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1.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 64-71, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31889183

RESUMO

Previous studies have shown that during severe acute pancreatitis (SAP) attacks, hydrogen sulfide (H2S) is released in the colon. However, the roles played by H2S in regulating enteric nerves remain unclear. In this study, we examined the association between SAP-induced H2S release and loss of intestinal motility, and also explored the relevant mechanism in enteric nerve cells. A rat SAP model was constructed and enteric nerve cells were prepared. Intestinal mobility was evaluated by measuring the number of bowel movements at indicated time points and by performing intestinal propulsion tests. The production of inflammatory cytokines during a SAP attack was quantified by ELISA, and the levels of cystathionine-γ-lyase (CSE) and cystathionine-ß-synthase (CBS) were examined by immunohistochemistry and western blot analysis. In vivo studies showed that PI3K/Akt/Sp1 signaling in enteric nerve cells was blocked, confirming the mechanism of endogenous H2S formation by western blot analysis and immunofluorescence. Our results also showed that rats with SAP symptoms had reduced intestinal motility. Furthermore, PI3K/Akt/Sp1 signaling was triggered and CSE expression was up-regulated, and these changes were associated with H2S formation in the colon. In addition, propargylglycine reduced the levels of inflammatory cytokines and suppressed the release of H2S. Enteric nerve cells that were incubated with LY294002 and transfected with a Sp1-knockdown vector displayed decreased levels of CSE production, which led to a decrease in H2S production. These results suggest that SAP symptoms suppressed the intestinal motility of rats via the release of H2S in enteric nerve cells, which was dependent on the inflammation-induced PI3K/Akt/Sp1 signaling pathway.


Assuntos
Movimento Celular , Sistema Nervoso Entérico/patologia , Sulfeto de Hidrogênio/metabolismo , Neurônios/metabolismo , Pancreatite/metabolismo , Animais , Cromonas/farmacologia , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Citocinas/metabolismo , Motilidade Gastrointestinal , Técnicas de Silenciamento de Genes , Inflamação/metabolismo , Masculino , Morfolinas/farmacologia , Pancreatite/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Ácido Taurocólico/efeitos adversos , Ácido Taurocólico/farmacologia , Transfecção
2.
Int J Mol Sci ; 20(20)2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614732

RESUMO

The rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the ability for the biosynthesis of long-chain (≥C20) polyunsaturated fatty acids (LC-PUFA) from C18 PUFA precursors, and all the catalytic enzymes including two fatty acyl desaturase 2 (Δ4 Fads2 and Δ6/Δ5 Fads2) and two elongases (Elovl4 and Elovl5) have been identified, providing a good model for studying the regulatory mechanisms of LC-PUFA biosynthesis in fish. Stimulatory protein 1 (Sp1) has been speculated to be a vital transcription factor in determining the promoter activity of Fads-like genes in fish, however its regulatory effects on gene expression and LC-PUFA biosynthesis have not been demonstrated. Bioinformatic analysis predicted potential Sp1 binding sites in the promoters of the rabbitfish Δ6/Δ5 fads2 and elovl5, but not in Δ4 fads2 promoter. Here we cloned full-length cDNA of the rabbitfish sp1 gene, which encoded a putative protein of 701 amino acids, and was expressed in all tissues studied with highest levels in gill and eyes. The dual luciferase reporter assay in HepG2 line cells demonstrated the importance of the Sp1 binding site for the promoter activities of both Δ6/Δ5 fads2 and elovl5. Moreover, the electrophoretic mobility shift assay confirmed the direct interaction of Sp1 with the two promoters. Insertion of the Sp1 binding site of Δ6/Δ5 fads2 promoter into the corresponding region of the Δ4 fads2 promoter significantly increased activity of the latter. In the Siganus canaliculatus hepatocyte line (SCHL) cells, mRNA levels of Δ6/Δ5 fads2 and elovl5 were positively correlated with the expression of sp1 when sp1 was overexpressed or knocked-down by RNAi or antagonist (mithramycin) treatment. Moreover, overexpression of sp1 also led to a higher conversion of 18:2n-6 to 18:3n-6, 18:2n-6 to 20:2n-6, and 18:3n-3 to 20:3n-3, which related to the functions of Δ6/Δ5 Fads2 and Elovl5, respectively. These results indicated that Sp1 is involved in the transcriptional regulation of LC-PUFA biosynthesis by directly targeting Δ6/Δ5 fads2 and elovl5 in rabbitfish, which is the first report of Sp1 involvement in the regulation of LC-PUFA biosynthesis in vertebrates.


Assuntos
Ácidos Graxos Dessaturases/genética , Ácidos Graxos Ômega-3/biossíntese , Proteínas de Peixes/genética , Fator de Transcrição Sp1/metabolismo , Animais , Ácidos Graxos Dessaturases/metabolismo , Proteínas de Peixes/metabolismo , Células Hep G2 , Humanos , Fígado/enzimologia , Fígado/metabolismo , Perciformes/genética , Perciformes/metabolismo , Fator de Transcrição Sp1/genética , Regulação para Cima
3.
Biomed Pharmacother ; 119: 109434, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536933

RESUMO

Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and activated Ras/Raf/MEK/ERK pathway. But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain. The mechanism of IQGAP1 overexpression and transcriptional regulation of IQGAP1 gene in myeloma cells was explored in the study. Through bioinformatics analysis and prediction we predicted and screened transcription factor Sp1 as a possible upstream regulator of IQGAP1.The proliferation, cell cycle and downstream ERK1/2 and p-ERK1/2 proteins were detected after siRNA-IQGAP1 was transfected to myeloma cells. The expression of Sp1, p300, IQGAP1, p-ERK1/2 and ERK1/2 were detected after Sp1 and p300 were inhibited or overexpressed respectively. The dual-luciferase reporter system was used to detect the activity of IQGAP1 gene promoter. CHIP was used to detect the binding of the Sp1 and IQGAP1 promoter regions.CO-IP was used to explore the interaction between Sp1 and p300.The mRNA expression levels of Sp1,p300 and IQGAP1 of the myeloma patients were detected, and the correlation analysis of their mRNA expression levels were carried out. The results showed IQGAP1-siRNA inhibits cell proliferation, cell cycle, IQGAP1 expression and phosphorylation of ERK1/2 protein. Inhibition of Sp1 or p300 down-regulated ERK1/2 and IQGAP1 expression; overexpression of Sp1 or p300 up-regulated ERK1/2 and IQGAP1 expression; Sp1 and p300 had a positive regulation effect on IQGAP1.Over expression of Sp1 or p300 significantly increased activity of IQGAP1 gene promoter. The transcription factor Sp1 plays a regulatory role in the IQGAP1 promoter region. There is an interaction between Sp1 and p300 in myeloma cells. The mRNA expression levels of Sp1, IQGAP1 and p300 in MM samples showed a positive correlation. In summary IQGAP1 is required for cell proliferation in MM cells, and the transcription of Sp1/p300 complex regulates expression of IQGAP1 gene.


Assuntos
Proteína p300 Associada a E1A/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Fator de Transcrição Sp1/metabolismo , Transcrição Genética , Proteínas Ativadoras de ras GTPase/genética , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Proteína p300 Associada a E1A/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Regiões Promotoras Genéticas , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Fator de Transcrição Sp1/genética , Proteínas Ativadoras de ras GTPase/metabolismo
4.
Anticancer Res ; 39(8): 4129-4136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366497

RESUMO

BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP). MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively. RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU. CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição Sp1/genética , Timidina Fosforilase/genética , Sítios de Ligação/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Decitabina/metabolismo , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/genética , Timidina Fosforilase/química
5.
Toxicol Lett ; 315: 77-86, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470059

RESUMO

T-2 toxin is a major pollutant in crops and feedstuffs. Due to its high toxicity in a variety of organisms, T-2 toxin is of great concern as a threat to humans and to animal breeding. Overexpression of CYP1A1 may contribute to carcinogenesis, and CYP1A1 may be a promising target for the prevention and treatment of human malignancies. Therefore, it is essential to understand the regulatory mechanism by which T-2 toxin induces CYP1A1 expression in human cells. In this study, we confirmed that T-2 toxin (100 ng/mL) induced the expression of CYP1A1 in HepG2 cells through NRF1 and Sp1 bound to the promoter instead of through the well-recognized Aromatic hydrocarbon receptors (AhR). In cells treated with T-2 toxin, Sp1, but not NRF1, was significantly upregulated. However, T-2 toxin apparently promoted the interaction between NRF1 and Sp1 proteins, as revealed by IP analysis. Furthermore, in T-2 toxin-treated HepG2 cells, nuclear translocation of NRF1 was enhanced, while knockdown of Sp1 ablated NRF1 nuclear enrichment. Our results revealed that the upregulation of CYP1A1 by T-2 toxin in HepG2 cells depended on enhanced interaction between Sp1 and NRF1. This finding suggests the tumorigenic features of T-2 toxin might be related to the CYP1A1, which provides new insights to understand the toxicological effect of T-2 toxin.


Assuntos
Citocromo P-450 CYP1A1/efeitos dos fármacos , Citocromo P-450 CYP1A1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/genética , Fator de Transcrição Sp1/genética , Toxina T-2/toxicidade , Regulação para Cima/efeitos dos fármacos , Carcinoma/fisiopatologia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Pesquisas com Embriões , Regulação Enzimológica da Expressão Gênica , Humanos , Rim , Neoplasias Hepáticas/fisiopatologia , Fator 1 Relacionado a NF-E2/efeitos dos fármacos , Fator 1 Relacionado a NF-E2/metabolismo , Fator de Transcrição Sp1/efeitos dos fármacos , Fator de Transcrição Sp1/metabolismo
6.
BMC Cancer ; 19(1): 746, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362717

RESUMO

PURPOSE: Expression of human chorionic gonadotropin beta subunit by cancers is extensively documented, yet regulation of the multiple genes that can code for this protein is poorly understood. The aim of the study was to examine the mechanisms regulating CGB gene expression in ovarian cancer. METHODS: Expression of CGB genes and SP1, SP3, TFAP2A transcription factor genes was evaluated by RT-qPCR. The methylation status of CGB genes promoter regions was examined by methylation-specific PCR. RESULTS: mRNA arising from multiple CGB genes was detected in both ovarian control and malignant tissues. However, expression of CGB3-9 genes was shown to be significantly higher in malignant than healthy ovarian tissues. CGB1 and CGB2 transcripts were shown to be present in 20% of ovarian cancers, but were not detected in any of the control samples. Malignant tissues were characterized by DNA demethylation of CGB promoter regions. In ovarian cancer CGB expression positively correlated with TFAP2A transcripts level and expression of TFAP2A transcription factor was significantly higher in cancer than in control tissues. In contrast SP3 expression level was significantly lower in ovarian tumours than in control ovarian tissue. CONCLUSIONS: In ovarian cancers increased expression of human chorionic gonadotropin beta subunit is associated with demethylation of CGB promoter regions. CGB3-9 expression level strongly correlates with expression of the TFAP2A transcription factor. Presence of mRNA arising from CGB1 and CGB2 genes appears to be a unique feature of a subset of ovarian cancers.


Assuntos
Gonadotropina Coriônica Humana Subunidade beta/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Ovarianas/genética , Metilação de DNA/genética , Desmetilação , Feminino , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp2/genética , Fator de Transcrição AP-2/genética , Transcrição Genética
7.
Nat Commun ; 10(1): 3784, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439839

RESUMO

Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.


Assuntos
Esclerose Amiotrófica Lateral/patologia , Anexina A2/metabolismo , Neurônios Motores/patologia , Degeneração Neural/patologia , Proteínas do Tecido Nervoso/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Proteínas S100/metabolismo , Fator de Transcrição Sp1/metabolismo , Esclerose Amiotrófica Lateral/etiologia , Animais , Membrana Celular/patologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Masculino , Potenciais da Membrana , Camundongos , Camundongos Transgênicos , Neurônios Motores/citologia , Degeneração Neural/etiologia , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Cultura Primária de Células , Regiões Promotoras Genéticas , Ratos , Fator de Transcrição Sp1/genética , Medula Espinal/citologia , Medula Espinal/patologia
8.
Cardiovasc Pathol ; 42: 21-29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220774

RESUMO

Cardiomyocyte hypertrophy is a heart response adapting to increasing cardiac load. Prolonged cardiomyocyte hypertrophy indicates a higher risk of heart failure or even cardiac death. Long noncoding RNAs have been largely reported to modulate human diseases. CTPB1-AS2 is a newly discovered lncRNA reported as an oncogene in papillary thyroid cancer, but its function in cardiomyocyte hypertrophy has never been probed. Toll-like receptor 4 (TLR4) is recognized to play important roles in cardiomyocyte hypertrophy. The present study aimed to investigate the role of CTBP1-AS2 in cardiomyocyte hypertrophy. First, we discovered the low expression of CTBP1-AS2 in normal heart tissues in GETx database. Then, we established cardiomyocyte hypertrophy models on mice and cardiomyocytes through transverse aortic constriction surgery and Ang II treatment. We revealed the up-regulation of CTBP1-AS2 and TLR4 in cardiomyocyte hypertrophy models. Also, we confirmed the positive correlation between CTBP1-AS2 and TLR4 expressions in cardiomyocyte hypertrophy tissues. Loss-of-function assays confirmed that inhibiting CTBP1-AS2 attenuated the Ang II-induced cardiomyocyte hypertrophy. Mechanism research showed that CTBP1-AS2 stabilized TLR4 mRNA by recruiting FUS. Rescue assays certified that CTBP1-AS2 regulated cardiomyocyte hypertrophy through TLR4. Finally, we found Sp1 as an upstream activator for CTBP1-AS2 expression. In conclusion, our study uncovered CTBP1-AS2 as a novel regulator of cardiomyocyte hypertrophy through regulating TLR4, providing a new potential treatment target for cardiomyocyte hypertrophy.


Assuntos
Cardiomegalia/metabolismo , Tamanho Celular , Miocárdio/metabolismo , RNA Longo não Codificante/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Fator de Transcrição Sp1/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Cardiomegalia/genética , Cardiomegalia/patologia , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , RNA Longo não Codificante/genética , Proteína FUS de Ligação a RNA/genética , Ratos Sprague-Dawley , Transdução de Sinais , Fator de Transcrição Sp1/genética , Receptor 4 Toll-Like/genética
9.
Int J Mol Med ; 44(2): 608-616, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173188

RESUMO

Hypercholesterolemia is a key factor leading to ß­cell dysfunction, but its underlying mechanisms remain unclear. Secretagogin (Scgn), a Ca2+ sensor protein that is expressed at high levels in the islets, has been shown to play a key role in regulating insulin secretion through effects on the soluble N­ethylmaleimide­sensitive factor attachment receptor protein complexes. However, further studies are required to determine whether Scgn plays a role in hypercholesterolemia­associated ß­cell dysfunction. The present study investigated the involvement of a microRNA­24 (miR­24)­to­Scgn regulatory pathway in cholesterol­induced ß­cell dysfunction. In the present study, MIN6 cells were treated with increasing concentrations of cholesterol and then, the cellular functions and changes in the miR­24­to­Scgn signal pathway were observed. Excessive uptake of cholesterol in MIN6 cells increased the expression of miR­24, resulting in a reduction in Sp1 expression by directly targeting its 3' untranslated region. As a transcriptional activator of Scgn, downregulation of Sp1 decreased Scgn levels and subsequently decreased the phosphorylation of focal adhesion kinase and paxillin, which is regulated by Scgn. Therefore, the focal adhesions in insulin granules were impaired and insulin exocytosis was reduced. The present study concluded that a miR­24­to­Scgn pathway participates in the mechanism regulating cholesterol accumulation­induced ß­cell dysfunction.


Assuntos
Colesterol/metabolismo , Secreção de Insulina , MicroRNAs/genética , Secretagoguinas/genética , Transdução de Sinais , Animais , Linhagem Celular , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Regulação da Expressão Gênica , Células Secretoras de Insulina/metabolismo , Camundongos , Fosforilação , Secretagoguinas/metabolismo , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo
10.
World J Gastroenterol ; 25(22): 2776-2787, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31236000

RESUMO

BACKGROUND: Aberrant expression of stanniocalcin 2 (STC2) is implicated in colon adenocarcinoma (COAD). A previous study identified that STC2 functions as a tumor promoter to drive development of some cancers, but the role of its overexpression in the development of COAD remains unclear. AIM: To evaluate the regulation mechanism of STC2 overexpression in COAD. METHODS: The expression of STC2 in COAD was assessed by TCGA COAD database and GEO (GSE50760). Methylation level of the STC2 promoter was evaluated with beta value in UALCAN platform, and the correlation between STC2 expression and survival rate was investigated with TCGA COAD. Transcription binding site prediction was conducted by TRANSFAC and LASAGNA, and a luciferase reporter system was used to identify STC2 promoter activity in several cell lines, including HEK293T, NCM460, HT29, SW480, and HCT116. Western blotting was performed to evaluate the role of Sp1 on the expression of STC2. RESULTS: The central finding of this work is that STC2 is overexpressed in COAD tissues and positively correlated with poor prognosis. Importantly, the binding site of the transcription factor Sp1 is widely located in the promoter region of STC2. A luciferase reporter system was successfully constructed to analyze the transcription activity of STC2, and knocking down the expression of Sp1 significantly inhibited the transcription activity of STC2. Furthermore, inhibition of Sp1 remarkably decreased protein levels of STC2. CONCLUSION: Our data provide evidence that the transcription factor Sp1 is essential for the overexpression of STC2 in COAD through activation of promoter activity. Taken together, our finding provides new insights into the mechanism of oncogenic function of COAD by STC2.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fator de Transcrição Sp1/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Metilação de DNA/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Prognóstico , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Fator de Transcrição Sp1/genética , Taxa de Sobrevida , Ativação Transcricional , Regulação para Cima
11.
Int J Cancer ; 145(12): 3285-3298, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31111958

RESUMO

Human epidermal growth factor receptor 2 (HER2/erbB2) is a key driver and therapeutic target for breast cancer. The treatment of HER2-positive breast cancer remains a clinical challenge largely due to the limited understanding of HER2-driving oncogenic signaling and the frequent resistance to simply HER2-targeted therapy. Here, we show that the histone deacetylase inhibitor, trichostatin A (TSA), suppresses HER2-overexpressing breast cancer via upregulation of miR-146a and the resultant repression of its oncogenic targets, interleukin-1 receptor-associated kinase 1 and the chemokine receptor CXCR4. Mechanistically, histone H3K56 acetylation and deacetylation on the MIR146A promoter are catalyzed respectively by the acetyltransferase p300 and histone deacetylase 1 (HDAC1), both of which are recruited to the genomic loci by the transcription factor specificity protein 1 (Sp1). HER2 signaling phosphorylates Sp1 and induces its predominant association with HDAC1, but not p300, leading to histone hypoacetylation and silencing of MIR146A. In addition, the death receptor Fas is similarly downregulated by the aforementioned epigenetic paradigm, indicating its wide involvement in impairing tumor suppressor gene expression. Consequently, TSA synergizes with lapatinib, a tyrosine kinase inhibitor of HER2, to suppress breast cancer in vitro and in rodent models. These findings demonstrate a novel mechanism of HER2-driven carcinogenesis and suggest the applicability of combined HER2 and HDAC targeting in breast cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Epigênese Genética/genética , Histona Desacetilase 1/genética , Inibidores de Histona Desacetilases/farmacologia , Receptor ErbB-2/genética , Fator de Transcrição Sp1/genética , Animais , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Histona Desacetilases/genética , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/genética , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
J Exp Clin Cancer Res ; 38(1): 200, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097000

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia stem cells (LSCs). LSCs are characterized by unrestricted self-renewal and contribute to the malignancy of leukemia. Aberrant protein fucosylation is associated with AML progression. However, it is still less understood that the miR-29b/Sp1/FUT4 crosstalk involved in the fucosylation-mediated LSCs malignancy in AML. METHODS: AML cell lines were sorted by magnetic microbeads to obtain the CD34 + CD38- sub-population. The key biomarkers for LSCs were identified by flow cytometry. Fucosyltransferase genes were screened by qRT-PCR, and FUT4 was focused. Effect of FUT4 on LSCs malignancy was determined by CCK8 assay, sphere formation assay, immunofluorescence staining, apoptosis and in vivo xenografts experiments. The linkage of FUT4 promoter and Sp1 was confirmed by dual-luciferase reporter gene assay. ChIP-PCR assay was used to show the directly binding of Sp1 and FUT4 promoter. Activity of Wnt//ß-catenin pathway was determined by western blot. Overall survival curves were diagrammed by Kaplan-Meier analysis. RESULTS: Here, the expressional profiles of 11 fucosyltransferase genes were different comparing LSCs and non-LSCs of KG-1a and MOLM13 cells, whereas CD34 + CD38- cells exhibited higher expression of FUT4. Functionally, alteration of FUT4 in CD34 + CD38- cells modulated LSCs malignant behaviors both in vitro and in vivo. Transcriptional inhibitor actinomycin D (Act D) or translational inhibitor cycloheximide (CHX) prevented LSCs progression, and Sp1 was identified as the efficient regulator of FUT4 transcription. Moreover, miR-29b directly affected the binding of Sp1 and FUT4 promoter region, which further mediated LSCs proliferation, apoptosis and drug-resistance through fucosylated-CD44 via activation of Wnt/ß-catenin pathway. Clinically, Sp1 and FUT4 were up-regulated and positively correlated with poor overall survival of AML patients. CONCLUSION: These data indicated that miR-29b/Sp1/FUT4 axis promoted the malignant behaviors of LSCs by regulating fucosylated CD44 via Wnt/ß-catenin pathway. Identifying LSCs surface markers and targeting LSCs were important for the development of potential therapies in AML.


Assuntos
Fucosiltransferases/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição Sp1/genética , Via de Sinalização Wnt , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Exp Clin Cancer Res ; 38(1): 205, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101117

RESUMO

BACKGROUND: The aim of this study is to explore the molecular mechanism of the LIM protein Ajuba and the transcription factor SP1 in the pathogenesis and progression of PDAC. Ajuba is a newly defined transcriptional co-regulator and plays important role in various cancer development, while SP1 is a classic transcription factor, and is closely related with a variety of gene expression and cancer development including PDAC. METHODS: The expression of Ajuba and SP1 in PDAC tissues was detected by immunohistochemistry (IHC), and the correlation between expression level and clinical prognosis of Ajuba and SP1 was extensively analyzed using online tools. The interaction between Ajuba and SP1 was examined by co-immunoprecipitation (co-IP) and GST-pulldown assays. Stable cell lines were established via lentiviral infection, and was examined by qRT-PCR and western blot assays. The effects of Ajuba/SP1 on PDAC cell proliferation were examined using CCK8 and colony formation assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were employed to examine the transcription activity. RESULTS: The expression level (protein and mRNA) of Ajuba and SP1 was elevated in PDAC tissues and was positively correlated; patients with high Ajuba and SP1 expression had a poor prognosis. Mechanistically, Ajuba binds to the C-terminus of SP1 and functions as a co-activator to enhance SP1 gene expression and promote cell proliferation; the promoter of Ajuba contains functional SP1 responsive elements and Ajuba itself is a target gene of SP1. CONCLUSION: Ajuba functions as a co-activator of SP1 to induce its target gene, and that Ajuba itself is a target genes of SP1. Ajuba/SP1 complex could form a feed forward loop to drive SP1 target gene transcription and promote cell proliferation of pancreatic cancer cells. Ajuba and SP1 might be biomarkers for PDAC diagnostics, prognosis and targets for new therapeutics.


Assuntos
Proliferação de Células/genética , Proteínas com Domínio LIM/genética , Neoplasias Pancreáticas/genética , Fator de Transcrição Sp1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Complexos Multiproteicos/genética , Neoplasias Pancreáticas/patologia , Regiões Promotoras Genéticas , Ligação Proteica/genética , Ativação Transcricional/genética
14.
Int J Cancer ; 145(9): 2496-2508, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30963560

RESUMO

JNK activity has been implicated in the malignant proliferation, invasion and drug-resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c-Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel-like factor-5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated-SP1 and acetylated-KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant-negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c-Jun activities was involved in the tumor-growth inhibitory effects induced by LMK235 in U87-xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c-Jun signaling-mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c-Jun signaling in GCs.


Assuntos
Glioma/genética , Histona Desacetilases/genética , Fatores de Transcrição Kruppel-Like/genética , MAP Quinase Quinase 7/genética , Proteínas Repressoras/genética , Fator de Transcrição Sp1/genética , Animais , Linhagem Celular Tumoral , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Regulação para Cima/genética
15.
Biochem J ; 476(8): 1247-1266, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914440

RESUMO

Tumors can be therapeutically targeted with novel antifolates (e.g. AGF94) that are selectively transported by the human proton-coupled folate transporter (hPCFT). Studies were performed to determine the transcription regulation of hPCFT in tumors and identify possible mechanisms that contribute to the highly disparate levels of hPCFT in HepG2 versus HT1080 tumor cells. Transfection of hPCFT-null HT1080 cells with hPCFT restored transport and sensitivity to AGF94 Progressive deletions of the hPCFT promoter construct (-2005 to +96) and reporter gene assays in HepG2 and HT1080 cells confirmed differences in hPCFT transactivation and localized a minimal promoter to between positions -50 and +96. The minimal promoter included KLF15, GC-Box and NRF-1 cis-binding elements whose functional importance was confirmed by promoter deletions and mutations of core consensus sequences and reporter gene assays. In HepG2 cells, NRF-1, KLF15 and Sp1 transcripts were increased over HT1080 cells by ∼5.1-, ∼44-, and ∼2.4-fold, respectively. In Drosophila SL2 cells, transfection with KLF15 and NRF-1 synergistically activated the hPCFT promoter; Sp1 was modestly activating or inhibitory. Chromatin immunoprecipitation and electrophoretic mobility shift assay (EMSA) and supershifts confirmed differential binding of KLF15, Sp1, and NRF-1 to the hPCFT promoter in HepG2 and HT1080 cells that paralleled hPCFT levels. Treatment of HT1080 nuclear extracts (NE) with protein kinase A increased Sp1 binding to its consensus sequence by EMSA, suggesting a role for Sp1 phosphorylation in regulating hPCFT transcription. A better understanding of determinants of hPCFT transcriptional control may identify new therapeutic strategies for cancer by modulating hPCFT levels in combination with hPCFT-targeted antifolates.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Transportador de Folato Acoplado a Próton/biossíntese , Elementos de Resposta , Fator de Transcrição Sp1/metabolismo , Animais , Drosophila melanogaster , Células HeLa , Células Hep G2 , Humanos , Fatores de Transcrição Kruppel-Like/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , Fator 1 Nuclear Respiratório/genética , Transportador de Folato Acoplado a Próton/genética , Fator de Transcrição Sp1/genética
16.
EMBO J ; 38(9)2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30886048

RESUMO

Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.


Assuntos
Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Poliubiquitina/metabolismo , Processamento de Proteína Pós-Traducional , Fator de Transcrição Sp1/metabolismo , Proteína com Valosina/metabolismo , Adulto , Idoso , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Células Cultivadas , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Fator de Transcrição Sp1/genética , Ubiquitinação , Proteína com Valosina/genética
17.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1617-1626, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30922813

RESUMO

Mitochondria are dynamic in structure, and undergo continuous fusion-fission to maintain their homeostasis. In diabetes, retinal mitochondria are swollen, their membrane is damaged and mitochondrial fusion protein, mitofusin 2 (Mfn2), is decreased. DNA methylation machinery is also activated and methylation status of genes implicated in mitochondrial damage and biogenesis is altered. This study aims to investigate the role of mitochondrial fusion in the development of diabetic retinopathy, and to illustrate the molecular mechanism responsible for Mfn2 suppression. Using human retinal endothelial cells, manipulated for Mfn2, we investigated the role of fusion in mitochondrial structural and functional damage in diabetes. The molecular mechanism of its suppression in diabetic milieu was determined by investigating Mfn2 promoter DNA methylation, and confirmed using molecular and pharmacological inhibitors of DNA methylation. Similar studies were performed in the retinal microvasculature (prepared by hypotonic shock method) of diabetic rats, and human donors with documented diabetic retinopathy. Overexpression of Mfn2 prevented glucose-induced increase in mitochondrial fragmentation, decrease in complex III activity and increase in membrane permeability, mtDNA damage and apoptosis. High glucose hypermethylated Mfn2 promoter and decreased transcription factor (SP1) binding, and Dnmt inhibition protected Mfn2 promoter from these changes. In streptozotocin-induced diabetic rats, intravitreal administration of Dnmt1-siRNA attenuated Mfn2 promoter hypermethylation and restored its expression. Human donors with diabetic retinopathy confirmed Mfn2 promoter DNA hypermethylation. Thus, regulating Mfn2 and its epigenetic modifications by molecular/pharmacological means will protect mitochondrial homeostasis in diabetes, and could attenuate the development of retinopathy in diabetic patients.


Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Epigênese Genética , GTP Fosfo-Hidrolases/genética , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Adulto , Idoso , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , GTP Fosfo-Hidrolases/metabolismo , Homeostase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Retina/metabolismo , Retina/patologia , Transdução de Sinais , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Estreptozocina/administração & dosagem
18.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836589

RESUMO

Mitotic bookmarking constitutes a mechanism for transmitting transcriptional patterns through cell division. Bookmarking factors, comprising a subset of transcription factors (TFs), and multiple histone modifications retained in mitotic chromatin facilitate reactivation of transcription in the early G1 phase. However, the specific TFs that act as bookmarking factors remain largely unknown. Previously, we identified the "early G1 genes" and screened TFs that were predicted to bind to the upstream region of these genes, then identified GA-binding protein transcription factor alpha subunit (GABPA) and Sp1 transcription factor (SP1) as candidate bookmarking factors. Here we show that GABPA and multiple histone acetylation marks such as H3K9/14AC, H3K27AC, and H4K5AC are maintained at specific genomic sites in mitosis. During the M/G1 transition, the levels of these histone acetylations at the upstream regions of genes bound by GABPA in mitosis are decreased. Upon depletion of GABPA, levels of histone acetylation, especially H4K5AC, at several gene regions are increased, along with transcriptional induction at 1 h after release. Therefore, we proposed that GABPA cooperates with the states of histone acetylation to act as a novel bookmarking factor which, may negatively regulate transcription during the early G1 phase.


Assuntos
Fator de Transcrição de Proteínas de Ligação GA/genética , Genoma/genética , Histonas/genética , Mitose/genética , Acetilação , Cromatina/genética , Fase G1/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Regiões Promotoras Genéticas , Fator de Transcrição Sp1/genética
19.
Biochem Biophys Res Commun ; 511(3): 510-517, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30819403

RESUMO

Long noncoding RNA ILF3-AS1 (ILF3-AS1) has been reported to be abnormally expressed in several tumors. However, its expression pattern and function in osteosarcoma have not been investigated. In this study, we showed that ILF3-AS1 expression was significantly up-regulated in both osteosarcoma tissues and cell lines. We first reported that ILF3-AS1 upregulation was induced by nuclear transcription factor SP1. Clinical assays revealed that higher expression of ILF3-AS1 was associated with advanced clinical stage, distant metastasis and shorter overall survival. in multivariate analysis, ILF3-AS1 expression level was found to be an independent prognostic factor for osteosarcoma patients. Functional investigations showed that knockdown of ILF3-AS1 suppressed the proliferation, migration and invasion of osteosarcoma cells, and promoted apoptosis. Bioinformatic software predicted that miR-212 both targeted the 3'-UTR of ILF3-AS1 and SOX5, which was confirmed using luciferase reporter assay, RT-PCR and Western blot. Taken together, ILF3-AS1 displayed its tumor-promotive roles in the progression of osteosarcoma through miR-212/SOX5 axis. Our findings help to elucidate the tumorigenesis of osteosarcoma, and future study will provide a novel therapeutic target for osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , MicroRNAs/genética , Osteossarcoma/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXD/genética , Fator de Transcrição Sp1/genética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Osteossarcoma/diagnóstico , Osteossarcoma/patologia , Prognóstico , Regulação para Cima
20.
Gastric Cancer ; 22(5): 955-966, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30778797

RESUMO

BACKGROUND: Oncostatin M receptor (OSMR) is a member of the interleukin 6 (IL-6) receptor family that transduces signaling events of Oncostatin M (OSM). OSM-OSMR signaling plays a key role in inflammation and cancer progression. However, the role of OSM-OSMR in gastric cancer (GC) is still unknown. METHODS: OSMR expression in GC was determined by real-time PCR (RT-PCR), immunohistochemistry (IHC) and Western blot. The effects of OSM-OSMR on GC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and metastasis in vivo were examined. The pathways underlying OSM-OSMR signaling were explored by Western blot. Regulatory mechanism between SP1 and OSMR was explored in vitro. RESULTS: OSMR was highly expressed in GC tissues and its expression level was closely associated with age, T stage, Lauren classification, lymph node metastasis, TNM stage and worse prognosis of patients with GC. Knockdown of OSMR expression in GC cells significantly inhibited cell proliferation, migration, invasion, and EMT in vitro, as well as tumorigenesis and peritoneal metastasis in vivo induced by OSM. These effects mediated by OSM-OSMR were dependent on the activation of STAT3/FAK/Src signaling. SP1 could bind to the promoter region of human OSMR gene from - 255 to - 246 bp, and transcriptionally regulated OSMR overexpression in GC cells. CONCLUSIONS: OSM-OSMR contributes to GC progression through activating STAT3/FAK/Src signaling, and OSMR is transcriptionally activated by SP1.


Assuntos
Adenocarcinoma/secundário , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade beta de Receptor de Oncostatina M/metabolismo , Oncostatina M/farmacologia , Fator de Transcrição Sp1/metabolismo , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Subunidade beta de Receptor de Oncostatina M/genética , Prognóstico , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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