Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.429
Filtrar
1.
Medicine (Baltimore) ; 98(38): e17224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567981

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a common autoimmune disease of the central nervous system (CNS), and is associated with genetic factors. FOXP3 gene polymorphism has been reported as the risk factor for MS, however, previous studies have showed conflicting results. The purpose of this study is to investigate the association between FOXP3 gene polymorphism and the susceptibility to MS. METHODS: Pubmed, Embase, library of Cochrane, and Web of Science were used to search the eligible articles from January 1980 up to October 2018. The odds ratio (ORs) and its 95% confidence intervals (CI) were used to evaluate the strength of association. Allele model, homozygote model, heterozygote model, dominant model, and recessive model were used to evaluate the association between FOXP3 gene polymorphism and MS. RESULTS: A total of 5 studies contained 1276 MS patients and 1447 controls (for rs3761548) and 600 MS patients and 640 controls (for rs2232365) were enrolled in this meta-analysis. The association showed significant differences in allele and dominant model for rs3761548 polymorphism. In addition, a clear tendency to significance was detected in homozygote and recessive model for rs3761548 (P = .052). Subgroup analysis indicated a significant risk of MS in all genotype models but heterozygotes in Asians. CONCLUSION: FOXP3 gene polymorphism rs3761548 was associated with a higher MS risk, especially in Asians. This conclusion needs to be validated in more large samples and multiracial studies. LEVEL OF EVIDENCE: Level III diagnostic study.


Assuntos
Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Genes/genética , Humanos , Esclerose Múltipla/etiologia
2.
Life Sci ; 234: 116779, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430452

RESUMO

Emerging evidence has revealed that microRNAs (miRNAs) play critical roles in keloid pathogenesis. However, potential molecular mechanism of keloid formation remains unclear. In the present study, our findings showed that miR-152-3p mRNA expression level was notably up-regulated in keloid tissues and keloid fibroblasts compared with that of normal skin tissues and normal skin fibroblasts, respectively. Furthermore, miR-152-3p inhibition remarkably suppressed cell proliferation, which was increased by miR-152-3p overexpression. Cell invasion was also significantly decreased by miR-152-3p inhibition, whereas was increased by miR-152-3p overexpression. The mRNA and protein expression levels of extracellular matrix components including type I collagen, type III collagen and fibronectin were decreased by miR-152-3p inhibition, but were increased by miR-152-3p overexpression. In addition, results of dual-luciferase reporter assay indicated that FOXF1 is a direct target of miR-152-3p. FOXF1 overexpression significantly inhibits cell proliferation, invasion, and extracellular matrix in keloid fibroblasts, and the suppressive effects of miR-152-3p mimic on these functions were notably partly reversed by FOXF1 overexpression. Taken together, these findings indicated that miR-152-3p regulates cell proliferation, invasion and extracellular matrix expression through targeting FOXF1 in keloid fibroblasts, suggesting that miR-152-3p is a novel and promising molecular target for keloid treatment.


Assuntos
Matriz Extracelular/patologia , Fibroblastos/patologia , Fatores de Transcrição Forkhead/genética , Queloide/patologia , MicroRNAs/genética , Regiões 3' não Traduzidas , Adolescente , Adulto , Movimento Celular , Proliferação de Células , Células Cultivadas , Matriz Extracelular/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Queloide/genética , Regulação para Cima , Adulto Jovem
3.
Zhonghua Yi Xue Za Zhi ; 99(24): 1887-1892, 2019 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-31269585

RESUMO

Objective: To clarify the effect of FOXR2 on the proliferation and apoptosis of prostate cancer cells and to reveal the mechanism. Methods: The expression of FOXR2 in clinical samples of prostate cancer were detected by Quantitative Real-time PCR (qRT-PCR) and Western blotting. The CCK8 proliferation kit and the Annexin V-FITC apoptosis kit, flow cytometry were used to detect the proliferation and apoptosis of prostate cancer cells with or without the FOXR2 knockdown. Combined with the results of microRNA chip, we predicted the related miR-152 and detected the relationship between miR-152 and FOXR2 by luciferase reporter gene assay. The correlation between HOTAIR and miR-152 is clearly defined by software prediction and qRT-PCR. Results: FOXR2 had a relatively high expression in the prostate cancer tissue.The mRNA expression of FOXR2 is 4.9 times that of adjacent tissues, and the protein level was also significantly up-regulated. In the PC3 cell line, the specific knock-down of FOXR2 inhibits the proliferation of cells and promotes cell apoptosis. According to the microRNA chip results and luciferase reporter gene assay, we found miR-152 could regulate the expression of FOXR2; and FOXR2 3 'UTR had two miR-152 binding sites, all of which could control the expression of FOXR2. The results of LNCediting and qRT-PCR suggest that HOTAIR is negatively correlated with the expression of miR-152, and is involved in the regulation of miR-152 expression in prostate cancer. Conclusion: FOXR2 up-regulation can promote the proliferation and inhibit the apoptosis of prostate cancer cells because that HOTAIR restrains the expression of miR-152.


Assuntos
Fatores de Transcrição Forkhead/genética , MicroRNAs/genética , Neoplasias da Próstata , RNA Longo não Codificante/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino
4.
Gene ; 713: 143974, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31301484

RESUMO

An orthologous gene of SEPALLATA1, designated as IiSEP1, was isolated from Isatis indigotica. The genomic DNA of IiSEP1 is 3.1 Kb in length. The full-length cDNA of IiSEP1 is 1481 bp and contains a 756 bp ORF encoding a 251-amino-acid protein. Sequence comparison revealed that IiSEP1 belonged to the MADS-box gene family. IiSEP1 contains 7 exons and 6 introns, showing similar exon-intron structure with Arabidopsis SEP1. Phylogenetic analysis suggested that IiSEP1 belonged to AGL2/SEP subfamily and was likely to be an I. indigotica ortholog of Arabidopsis SEP1. Quantitative real-time PCR showed that IiSEP1 was predominantly expressed in the reproductive organs. Ectopic expression of IiSEP1 in Arabidopsis resulted in early flowering, accompanied with the reduction of inflorescence number and the production of terminal flower on the top of the main stems. Moreover, IiSEP1 overexpressing flowers generated numerous variations in phenotype. The sepals were changed into petal-sepal mosaic structures or displayed carpelloid features, and transparent ovules were formed in internal surface of these sepals. In addition, some flowers were constituted by sepals and pistil, but lacked petals and stamens. Taken together, IiSEP1 might play important roles in reproductive growth of I. indigotica and could affect the morphogenesis of flowers and fruits.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Flores/crescimento & desenvolvimento , Fatores de Transcrição Forkhead/genética , Isatis/crescimento & desenvolvimento , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Proteínas de Schizosaccharomyces pombe/genética , Sequência de Aminoácidos , Arabidopsis/genética , Flores/genética , Regulação da Expressão Gênica de Plantas , Isatis/genética , Proteínas de Domínio MADS/genética , Fenótipo , Plantas Geneticamente Modificadas/genética , Homologia de Sequência
6.
Mol Biol (Mosk) ; 53(3): 476-484, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184613

RESUMO

It is known that long (200-300 nucleotides and longer) non-protein-coding RNAs (ncRNAs) tissue-specifically expressed from the regulatory regions of developmental genes can regulate the transcription of the mRNA of these genes. In this study, an attempt is made to identify differentially expressed ncRNAs in the extended promoter region of the fork head (fkh) gene of the fruit fly Drosophila melanogaster. We investigated four preparations of the total RNA: from embryos, from adult flies (separately from females and males), and from the S2 cell line of cultured Drosophila cells. In the total RNA preparations from embryos and adult flies, the levels of fkh expression differed substantially, whereas in S2 cells its expression is not detected at all (shown in this work). We perform classical Northern blot analysis of gel-separated RNAs hybridized to a series of radioactively labeled DNA fragments corresponding to the adjacent and partially overlapping regions of the promoter region of the fkh gene. Several previously unknown differentially expressed ncRNAs are detected, including those in the regions overlapping with the previously detected regulatory elements (TRE1 and salivary gland enhancer sgE) and the transcription start site of the fkh gene. The collected data complement and clarify the results of the previously conducted RNA-seq experiments, in particular, in terms of the length of the detected RNAs. These results may serve as a foundation for further studies of the mechanisms of tissue-specific regulation of the fkh gene expression.


Assuntos
Northern Blotting , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/análise , RNA Longo não Codificante/genética , Animais , Linhagem Celular , Drosophila melanogaster/embriologia , Drosophila melanogaster/crescimento & desenvolvimento , Elementos Facilitadores Genéticos/genética , Feminino , Masculino , Especificidade de Órgãos
7.
J Cancer Res Clin Oncol ; 145(8): 2013-2025, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177386

RESUMO

PURPOSE: FOXP3 is a marker of the T regulatory (Treg) cell subset and drives its function and homeostasis. Its expression maintains the host immunosuppressive state that favors persistence of human papillomavirus (HPV) infection and squamous intraepithelial lesion (SIL) appearance. The present study evaluated the effects of the rs3761548 and rs2232365 intronic single-nucleotide variants (SNVs) and their haplotypes on HPV infection and SIL diagnosis in HPV-infected and -uninfected women. METHODS: HPV DNA-based detection in cervical specimens was performed by PCR. FOXP3 variants were genotyped by PCR-restriction fragment length polymorphism and haplotype recombination sites were inferred for 208 HPV-infected and 218 HPV-uninfected women diagnosed or not with low- or high-grade intraepithelial lesions of cervix. Case-control analyses were carried out by logistic regression adjusted for several socio-demographic, sexual lifestyle, and clinical data. RESULTS: The homozygous genotype of the rs3761548 variants (A/A) (related to decreased FOXP3 expression) may exert a protective role against HPV infection in women (ORAj: 0.60; 95% CI 0.36-0.99; p = 0.049) and was an independent predictor of protection against HSIL development (ORAdj: 0.28; 95% CI 0.11-0.68; p = 0.006). In addition, the homozygous genotype (G/G) of the rs2232365 variants (related to increased FOXP3 expression) was independently associated with the HPV infection (ORAdj: 2.10; 95% CI 1.06-4.15; p = 0.033). Haplotype analysis revealed no significant associations in our study. CONCLUSIONS: Our results reveal the significant and independent associations between FOXP3 genetic variants and susceptibility to HPV infection and SIL diagnosis and their role as biomarkers of HPV infection and cervical lesion management.


Assuntos
Fatores de Transcrição Forkhead/genética , Fatores Imunológicos/genética , Infecções por Papillomavirus/diagnóstico , Polimorfismo de Nucleotídeo Único , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Adulto , Brasil , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/diagnóstico , Neoplasia Intraepitelial Cervical/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Pessoa de Meia-Idade , Papillomaviridae/imunologia , Infecções por Papillomavirus/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Prognóstico , Fatores de Risco , Lesões Intraepiteliais Escamosas Cervicais/genética , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Adulto Jovem
8.
Scand J Immunol ; 90(4): e12800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31241785

RESUMO

Lymphatic malformations (LMs) are disfiguring congenital anomalies characterized by aberrant growth of lymphatic vessels. They are broadly categorized histopathologically as macrocystic and microcystic. Although sclerotherapy has shown some success in the treatment of macrocystic malformations, there has been less progress with developing treatment strategies for microcystic malformations. In this study, we characterized lymphatic endothelial cells isolated from lymphatic and lymphaticovenous malformations. When compared to cells from normal lymphatic vessels, we found that the primary cultured malformed cells are morphologically different and also exhibited differences in binding, proliferation, migration and tube formation. Transcriptome analysis identified several genes whose expression was substantially higher in malformed compared to normal lymphatic endothelium, including DIRAS3 and FOXF1. Further analysis of LM tissue samples revealed distinguishing gene expression patterns that could pave the way to understanding the molecular pathogenesis of LMs. Based on gene expression signatures, we propose a new hypothesis that the subtype of localized LMs could be formed because of disruptions in lymph node development.


Assuntos
Linfonodos/crescimento & desenvolvimento , Anormalidades Linfáticas/genética , Vasos Linfáticos/patologia , Transcriptoma , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Linfonodos/embriologia , Cultura Primária de Células , Ligação Proteica , Análise Serial de Tecidos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas rho de Ligação ao GTP/genética
9.
BMC Med Genet ; 20(1): 65, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046704

RESUMO

BACKGROUND: Mutations in the coding region of FOXP2 are known to cause speech and language impairment. However, it is not clear how dysregulation of the gene contributes to language deficit. Interestingly, microdeletions of the region downstream the gene have been associated with cognitive deficits. METHODS: Here, we investigate changes in FOXP2 expression in the SK-N-MC neuroblastoma human cell line after deletion by CRISPR-Cas9 of two enhancers located downstream of the gene. RESULTS: Deletion of any of these two functional enhancers downregulates FOXP2, but also upregulates the closest 3' gene MDFIC. Because this effect is not statistically significant in a HEK 293 cell line, derived from the human kidney, both enhancers might confer a tissue specific regulation to both genes. We have also found that the deletion of any of these enhancers downregulates six well-known FOXP2 target genes in the SK-N-MC cell line. CONCLUSIONS: We expect these findings contribute to a deeper understanding of how FOXP2 and MDFIC are regulated to pace neuronal development supporting cognition, speech and language.


Assuntos
Elementos Facilitadores Genéticos , Fatores de Transcrição Forkhead/genética , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Células HEK293 , Humanos
10.
Life Sci ; 228: 128-134, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31054270

RESUMO

AIMS: Forkhead box (FOX) proteins constitute a huge family of transcriptional regulators, which are involved in a wide range of cancers. FOXK1 is a little studied member of FOXK subfamily. This study aimed to investigate the potential prognostic value of FOXK1 in human hepatocellular carcinoma (HCC) and explore potential underlying mechanisms. MAIN METHODS: We performed bioinformatic analyses to evaluate the prognostic value of FOXK1 expression in human HCC and to reveal the underlying mechanism by which FOXK1 regulates HCC. RT-PCR, FACS analysis and sphere formation assay were carried out to investigate the role of FOXK1 in regulating liver cancer stem cells. KEY FINDINGS: Our results demonstrated that FOXK1 was overexpressed in human HCC and positively correlated with cancer progression. DNA hypomethylation and gene copy number variation contributed to the overexpression of FOXK1. Importantly, high FOXK1 expression was associated with both low overall survival probability (OS) and low relapse free survival probability (RFS) of HCC patients. Intriguingly, we found that high FOXK1 expression was correlated with activation of stem cell-regulating pathways in human HCC. Knockdown of FOXK1 resulted in downregulation of the cancer stem cell marker EpCAM and ALDH1 and decreased sphere-forming ability of hepatocellular carcinoma cells. SIGNIFICANCE: Overall, our study identified FOXK1 as a new biomarker for prognosis of HCC patients and revealed its role in regulating stemness of hepatocellular carcinoma cells.


Assuntos
Carcinoma Hepatocelular/genética , Fatores de Transcrição Forkhead/genética , Neoplasias Hepáticas/genética , Regulação para Cima , Adulto , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Metilação de DNA , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
11.
Gene ; 706: 62-68, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31048069

RESUMO

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant entity characterized by eyelid malformations and caused by mutations in the forkhead box L2 (FOXL2) gene. Clinical and genetic analyses of large cohorts of BPES patients from different ethnic origins are important for a better characterization of FOXL2 mutational landscape. The purpose of this study is to describe the phenotypic features and the causal FOXL2 variants in a Mexican cohort of BPES patients. A total of 12 individuals with typical facial findings were included. Clinical evaluation included palpebral measurements and levator function assessment. The complete coding sequence of FOXL2 was amplified by PCR and subsequently analyzed by Sanger sequencing. A total of 11 distinct FOXL2 pathogenic variants were identified in our cohort (molecular diagnostic rate of 92%), including 5 novel mutations. Our results broaden the BPES-related mutational spectrum and supports considerable FOXL2 allelic heterogeneity in our population.


Assuntos
Blefarofimose/genética , Proteína Forkhead Box L2/genética , Anormalidades da Pele/genética , Anormalidades Urogenitais/genética , Adolescente , Adulto , Blefarofimose/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Pálpebras/metabolismo , Feminino , Proteína Forkhead Box L2/fisiologia , Fatores de Transcrição Forkhead/genética , Humanos , Lactente , Recém-Nascido , Masculino , México , Pessoa de Meia-Idade , Mutação , Fenótipo , Anormalidades da Pele/fisiopatologia , Anormalidades Urogenitais/fisiopatologia
12.
DNA Cell Biol ; 38(6): 583-591, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30994379

RESUMO

Atherosclerosis is a chronic vascular inflammatory disease that involves diverse cell types and circulating regulatory factors, including intercellular adhesion molecule (ICAM)-1, a proinflammatory cytokine. Lipopolysaccharides (LPS) increase ICAM-1 expression and promote cell adhesion, but the mechanism is not clear. We found that LPS induced time- and dose-regulated upregulation of ICAM-1 expression and downregulation of forkhead box protein C2 (Foxc2) expression in human umbilical vein endothelial cells (HUVECs). Overexpression of Foxc2 significantly inhibited both LPS-induced ICAM-1 expression in HUVECs and LPS-induced adhesion of THP-1 cells to HUVECs. Foxc2 siRNA dramatically increased both LPS-induced ICAM-1 expression and LPS-induced adhesion of THP-1 human monocytes cells to HUVECs. We conclude that Foxc2 inhibited LPS-induced adhesion of THP-1 cells to HUVECs by suppressing ICAM-1 expression in HUVECs.


Assuntos
Adesão Celular , Fatores de Transcrição Forkhead/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/genética , Lipopolissacarídeos/farmacologia , RNA Mensageiro/metabolismo
13.
Cell Biochem Funct ; 37(4): 239-244, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017311

RESUMO

For women, breast cancer is the most commonly diagnosed cancer and the leading cause of women deaths due to cancer. In recent years, increasing long noncoding RNA (lncRNA) has been discovered to be related to tumorigenesis, progression, and prognosis. FOXD3-AS1 is a lncRNA and has been identified as a cancer-promoting gene in glioma. By analysing the FOXD3-AS1 expression in The Cancer Genome Atlas (TCGA) database, we found that FOXD3-AS1 has significantly high expression in breast cancer tumour comparing with the normal tissue. And patients with low FOXD3-AS1 expression had greater survival probability, smaller tumour size, and less distant metastasis. This leads us to peep inquisitively biological function of FOXD3-AS1 in breast cancer. Biological assays demonstrated that silenced FOXD3-AS1 impaired cell proliferation and inhibited cell migration and invasion in breast cancer cell lines (BT549, MDA-MB-231). These results suggest that FOXD3-AS1 could play a potential diagnostics or prognostic biomarker for patients with breast cancer. SIGNIFICANCE OF THE STUDY: We demonstrated that lncRNA FOXD3-AS1 has significantly high expression in breast cancer cell lines comparing with the normal tissue. Besides, our findings suggested that lncRNA FOXD3-AS1 could play a potential diagnostics or prognostic biomarker for patients with breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/genética , Progressão da Doença , Fatores de Transcrição Forkhead/genética , Invasividade Neoplásica/genética , RNA Longo não Codificante/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais Cultivadas , Regulação para Cima
14.
J Exp Clin Cancer Res ; 38(1): 153, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971290

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is the major histological type of liver cancer with high morbidity and mortality worldwide. Long noncoding RNAs (lncRNA) has been proved to be associated with various cancer types, while its regulation in HCC is largely unknown. METHODS: To figure out the specific role of lncRNA EPB41L4A-AS2 in HCC. Fluorescence in situ hybridization (FISH) was first used to determine the cellular sublocalization of EPB41L4A-AS2 to determine its primary mode of action. QRT-PCR, Western blot and hematoxylin-eosin staining were then used to measure the expression of genes in cells and tissues. Cell proliferation and invasion assays were performed to determine the effects of EPB41L4A-AS2, miR-301a-5p and FOXL1 on the malignant phenotype of tumor cells. With luciferase reporter assay, the direct interaction between target genes were further confirmed for research on molecular mechanism. Finally, the mice hepatocarcinoma model was also established to disclose the tumor suppressor effects of EPB41L4A-AS2 in vivo. RESULTS: Here, we have identified a novel lncRNA EPB41L4A-AS2, which is significantly downregulated both in HCC cells and tissues, and plays a negative regulatory role in HCC proliferation and invasion. Mechanistically, cytoplasmic lncRNA EPB41L4A-AS2 functions as an efficient miR-301a-5p sponge, thereby release the expression inhibition of forkhead box L1 (FOXL1). Indeed, lncRNA EPB41L4A-AS2 inhibits proliferation and migration by upregulating FOXL1 expression and FOXL1 was confirmed as a direct target of miR-301a-5p. MiR-301a-5p shows an inverse correlation with EPB41L4A-AS2 expression and was verified as a direct target of EPB41L4A-AS2 as well. Correspondingly, FOXL1 and miR-301a-5p show opposite biological effects in cell proliferation and migration. Moreover, miR-301a-5p overexpression rescued the EPB41L4A-AS2 upregulation induced depression in proliferation, migration and invasion of HCC cells, as well as promotion effect on FOXL1 expression. Also, in vivo experiments proved that EPB41L4A-AS2 suppress tumor growth and extrahepatic metastasis (lung) via the miR-301a-5p-FOXL1 axis. CONCLUSIONS: Taken together, this research revealed a concrete mechanism of lncRNA EPB41L4A-AS2 in HCC, which may serve as a potential biomarkers and novel therapeutic targets for further clinical application.


Assuntos
Carcinoma Hepatocelular/genética , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Fatores de Transcrição Forkhead/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética
15.
Nat Commun ; 10(1): 1823, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015452

RESUMO

Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 µm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.


Assuntos
Linfócitos B/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculoma/imunologia , Tuberculose Pulmonar/imunologia , Animais , Linfócitos B/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/metabolismo , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/isolamento & purificação , RNA Mensageiro/isolamento & purificação , Fatores de Tempo , Tuberculoma/microbiologia , Tuberculoma/patologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
16.
Med Sci Monit ; 25: 2169-2178, 2019 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-30904920

RESUMO

BACKGROUND Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat colon cancer. Despite impressive initial clinical responses, drug resistance has dramatically compromised the effectiveness of DOX. However, the underlying mechanisms of chemotherapeutic resistance in colon cancer remain poorly understood. MATERIAL AND METHODS In this study, we compared the expression of miR-222-3p in DOX-resistant colon cancer cells (LoVo/ADR) with the corresponding DOX-sensitive parental cells (LoVo/S) using quantitative real-time PCR. In addition, miR-222-3p inhibitors were infected into LoVo/ADR cell lines and the effects of this treatment were assessed. The Cell Counting Kit 8 assay was employed to verify the sensitivity of colon cancer cell lines to DOX. EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry, and in vivo subcutaneous tumorigenesis were used to assess cell proliferation and apoptosis. Transwell and wound healing assays were used to investigate cell migration after adding DOX. Additionally, the expression of forkhead box protein P2 (FOXP2), P-glycoprotein (P-gp) and caspase pathway-associated markers was assessed by western blotting. RESULTS Our results showed that miR-222-3p was upregulated in LoVo/ADR compared with the expression in LoVo/S cells. Additionally, downregulation of miR-222-3p in LoVo/ADR cells increased their sensitivity to DOX, reduced P-gp expression, and activated the caspase pathway. However, the downregulation of FOXP2 could efficiently reverse the effect of miR-222-3p inhibitors on LoVo/ADR cells. CONCLUSIONS Taken together, our results showed that miR-222-3p induced DOX resistance via suppressing FOXP2, upregulating P-gp, and inhibiting the caspase pathway.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Doxorrubicina/farmacologia , Fatores de Transcrição Forkhead/metabolismo , MicroRNAs/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação para Baixo/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Fatores de Transcrição Forkhead/genética , Humanos , MicroRNAs/genética , Ativação Transcricional , Regulação para Cima/efeitos dos fármacos
17.
BMC Cancer ; 19(1): 261, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902074

RESUMO

BACKGROUND: The immune system is a crucial component in cancer progression or regression. Molecular iodine (I2) exerts significant antineoplastic effects, acting as a differentiation inductor and immune modulator, but its effects in antitumor immune response are not elucidated. METHODS: The present work analyzed the effect of I2 in human breast cancer cell lines with low (MCF-7) and high (MDA-MB231) metastatic potential under both in vitro (cell proliferation and invasion assay) and in vivo (xenografts of athymic nude mice) conditions. RESULTS: In vitro analysis showed that the 200 µM I2 supplement decreases the proliferation rate in both cell lines and diminishes the epithelial-mesenchymal transition (EMT) profile and the invasive capacity in MDA-MB231. In immunosuppressed mice, the I2 supplement impairs implantation (incidence), tumoral growth, and proliferation of both types of cells. Xenografts of the animals treated with I2 decrease the expression of invasion markers like CD44, vimentin, urokinase plasminogen activator and its receptor, and vascular endothelial growth factor; and increase peroxisome proliferator-activated receptor gamma. Moreover, in mice with xenografts, the I2 supplement increases the circulating level of leukocytes and the number of intratumoral infiltrating lymphocytes, some of them activated as CD8+, suggesting the activation of antitumor immune responses. CONCLUSIONS: I2 decreases the invasive potential of a triple negative basal cancer cell line, and under in vivo conditions the oral supplement of this halogen activates the antitumor immune response, preventing progression of xenografts from laminal and basal mammary cancer cells. These effects allow us to propose iodine supplementation as a possible adjuvant in breast cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Imunidade Celular/efeitos dos fármacos , Iodo/farmacologia , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Iodo/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Nus , Camundongos Transgênicos , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Biochim Biophys Acta Gene Regul Mech ; 1862(4): 493-508, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30831269

RESUMO

Leukocyte integrin-dependent downregulation of the transcription factor FOXP1 is required for monocyte differentiation and macrophage functions, but the precise gene regulatory mechanism is unknown. Here, we identify multi-promoter structure (P1, P2, and P3) of the human FOXP1 gene. Clustering of the ß2-leukocyte integrin Mac-1 downregulated transcription from these promoters. We extend our prior observation that IL-1 receptor-associated kinase 1 (IRAK1) is physically associated with Mac-1 and provide evidence that IRAK1 is a potent suppressor of human FOXP1 promoter. IRAK1 reduced phosphorylation of histone deacetylase 4 (HDAC4) via inhibiting phosphorylation of calcium/calmodulin dependent protein kinase II delta (CaMKIIδ), thereby promoting recruitment of HDAC4 to P1 chromatin. A novel human FOXP1 intronic transcript 1 (FOXP1-IT1) long non-coding RNA (lncRNA), whose gene is embedded within that of FOXP1, has been cloned and found to bind directly to HDAC4 and regulate FOXP1 in cis manner. Overexpression of FOXP1-IT1 counteracted Mac-1 clustering-dependent downregulation of FOXP1, reduced IRAK1 downregulation of HDAC4 phosphorylation, and attenuated differentiation of THP-1 monocytic cells. In contrast, Mac-1 clustering inhibited FOXP1-IT1 expression with reduced binding to HDAC4 as well as phosphorylation of CaMKIIδ to activate the IRAK1 signaling pathway. Importantly, both IRAK1 and HDAC4 inhibitors significantly reduced integrin clustering-triggered downregulation of FOXP1 expression in purified human blood monocytes. Identification of this Mac-1/IRAK-1/FOXP1-IT1/HDAC4 signaling network featuring crosstalk between lncRNA and epigenetic factor for the regulation of FOXP1 expression provides new targets for anti-inflammatory therapeutics.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Antígeno de Macrófago 1/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/genética , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diferenciação Celular , Linhagem Celular , Cromatina/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Histona Desacetilases/metabolismo , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Transcrição Genética
19.
Mucosal Immunol ; 12(3): 746-760, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872761

RESUMO

CD4+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREG cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREG cell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adaptation of TREG cells. Through respiratory infection models, we show that the IL-33 receptor (ST2) and the IL-1 receptor (IL1R1) selectively identify stable and unstable TREG cells at mucosal surfaces, respectively. IL-33, not IL-1, is specifically required for maintaining the suppressive function of TREG cells. In the absence of ST2, TREG cells are prone to lose Foxp3 expression and acquire RORγT and IL1R1, while, in the absence of IL-1R1, they maintain Foxp3 expression and resist the acquisition of a Th17 phenotype. Finally, lack of IL-1 signalling enhances the accumulation of ST2+ TREG over pro-inflammatory TREG cells in a Cryptococcus neoformans infection. These observations show that IL-1 and IL-33 exert opposing functions in controlling the functional adaptation of TREG cells, ultimately dictating the dynamics of adaptive immunity to pathogens.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Mucosa Respiratória/imunologia , Linfócitos T Reguladores/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Tolerância Imunológica , Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Tipo I de Interleucina-1/genética
20.
Gen Comp Endocrinol ; 277: 56-65, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30878349

RESUMO

Unlike its paralog Foxl2, which is well known for its role in ovarian development in vertebrates, the function of Foxl3 is still unclear. Foxl3 is an ancient duplicated copy of Foxl2. It is present as a single copy in ray-finned fish. But, due to repeated losses, it is absent in most tetrapods. Our transcriptomic data, however, show that two Foxl3s (Foxl3a and its paralog Foxl3b) are present in Japanese eel. Foxl3a is predominantly expressed in the pituitary, and Foxl3b is predominantly expressed in the gills. Both Foxl3s show a sex-dimorphic expression, being higher expression in testes than in ovaries. Moreover, Foxl3a and Foxl3b were exclusively expressed during gonadal differentiation in control eels (100% male). Conversely, Foxl3a and Foxl3b significantly decreased after gonadal differentiation in E2-treated eels (100% female). Furthermore, in accordance the difference in adhesive ability between somatic cells and germline cells in testes, Foxl3s showed a high expression in suspension cells (putative germline cells) and low expression in adhesive cells (putative somatic cells). In situ hybridization further showed that Foxl3a and Foxl3b were expressed in the testicular germline cells. In addition, Foxl3s expression was not changed by sex steroids in in vitro testes culture. Taken together, our results suggest that the teleost-specific Foxl3 paralog was repeatedly lost in most fish after the third round of whole genome duplication. The two germline-expressed Foxl3s had higher expression levels in males than in females during gonadal differentiation in Japanese eel. These results demonstrated that Foxl3s might play an important role in germline sexual fate determination from ancient fish to modern fish.


Assuntos
Anguilla/genética , Anguilla/fisiologia , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas/metabolismo , Gônadas/fisiologia , Diferenciação Sexual/fisiologia , Sequência de Aminoácidos , Animais , Tamanho Corporal/efeitos dos fármacos , Estradiol/farmacologia , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Células Germinativas/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Masculino , Filogenia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Diferenciação Sexual/efeitos dos fármacos , Diferenciação Sexual/genética , Esteroides/farmacologia , Testículo/citologia , Testículo/efeitos dos fármacos , Testículo/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA