Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros

Bases de dados
País/Região como assunto
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Circulation ; 147(22): 1684-1704, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37066795

RESUMO

BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSIONS: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.


Assuntos
Cardiomiopatia Dilatada , Insuficiência Cardíaca , Humanos , Miócitos Cardíacos/metabolismo , Cardiomiopatia Dilatada/patologia , Insuficiência Cardíaca/patologia
2.
Acta Pharmacol Sin ; 43(1): 240-250, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33686244

RESUMO

Cardiovascular safety assessment is vital for drug development, yet human cardiovascular cell models are lacking. In vitro mass-generated human pluripotent stem cell (hPSC)-derived cardiovascular cells are a suitable cell model for preclinical cardiovascular safety evaluations. In this study, we established a preclinical toxicology model using same-origin hPSC-differentiated cardiomyocytes (hPSC-CMs) and endothelial cells (hPSC-ECs). For validation of this cell model, alirocumab, a human antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), was selected as an emerging safe lipid-lowering drug; atorvastatin, a common statin (the most effective type of lipid-lowering drug), was used as a drug with reported side effects at high concentrations, while doxorubicin was chosen as a positive cardiotoxic drug. The cytotoxicity of these drugs was assessed using CCK8, ATP, and lactate dehydrogenase release assays at 24, 48, and 72 h. The influences of these drugs on cardiomyocyte electrophysiology were detected using the patch-clamp technique, while their effects on endothelial function were determined by tube formation and Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake assays. We showed that alirocumab did not affect the cell viability or cardiomyocyte electrophysiology in agreement with the clinical results. Atorvastatin (5-50 µM) dose-dependently decreased cardiovascular cell viability over time, and at a high concentration (50 µM, ~100 times the normal peak serum concentration in clinic), it affected the action potentials of hPSC-CMs and damaged tube formation and Dil-Ac-LDL uptake of hPSC-ECs. The results demonstrate that the established same-origin hPSC-derived cardiovascular cell model can be used to evaluate lipid-lowering drug safety in cardiovascular cells and allow highly accurate preclinical assessment of potential drugs.


Assuntos
Anticolesterolemiantes/farmacologia , Atorvastatina/farmacologia , Células Endoteliais/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Anticolesterolemiantes/química , Atorvastatina/química , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
3.
Small ; 17(40): e2102884, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34480523

RESUMO

Chiral hybrid organic-inorganic perovskites (HOIPs) have been well developed for circularly polarized light (CPL) detection, while new members that target at solar-blind ultraviolet (UV) region remain completely unexplored. Here, an effective design strategy to demonstrate circular polarization-sensitive solar-blind UV photodetection by growing wide-bandgap chiral HOIP [(R)-MPA]2 PbCl4 ((R)-MPA = methylphenethylammonium) single crystals onto silicon wafers, with well-defined heterostructures, is reported. The solid mechanical and electrical connection between the chiral HOIP and silicon wafer results in strong built-in electric field at heterojunction, providing a desirable driving force for separating/transporting carriers generated under CPL excitation at 266 nm. Unexpectedly, during such a transport process, not only the chirality of HOIP crystal is transferred to the heterostructure, but also the circular polarization sensitivity is significantly amplified. Consequently, anisotropy factor of the resultant detectors can reach up to 0.4 at zero bias, which is much higher than that of the pristine single-phase chiral HOIP (≈0.1), reaching the highest among the reported CPL-UV photodetectors. As far as we know, the integration of chiral HOIP crystals with silicon technology is unprecedent, which paves a way for designing boosted-performance CPL detectors in solar-blind UV region as well as for other advanced optoelectronic devices.

4.
J Cell Mol Med ; 24(23): 13775-13788, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33084169

RESUMO

Myocardial infarction (MI) results in cardiomyocyte death and ultimately leads to heart failure. Pyroptosis is a type of the inflammatory programmed cell death that has been found in various diseased tissues. However, the role of pyroptosis in MI heart remains unknown. Here, we showed that CXADR-like membrane protein (CLMP) was involved in pyroptosis in the mouse MI heart. Our data showed that CLMP was strongly expressed in fibroblasts of the infarcted mouse hearts. The Clmp+/- mice showed more serious myocardial fibrosis and ventricular dysfunction post-MI than wild-type (Clmp+/+ ) mice, indicating a protective effect of the fibroblast-expressed CLMP against MI-induced heart damage. Transcriptome analyses by RNA sequencing indicated that Il-1ß mRNA was significantly increased in the MI heart of Clmp+/- mouse, which indicated a more serious inflammatory response. Meanwhile, cleaved caspase-1 and Gasdermin D were significantly increased in the Clmp+/- MI heart, which demonstrated enhanced pyroptosis in the Clmp knockdown heart. Further analysis revealed that the pyroptosis mainly occurred in cardiac fibroblasts (CFs). Compared to wild-type fibroblasts, Clmp+/- CFs showed more serious pyroptosis and inflammatory after LPS plus nigericin treatment. Collectively, our results indicate that CLMP participates in the pyroptotic and inflammatory response of CFs in MI heart. We have provided a novel pyroptotic insight into the ischaemic heart, which might hold substantial potential for the treatment of MI.


Assuntos
Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Piroptose/genética , Animais , Biomarcadores , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Ecocardiografia , Fibroblastos/metabolismo , Expressão Gênica , Genótipo , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Modelos Biológicos , Mutação , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/etiologia , Fenótipo
5.
Opt Lett ; 45(8): 2291-2294, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32287216

RESUMO

We report on the development and application of a novel, to the best of our knowledge, all-solid-state tunable narrow-linewidth 226 nm UV laser system. The laser system consists of three parts: a tunable single-frequency Ti:sapphire 787 nm laser, a single-frequency long-pulse-width flattop-shaped 532 nm laser, and a nonlinear frequency transformation system. The 532 nm laser is a sum-frequency mixed with the second harmonic of the 787 nm laser to produce the 226 nm laser. The maximum output pulse energy at 226 nm is 3 mJ. Nitric oxide planar laser-induced fluorescence velocimetry is demonstrated in the China Aerodynamics Research and Development Center's FD14 hypersonic shock tunnel using this 226 nm laser system. It is proven that this laser is convenient for high-resolution molecular tagging fluorescence spectroscopy.

6.
J Mol Cell Cardiol ; 134: 1-12, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31233755

RESUMO

MicroRNAs (miRNAs), as a class of naturally occurring RNAs, play important roles in cardiac physiology and pathology. There are many miRNAs that show multifarious expression patterns during cardiomyocyte genesis. Here, we focused on the MIR148A family, which is composed of MIR148A, MIR148B and MIR152, and shares the same seed sequences. The expression levels of all MIR148A family members progressively increased during the differentiation of human embryonic stem cells (hESCs) into cardiomyocytes. The deletion of MIR148A family (MIR148A-TKO) resulted in a decreased proportion of cardiomyocytes after cardiac induction, which was restored by the ectopic expression of MIR148A family members. Transcriptome analyses indicated that the MIR148A family could partially repress paraxial mesodermal differentiation from primitive streak cells. In turn, these miRNAs promoted lateral mesoderm and cardiomyocyte differentiation. Furthermore, the NOTCH ligand Delta-like 1 (DLL1) was validated as the target gene of MIR148A family, and knockdown of DLL1 could promote the cardiomyocyte differentiation of MIR148A-TKO hESCs. Thus, our results demonstrate MIR148A family could promote cardiomyocyte differentiation by inhibiting undesired paraxial mesoderm lineage commitment, which improves our understanding on cardiomyocyte differentiation from hESCs.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Diferenciação Celular/genética , Células-Tronco Embrionárias Humanas/fisiologia , Proteínas de Membrana/genética , MicroRNAs/genética , Miócitos Cardíacos/fisiologia , Receptores Notch/genética , Transdução de Sinais/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Mesoderma/fisiologia , Transcriptoma/genética
7.
Gene Ther ; 25(8): 511-523, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30287867

RESUMO

Myocardial infarction (MI), with a major process of cardiomyocyte death, remains a leading cause of morbidity and mortality worldwide. To date, it has been shown that lncRNAs play important roles in cardiovascular pathology. However, the detailed studies on lncRNAs regulating cardiomyocyte death in myocardial infarction are still limited. In this study, we found a progressively upregulated expression of Meg3 in mouse injured heart after MI. Gain-of-function and loss-of-function approaches further revealed pro-apoptotic functions of Meg3 in rodent cardiomyocytes. Moreover, Meg3 was directly upregulated by p53 in hypoxic condition, and involved in apoptotic regulation via its direct binding with RNA-binding protein FUS (fused in sarcoma). Afterwards, adult MI mice that underwent intramyocardial injection with adeno-associated virus serotype 9 (AAV9) system carrying Meg3 shRNA showed a significant improvement of cardiac function. Moreover, we also found that MEG3 was increased in clinical heart failure samples, and had conservatively pro-apoptotic function in human cardiomyocytes that were differentiated from the human embryonic stem cells. Together, these results indicate that p53-induced Meg3-FUS complex plays an important role in cardiomyocyte apoptosis post-MI, and its specific knockdown in cardiomyocytes with AAV9 system represents a promising method to treat MI for preclinical investigation.


Assuntos
Apoptose , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , Terapêutica com RNAi/métodos , Animais , Hipóxia Celular , Células Cultivadas , Dependovirus/genética , Feminino , Humanos , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , RNA Longo não Codificante/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteína Supressora de Tumor p53/metabolismo
8.
Opt Lett ; 43(6): 1271-1274, 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29543269

RESUMO

We realize Ho laser operation in a composite Tm/Ho:YAG gain medium for the first time, to the best of our knowledge, which was integrated via diffusion bonding the Tm-doped and Ho-doped crystals into a single bulk structure. A maximum output power around 6 W was obtained with a slope efficiency of 40.1% and conversion efficiency (CE) of 33.6% from the absorbed 785 nm laser diode to 2122 nm Ho laser, which is comparable with CE in 1.9 µm LD pumped Ho lasers. Such a scheme is demonstrated to be another valid way for Ho laser generation here, which is of significance to be adopted in other host media or waveguide structures for an assessable, compact, and efficient Ho laser.

9.
Gastroenterology ; 146(7): 1714-26.e5, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24631494

RESUMO

BACKGROUND & AIMS: Thousands of long intergenic non-protein coding RNAs (lincRNAs) have been identified in mammals via genome-wide sequencing studies. Many are functional, but are expressed aberrantly by cancer cells. We investigated whether levels of lincRNAs are altered during the development of esophageal squamous cell carcinoma (ESCC). METHODS: We used quantitative real-time polymerase chain reaction to measure levels of 26 highly conserved lincRNAs in ESCC and surrounding nontumor tissues. A total of 182 ESCC and paired adjacent nontumor tissue samples were collected from patients undergoing tylectomy at The First Affiliate Hospital of Soochow University from 2001 through 2009; another 178 ESCC tissue pairs were collected from Guangzhou Medical University from 2002 through 2009. LincRNAs were expressed from lentiviral vectors or knocked down with small hairpin RNAs in Eca-109 and TE-1 cells. RESULTS: Levels of a lincRNA encoded by a gene located next to POU3F3 (linc-POU3F3) were significantly higher in ESCC than neighboring nontumor tissues. In RNA immunoprecipitation assays, linc-POU3F3 was associated with the EZH2 messenger RNA (mRNA). Overexpression of linc-POU3F3 in cell lines increased their proliferation and ability to form colonies, and reduced the expression of POU3F3 mRNA, whereas knockdown of linc-POU3F3 increased the levels of POU3F3 mRNA. CpG islands in POU3F3 were densely hypermethylated in cell lines that overexpressed linc-POU3F3; methylation at these sites was reduced by knockdown of linc-POU3F3. Pharmacologic inhibition of EZH2 increased the levels of POU3F3 mRNA and significantly reduced binding of DNA methyltransferase (DNMT)1, DNMT3A, and DNMT3B to POU3F3. ESCC cells with knockdown of linc-POU3F3 formed xenograft tumors more slowly in mice than control ESCC cells. CONCLUSIONS: Levels of linc-POU3F3 are increased in ESCC samples from patients compared with nontumor tissues. This noncoding RNA contributes to the development of ESCC by interacting with EZH2 to promote methylation of POU3F3, which encodes a transcription factor.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ilhas de CpG , Metilação de DNA , Neoplasias Esofágicas/metabolismo , Fatores do Domínio POU/metabolismo , RNA Longo não Codificante/metabolismo , Adulto , Animais , Sequência de Bases , Sítios de Ligação , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Linhagem Celular Tumoral , Proliferação de Células , China , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , DNA Metiltransferase 3A , Proteína Potenciadora do Homólogo 2 de Zeste , Inibidores Enzimáticos/farmacologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fatores do Domínio POU/genética , Complexo Repressor Polycomb 2/antagonistas & inibidores , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , RNA Mensageiro/metabolismo , Fatores de Tempo , Transfecção , Carga Tumoral , Regulação para Cima , DNA Metiltransferase 3B
10.
Mol Carcinog ; 54(2): 102-10, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24038513

RESUMO

CD44 is such one adhesion molecule that mediates interactions between acute myeloid leukemia (AML) cells and stromal. It has been demonstrated that CD4 plays a critical role in AML development. However, studies of functional single nucleotide polymorphisms (SNPs) in CD44 gene have not touched upon AML. This case-control study probed the contribution of functional SNPs in CD44 gene to AML susceptibility in eastern Chinese population. Five representative SNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were opted and genotyped in 421 AML patients and 461 healthy subjects and the association with risk of AML was estimated by logistic regression. Moreover, the potential role of rs13347C > T in AML was further explored. Compared with the rs13347CC genotype, CT carriers had a significant increase in AML susceptibility (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.32-2.34), TT carriers had a further increased risk of AML (OR = 2.67; 95% CI = 1.69-4.21). Furthermore, our transient transfection assay and Western blot results demonstrated that the presence of rs13347T allele led to more CD44 expression. Yet, there exists no significant difference in genotype frequencies of the other four sites between cases and controls. Above findings suggest that rs13347C>T in 3'UTR of CD44 may be a genetic modifier for developing AML.


Assuntos
Povo Asiático/genética , Receptores de Hialuronatos/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Adulto , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Células HL-60 , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade
11.
Carcinogenesis ; 35(12): 2687-97, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25239642

RESUMO

Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development.


Assuntos
Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas do Tecido Nervoso/genética , Splicing de RNA/genética , Proteínas Repressoras/metabolismo , Adolescente , Idoso , Animais , Apoptose , Western Blotting , Fator de Ligação a CCCTC , Ciclo Celular , Proliferação de Células , Criança , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Endométrio/metabolismo , Feminino , Rearranjo Gênico , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Nus , Gradação de Tumores , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Front Cell Dev Biol ; 12: 1423553, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39045460

RESUMO

Alternative splicing is a complex gene regulatory process that distinguishes itself from canonical splicing by rearranging the introns and exons of an immature pre-mRNA transcript. This process plays a vital role in enhancing transcriptomic and proteomic diversity from the genome. Alternative splicing has emerged as a pivotal mechanism governing complex biological processes during both heart development and the development of cardiovascular diseases. Multiple alternative splicing factors are involved in a synergistic or antagonistic manner in the regulation of important genes in relevant physiological processes. Notably, circular RNAs have only recently garnered attention for their tissue-specific expression patterns and regulatory functions. This resurgence of interest has prompted a reevaluation of the topic. Here, we provide an overview of our current understanding of alternative splicing mechanisms and the regulatory roles of alternative splicing factors in cardiovascular development and pathological process of different cardiovascular diseases, including cardiomyopathy, myocardial infarction, heart failure and atherosclerosis.

13.
Stem Cell Res ; 78: 103467, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38861774

RESUMO

Dilated cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in dozens of cardiac genes have been connected to the development of DCM including the Troponin T2 gene (TNNT2). Here, we generated a human induced pluripotent stem cells (hiPSCs) from a DCM patient with a familial history that carries a missense mutation in TNNT2. The hiPSCs show typical morphology of pluripotent stem cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers.


Assuntos
Cardiomiopatia Dilatada , Células-Tronco Pluripotentes Induzidas , Troponina T , Humanos , Cardiomiopatia Dilatada/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Troponina T/metabolismo , Troponina T/genética , Diferenciação Celular , Linhagem Celular , Masculino , Cariótipo
14.
Hum Mutat ; 34(4): 619-28, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23378296

RESUMO

FOXP3 (forkhead box P3: also known as IPEX, XPID) is not only a hallmark of immunosuppressive regulatory T cells (Tregs), but also an X-linked breast cancer suppressor gene expressed in tumor cells. A two-stage investigation was conducted in individuals from northern, southern and eastern China. Individuals carrying a FOXP3 rs2294021CT genotype showed about 1.5-fold increased risk of breast cancer compared with TT carriers. In a related biochemical assay, the rs2294021C allele was found to significantly enhance transcription activity, leading to higher mRNA levels of FOXP3 compared with T allele. Moreover, the number of Tregs and its corresponding interleukin-10 (IL-10) secretion were elevated whereas the proliferation of antitumor T cells was decreased in the C-allele carriers. The breast cancer oncogenes Her-2/ErbB2 and Skp2 were also found to be significantly inhibited in C-allele carriers. Moreover, skewed X-chromosome inactivation (SXCI) analysis showed that rs2294021CT carriers with SXCI showed higher risk than the homozygous carriers and CT carriers without SXCI, suggesting a possible interaction between the rs2294021CT genotype and SXCI. Taken together, these findings indicate that the rs2294021CT genotype may increase an individual's susceptibility to breast cancer by breaking the balance between Treg-mediated immune tolerance and FOXP3-controlled tumor-suppressive effect.


Assuntos
Povo Asiático/genética , Neoplasias da Mama/genética , Fatores de Transcrição Forkhead/genética , Variação Genética , Heterozigoto , Inativação do Cromossomo X , Adulto , Idade de Início , Idoso , Alelos , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , China , Feminino , Genótipo , Humanos , Interleucina-10/biossíntese , Ativação Linfocitária/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Risco , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Linfócitos T Reguladores/imunologia , Transcrição Gênica
15.
Carcinogenesis ; 34(12): 2908-17, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23872665

RESUMO

The development of esophageal squamous cell carcinoma (ESCC) is a multifactorial process, and associations between genetic variants and ESCC have been identified in genome-wide association studies. The aim of this study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on ESCC susceptibility in Chinese populations. We scoured exons of lincRNAs located in ESCC susceptibility loci for all probable functional SNPs. These 52 SNPs were opted for and genotyped in 1493 ESCC patients and 1553 cancer-free controls from eastern and southern Chinese populations, and their associations with the risk for ESCC were estimated using logistic regression. Functional relevance was further examined by biochemical assays. Significant differences were found between patients and controls in the genotype frequencies for the rs11752942A>G site in the lincRNA-uc003opf.1 exon. Compared with the rs11752942AA genotype, AG and GG genotypes had a significantly reduced risk of ESCC (adjusted odds ratio = 0.73; 95% confidence interval = 0.63-0.84). Biochemical analysis demonstrated that, when compared with the A allele, the rs11752942G allele could markedly attenuate the level of lincRNA-uc003opf.1 both in vivo and in vitro by binding micro-RNA-149*, thereby affecting cell proliferation and tumor growth. These findings indicated that functional polymorphism rs11752942A>G in lincRNA-uc003opf.1 exon might be a genetic modifier for the development of ESCC.


Assuntos
Povo Asiático/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Proliferação de Células , Carcinoma de Células Escamosas do Esôfago , Éxons/genética , Frequência do Gene/genética , Genótipo , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Risco , Adulto Jovem
16.
Breast Cancer Res Treat ; 137(3): 893-901, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23288348

RESUMO

Interleukin (IL)-21, which is secreted by activated CD4(+) T cells and NKT cells, has been found to be able to influence the humoral and cell-mediated immune responses and have potent antitumor activity in animal models. This study was to investigate the impact of genetic polymorphisms in IL-21 on survival of breast cancer. Four TagSNPs of IL-21 (rs12508721C>T, rs907715G>A, rs13143866G>A, rs2221903A>G) were selected and then genotyped in 891 patients with breast cancer in Eastern and Southern Chinese populations. We then examined the associations between these SNPs and overall survival. Potential function of rs12508721C>T and association between this variation and breast cancer prognosis were further studied. Overall, 121 of the patients had died over the followed-up period of 5 years. The IL-21 rs12508721T allele predicted longer five-year survival (HR = 0.347, 95 % CI = 0.187-0.644, P < 0.0001) in the discovery cohort, the independent validation cohort (HR = 0.429, 95 % CI = 0.244-0.755, P = 0.012), and combined group (HR = 0.447, 95 % CI = 0.301-0.667, P < 0.0001). Furthermore, our luciferase assay revealed that rs12508721T variant allele had a higher transcription activity and the RT-PCR and ELISA assay showed that rs12508721 variant genotypes (CT and TT) carriers have more IL-21 expression than CC carriers (P < 0.05). Our present study established a robust association between the functional polymorphism (rs12508721C>T) in IL-21 and prognosis of breast cancer, indicating that this polymorphism may be a potential biomarker for prognosis of breast cancer.


Assuntos
Povo Asiático/genética , Neoplasias da Mama/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucinas/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Fatores de Risco , Linfócitos T/metabolismo , Ativação Transcricional , Adulto Jovem
17.
Mol Biol Rep ; 40(2): 829-38, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23054026

RESUMO

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which regulates the conformation of Pro-directed phosphorylation sites, has been identified as a critical catalyst involved in multiple oncogenic signaling pathways. Recently, it has been demonstrated that several putative functional polymorphisms of PIN1 gene were associated with cancer risk. This study examined whether genetic polymorphisms in promoter of PIN1 are associated with esophageal carcinoma susceptibility. Two common polymorphisms in PIN1, rs2233678 (-842G>C) and rs2233679 (-667C>T) were genotyped in this hospital-based case-control study of 699 esophageal carcinoma patients and 729 healthy controls. The results revealed that compared with the most common -842GG genotype carriers, the carriers of -842C variant genotypes (GC+CC) had significantly decreased risk of esophageal carcinoma [odds ratio (OR) = 0.55, 95 % CI = (0.40-0.75), P = 0.001]. No association was observed between the -667C>T polymorphism and the risk of esophageal carcinoma. Furthermore, we found that the haplotype of 'C(-842)-C(-667)' had a greater protected effect [OR = 0.67, 95 % CI = (0.47-0.96), P = 0.021]. Functional assay revealed that -842C variant genotypes (GC+CC) carriers had a lower transcription activity and mRNA expression level than the -842GG carriers. These results indicated that -842G>C genetic variant in PIN1 promoter may decrease the promoter activity, resulting in changes in the levels of PIN1 and modifying cancer susceptibility.


Assuntos
Carcinoma/genética , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Peptidilprolil Isomerase/genética , Polimorfismo de Nucleotídeo Único , Sequência de Bases , Linhagem Celular , China , Feminino , Regulação Enzimológica da Expressão Gênica , Frequência do Gene , Genes Reporter , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Luciferases/biossíntese , Luciferases/genética , Masculino , Pessoa de Meia-Idade , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/metabolismo , Regiões Promotoras Genéticas , Risco , Análise de Sequência de DNA , Ativação Transcricional
18.
Mol Biol Rep ; 40(5): 3749-56, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23283743

RESUMO

As a key encoding protein gene of MRN (MRE11-RAD50-NBS1) complex, NBS1 plays a crucial role in maintaining genomic stability and preventing cell apoptosis, inflammation and tumorgenesis. Single nucleotide polymorphisms (rs2735383 and rs1805794) in NBS1 have been frequently studied in some cancers with discordant results in previous case-control studies. However, the relationship between these two functional polymorphisms and the susceptibility to acute myeloid leukemia (AML) in Chinese population has not been investigated. We performed a case-control study with 428 patients and 600 controls to detect the association between the two polymorphisms of NBS1 and the risk of AML in a Chinese population. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was carried out to determine the genotypes of potential functional SNPs in NBS1 gene. The results showed that compared with the homozygous carriers rs1805794CC, rs1805794GC genotype was significantly associated with decreased risk of AML in total subjects (adjusted odds ratio (OR) = 0.50; 95% CI = 0.37-0.67), the risk decreased even further in those carrying rs1805794GG genotype (OR = 0.23; 95% CI = 0.16-0.34). No significant association was found between rs2735383C>G polymorphism and the risk of AML (OR = 0.93; 95% CI = 0.71-1.22 for GC; OR = 0.78; 95% CI = 0.53-1.13 for CC, P = 0.152). These findings indicated that rs1805794G/C polymorphism in NBS1 may play a protective role in mediating the risk of AML.


Assuntos
Povo Asiático/genética , Proteínas de Ciclo Celular/genética , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Risco , Adolescente , Adulto , Idoso , Sequência de Bases , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Adulto Jovem
19.
Mol Ther Nucleic Acids ; 32: 582-593, 2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37200858

RESUMO

Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) represent a promising source of human ECs urgently needed for the study of cardiovascular disease mechanisms, cell therapy, and drug screening. This study aims to explore the function and regulatory mechanism of the miR-148/152 family consisting of miR-148a, miR-148b, and miR-152 in hPSC-ECs, so as to provide new targets for improving EC function during the above applications. In comparison with the wild-type (WT) group, miR-148/152 family knockout (TKO) significantly reduced the endothelial differentiation efficiency of human embryonic stem cells (hESCs), and impaired the proliferation, migration, and capillary-like tube formatting abilities of their derived ECs (hESC-ECs). Overexpression of miR-152 partially restored the angiogenic capacity of TKO hESC-ECs. Furthermore, the mesenchyme homeobox 2 (MEOX2) was validated as the direct target of miR-148/152 family. MEOX2 knockdown resulted in partial restoration of the angiogenesis ability of TKO hESC-ECs. The Matrigel plug assay further revealed that the in vivo angiogenic capacity of hESC-ECs was impaired by miR-148/152 family knockout, and increased by miR-152 overexpression. Thus, the miR-148/152 family is crucial for maintaining the angiogenesis ability of hPSC-ECs, and might be used as a target to enhance the functional benefit of EC therapy and promote endogenous revascularization.

20.
Carcinogenesis ; 33(12): 2409-16, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23042301

RESUMO

Interleukin-23 receptor (IL-23R) is a key element in the T-helper 17 cell-mediated inflammatory process, which plays an important role in the pathogenesis of cancer. In this study, we examined whether genetic polymorphisms in IL-23R are associated with cancer risk in 4936 cancer patients and 5664 control subjects from eastern and southern Chinese populations. We found that the C allele of the rs10889677A>C polymorphism in the 3'-untranslated region of IL-23R was inversely associated with risk of multiple types of cancer, including breast cancer, lung cancer and nasopharyngeal carcinoma. Healthy controls who harbored the rs10889677C allele had significantly decreased cancer risk (odds ratio = 0.74, 95% confidence interval = 0.71-0.78) compared with those who harbored the rs10889677A allele. Biochemical analysis demonstrated that the rs10889677A allele disrupted the binding site for the microRNA miR-let-7f, thereby increasing the transcription of the IL-23R in vitro and in vivo. Furthermore, cancer-free individuals carrying the rs10889677CC homozygous genotype had a lower proportion of regulatory T cells (Tregs) and a higher T-cell proliferation rate upon stimulation with concanavalin A than individuals carrying the rs10889677AA homozygous genotype. Our findings indicate that the IL-23R rs10889677A>C polymorphism may influence T-cell proliferation, resulting in changes in the levels of Tregs in vivo and modifying cancer susceptibility.


Assuntos
Neoplasias da Mama/genética , Neoplasias Pulmonares/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Adulto , Neoplasias da Mama/etiologia , Neoplasias da Mama/imunologia , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Interleucina-17/sangue , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/etiologia , Neoplasias Nasofaríngeas/imunologia , Risco , Linfócitos T/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA