transcrição Genética , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
18.
Gene ; 674: 37-48, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29940273

RESUMO

Y-box binding protein 1 (YB-1) is a member of the cold shock domain protein superfamily and is involved in development, environmental stresses and DNA oxidative damage in many organisms. However, the precise functions of YB-1 are still not well understood in various insects, including bees. In the current study, we identified a YB-1 gene in Apis cerana cerana (AccYB-1). The predicted cis-acting elements in the promoter sequence of AccYB-1 indicated its possible roles in development and stress responses. AccYB-1 expression was higher in one-day-old larvae and dark-eyed pupae than in other development stages. Tissue-specific expression analysis showed that the mRNA level of AccYB-1 was higher in the thorax and midgut than in other tissues. The results from real-time PCR showed that AccYB-1 was induced by many environmental stresses. Silencing AccYB-1 downregulated the transcriptional level of some growth- and development-related genes and antioxidant genes and decreased the enzyme activities of several antioxidant-related enzymes, further indicating a possible function of AccYB-1 in growth, development and stress responses. Taken together, our findings suggest that AccYB-1 may play an indispensable role in growth and development and environmental stress responses in Apis cerana cerana. To our knowledge, this is the first paper to explore the role of YB-1 in bees.


Assuntos
Abelhas/crescimento & desenvolvimento , Abelhas/metabolismo , Proteínas de Insetos/fisiologia , Estresse Fisiológico , Proteína 1 de Ligação a Y-Box/fisiologia , Animais , Antioxidantes/metabolismo , Abelhas/enzimologia , Abelhas/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , Interferência de RNA , Análise de Sequência de DNA , Estresse Fisiológico/genética , Proteína 1 de Ligação a Y-Box/química , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo
19.
Nat Commun ; 9(1): 1734, 2018 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-29712925

RESUMO

The integrity of stratified epithelia depends on the ability of progenitor cells to maintain a balance between proliferation and differentiation. While much is known about the transcriptional pathways underlying progenitor cells' behavior in the epidermis, the role of posttranscriptional regulation by mRNA binding proteins-a rate-limiting step in sculpting the proteome-remains poorly understood. Here we report that the RNA binding protein YBX1 (Y-box binding protein-1) is a critical effector of progenitors' function in the epidermis. YBX1 expression is restricted to the cycling keratinocyte progenitors in vivo and its genetic ablation leads to defects in the architecture of the skin. We further demonstrate that YBX1 negatively controls epidermal progenitor senescence by regulating the translation of a senescence-associated subset of cytokine mRNAs via their 3' untranslated regions. Our study establishes YBX1 as a posttranscriptional effector required for maintenance of epidermal homeostasis.


Assuntos
Queratinócitos/metabolismo , Processamento Pós-Transcricional do RNA , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Proteína 1 de Ligação a Y-Box/genética , Regiões 3' não Traduzidas , Animais , Ciclo Celular/genética , Diferenciação Celular , Proliferação de Células , Senescência Celular , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Embrião de Mamíferos , Células Epidérmicas , Epiderme/crescimento & desenvolvimento , Epiderme/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Queratinócitos/citologia , Camundongos , Cultura Primária de Células , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Células-Tronco/citologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Proteína 1 de Ligação a Y-Box/metabolismo
20.
Mol Cancer Res ; 16(7): 1149-1160, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29743296

RESUMO

Cutaneous melanoma represents one of the most aggressive human tumor entities possessing a high tendency to metastasize. Cancer cells frequently exploit a highly conserved developmental program, the epithelial-to-mesenchymal transition (EMT), to gain migratory and invasive properties promoting their metastatic spread. Cytoplasmic localization of the oncogenic transcription and translation factor Y-box binding protein 1 (YB-1) is a powerful inducer of EMT in breast carcinoma cells. Interestingly, EMT-like processes have also been observed in cutaneous melanoma despite its neural crest origin. Here, increased expression of YB-1 negatively affects patient survival in malignant melanoma and promotes melanoma cell tumorigenicity both in vitro and in vivo Intriguingly, this effect seems to be mainly mediated by cytoplasmic YB-1 that does not exhibit phosphorylation at serine-102 (S102). Moreover, S102 unphosphorylated YB-1 enhances the migratory and invasive potential of human melanoma cells in two-dimensional (2D) and three-dimensional (3D) culture systems and facilitates acquisition of a mesenchymal-like invasive phenotype in the chick embryo model. Collectively, these data demonstrate that the cytoplasmic activity of YB-1 stimulates tumorigenicity and metastatic potential of melanoma cells by promoting EMT-like properties.Implications: This study reveals for the first time that YB-1 efficiently drives tumorigenicity and invasiveness of melanoma cells in its S102 unphosphorylated cytoplasmic state and that YB-1 expression represents a negative prognostic factor in primary melanoma patients. Mol Cancer Res; 16(7); 1149-60. ©2018 AACR.


Assuntos
Carcinogênese/genética , Transição Epitelial-Mesenquimal/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Proteína 1 de Ligação a Y-Box/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Embrião de Galinha , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/patologia , Camundongos , Invasividade Neoplásica/genética , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA