RESUMEN
Noncoding RNAs (ncRNAs) were initially thought to be transcriptional byproducts. However, recent advances of ncRNAs research have increased our understanding of the importance of ncRNA in gene regulation and disease pathogenesis. Consistent with these developments, liver fibrosis research is also experiencing rapid growth in the investigation of links between ncRNAs and the pathology of this disease. The initial focus was on studying the function and regulation mechanisms of microRNAs (miRNAs). However, recently, elucidation of the mechanisms of long noncoding RNAs (lncRNAs) and lncRNA-mediated liver fibrosis has just commenced. In this review, we emphasize on abnormal expression of lncRNAs in liver fibrosis. Furthermore, we also discuss that the interaction of lncRNAs with miRNAs is involved in the regulation of the expression of protein-coding genes in liver fibrosis. Recent advances in understanding dysregulated lncRNAs expression and the lncRNAs-miRNAs interaction in liver fibrosis will help for developing new therapeutic targets and biomarkers of liver fibrosis.
Asunto(s)
Cirrosis Hepática/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Biomarcadores/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Cirrosis Hepática/patologíaRESUMEN
Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-ß1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect. Furthermore, we found that Hotair may act as an endogenous 'sponge' of miR-148b, which regulates expression of the DNMT1/MEG3/p53 pathways in HSCs. Intriguingly, Hotair enhanced polycomb repressive complex 2 (PRC2) occupancy and histone H3K27me3 repressive marks, specifically at the MEG3 promoter region. Finally, we found that Hotair forms an RNA/DNA hybrid and recruits PRC2 to MEG3 promoter. These data suggest that Hotair inhibition may represent a promising therapeutic option for suppressing liver fibrosis.
Asunto(s)
Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/genética , ARN Largo no Codificante/genética , Regulación hacia Arriba , Animales , Línea Celular , ADN (Citosina-5-)-Metiltransferasa 1/genética , Epigénesis Genética , Regulación de la Expresión Génica , Células Estrelladas Hepáticas/patología , Humanos , Cirrosis Hepática/patología , Masculino , Ratones Endogámicos C57BL , MicroARNs/genéticaRESUMEN
Gliomas are the most common primary malignancy in the brain, accounting for 50-60%. Despite all the efforts of cytoreductive surgery in combination with intense chemoradiotherapy, glioma remains an incurable disease. Recent studies have shown that long noncoding RNAs (lncRNAs) are involved in the pathology of gliomas. LncRNAs are involved in many cellular processes, such as angiogenesis, invasion, cell proliferation, and apoptosis. In this review we focus on the dysregulation of lncRNAs in gliomas. We also address that epigenetic modification such as DNA methylation and microRNAs interact with lncRNAs in gliomas. In addition, the interaction of lncRNAs with signaling pathways in gliomas is discussed systematically, with particular emphasis on the interaction of lncRNAs with EZH2. Such approaches provide valuable insights into the potential future applications of lncRNAs in the treatment of gliomas.
Asunto(s)
Glioma/genética , Terapia Molecular Dirigida , Complejo Represivo Polycomb 2/genética , ARN Largo no Codificante/genética , Apoptosis/genética , Proliferación Celular/genética , Metilación de ADN/genética , Proteína Potenciadora del Homólogo Zeste 2 , Glioma/patología , Humanos , Invasividad Neoplásica/genética , Neovascularización Patológica/genética , Complejo Represivo Polycomb 2/biosíntesis , ARN Largo no Codificante/metabolismo , Transducción de SeñalRESUMEN
Malignant brain tumors are thought to be originate from a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues. Cancer stem cells (CSCs) have been identified in gliomas in which they are named as glioma stem cells (GSCs). GSCs, sharing some characteristics with normal neural stem cells (NSCs), contribute to the cellular origin for primary gliomas and the recurrence of malignant gliomas after current conventional therapy. Recently, increasing evidences have showed that miRNAs play a central role in GSCs. In this review we focus on the role of GSCs in gliomas and in the abnomal expression of miRNAs in GSCs. Furthermore, we also discuss epigenetic dysregulation of tumor-suppressor miRNAs by promoter DNA methylation is involved in the regulation of GSCs biology. Recent advances in understanding dysregulated expression of miRNAs and methylation of tumor-suppressor miRNAs in GSCs and their possible use as new therapeutic targets of gliomas.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Metilación de ADN , Glioma/metabolismo , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , Células-Madre Neurales/metabolismo , Animales , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Metilación de ADN/efectos de los fármacos , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/patología , Humanos , MicroARNs/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/patología , Regiones Promotoras GenéticasRESUMEN
DNA methylation at the 5-position of cytosine (5mC) in the mammalian genome has emerged as a pivotal epigenetic event that plays important roles in development, aging and disease. The three members of the TET protein family, which convert 5mC to 5-hydroxymethylcytosine, has provided a potential mechanism resulting in DNA demethylation and maintaining cellular identity. Recent studies have shown that epigenetic modifications play a key role in the regulation of the molecular pathogenesis of gliomas. In this review we focus on demonstrating the TET proteins in DNA demethylation and transcriptional regulation of different target genes. In addition, we address the role of TET proteins in gliomas. This review will provide valuable insights into the potential targets of gliomas, and may open the possibility of novel therapeutic approaches to this fatal disease.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Glioma/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Metilación de ADN , Proteínas de Unión al ADN , Dioxigenasas , Humanos , Oxigenasas de Función MixtaRESUMEN
Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a negative regulator of this process. PTEN promoter hypermethylation is a major epigenetic silencing mechanism in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in HSC activation and liver fibrosis. Treatment of activated HSCs with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) decreased aberrant hypermethylation of the PTEN gene promoter and prevented the loss of PTEN expression that occurred during HSC activation. Silencing DNA methyltransferase 1 (DNMT1) gene also decreased the PTEN gene promoter methylation and upregulated the PTEN gene expression in activated HSC-T6 cells. In addition, knockdown of DNMT1 inhibited the activation of both ERK and AKT pathways in HSC-T6 cells. These results suggest that DNMT1-mediated PTEN hypermethylation caused the loss of PTEN expression, followed by the activation of the PI3K/AKT and ERK pathways, resulting in HSC activation.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática Experimental/patología , Fosfohidrolasa PTEN/metabolismo , Animales , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , Decitabina , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Sistema de Señalización de MAP Quinasas , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Regulación hacia ArribaRESUMEN
Glioma invasion is a main cause of a poor prognosis and relapse in patients suffering from the disease. However, the molecular mechanisms responsible for glioma cell invasion remain poorly understood. In this study, the characteristics of exosomes were identified using electron microscope (TEM), and western blot analysis. The potential mechanism of long noncoding RNA (lncRNA) activated by TGFß (lncRNAATB) was demonstrated using luciferase reporter assays and RNA immunoprecipitation. We found that glioma cellderived exosomes promoted the activation of astrocytes and had the ability to shuttle long noncoding RNA (lncRNA) activated by TGFß (lncRNAATB) to astrocytes. More importantly, lncRNAATB activated astrocytes through the suppression of microRNA (miRNA or miR)2043p in an Argonaute 2 (Ago2)dependent manner. Furthermore, astrocytes activated by lncRNAATB in turn promoted the migration and invasion of glioma cells. Taken together, the findings of this study suggest that lncRNAATB may play an important role in modulating glioma microenvironment through exosomes. Thus, a better understanding of this process may provide implications for the prevention of highly invasive glioma.
Asunto(s)
Exosomas/genética , Glioma/genética , ARN Largo no Codificante/genética , Factor de Crecimiento Transformador beta/genética , Astrocitos/metabolismo , Astrocitos/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Humanos , MicroARNs/genética , Microscopía Electrónica , Invasividad Neoplásica/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Microambiente Tumoral/genéticaRESUMEN
The long non-coding RNA SPRY4-intronic transcript 1 (SPRY4-IT1) has been shown to promote the progression of cancer; however, the role of SPRY4-IT1 in glioma remains unclear. The present study demonstrated that SPRY4-IT1 expression was markedly increased in glioma tissues and cells compared with normal brain tissues, whereas knockdown of SPRY4-IT1 inhibited cell proliferation, migration, and invasion in U251 cells. Spindle and kinetochore associated complex subunit 2 (SKA2) was found to be a target of SPRY4-IT1 and was downregulated by SPRY4-IT1-knockdown. Additionally, SPRY4-IT1 expression was positively correlated with SKA2 in glioma tissues. To the best of our knowledge, the present study provides the first demonstration that SKA2 may have an oncogenic role in U251 cells. These results indicate that SPRY4-IT1 may serve a notable role in the molecular etiology of glioma and represents a potential target in glioma therapy.
RESUMEN
Malignant glioma is one of the most common primary human tumors in the central nervous system. The molecular mechanisms of the progression and development of glioma have been largely unexplored. In this study, we illustrated that the expression of Dok7 was downregulation in human glioma tissues. Dok7 overexpression significantly inhibits proliferation and colony formation in vitro, and the xenograft tumor formation in vivo. In addition, 5-Aza-2'-deoxycytidine (5-Aza), a DNA methylation inhibitor, preventing the loss of Dok7 expression by decreasing aberrant hypermethylation of Dok7 promoter in glioma cells. More importantly, DNMT1 knockdown induced the demethylation of Dok7 promoter, and enhanced the expression of Dok7 in gliomas. These results suggest that epigenetic silencing of Dok7 may provide a novel glioma treatment strategy.
Asunto(s)
Neoplasias Encefálicas/enzimología , Proliferación Celular , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Glioma/enzimología , Proteínas Musculares/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN , Epigénesis Genética , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/patología , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Proteínas Musculares/genética , Regiones Promotoras Genéticas , Transducción de Señal , Factores de Tiempo , Carga TumoralRESUMEN
Aberrant expression of miR-141 has recently implicated in the occurrence and development of various types of malignant tumors. However whether the involvement of miR-141 in the pathogenesis of glioma remains unknown. Here, we showed that miR-141 was markedly downregulated in glioma tissues and cell lines compared with normal brain tissues, and its expression correlated with the pathological grading. Enforced expression of miR-141 in glioma cells significantly inhibited cell proliferation, migration and invasion, whereas knockdown of miR-141 exerted opposite effect. Mechanistic investigations revealed that HOTAIR might act as an endogenous 'sponge' of miR-141, thereby regulating the derepression of SKA2. Further, we explored the molecular mechanism by which miR-141 expression was regulated, and found that the miR-141 promoter was hypermethylated and that promoter methylation of miR-141 was mediated by DNMT1 in glioma cells. Finally, both overexpression of miR-141 and knockdown of HOTAIR in a mouse model of human glioma resulted in significant reduction of tumor growth in vivo. Collectively, these results suggest that epigenetic modification of miR-141 and the interaction of ceRNA regulatory network will provide a new approach for therapeutics against glioma.
Asunto(s)
Neoplasias Encefálicas/genética , Proteínas Cromosómicas no Histona/genética , Metilación de ADN , Glioma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Regiones no Traducidas 3'/genética , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas Cromosómicas no Histona/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Glioma/patología , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Regiones Promotoras Genéticas/genética , Trasplante Heterólogo , Carga Tumoral/genéticaRESUMEN
BACKGROUND: Glioma is one of the most common and aggressive primary malignant tumor in the brain. Accumulating evidences indicated that aberrantly expressed non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), contribute to tumorigenesis. However, potential mechanisms between lncRNAs and miRNAs in glioma remain largely unknown. METHODS: Long non-coding RNA activated by TGF-ß (LncRNA-ATB) expression in glioma tissues and cells was quantified by quantitative reverse transcription-PCR. Glioma cell lines U251 and A172 were transfected with sh-ATB, miR-200a mimics, miR-200a inhibitors, after we assayed the cell phenotype and expression of the relevant molecules. Dual-luciferase reporter assay, RIP and a xenograft mouse model were used to examine the expression of sh-ATB and its target gene miR-200a. RESULTS: ATB is abnormally up-regulated both in glioma tissues and cell lines compared with normal brain tissues, and glioma patients with high ATB expression had shorter overall survival time. Knockdown of ATB significantly inhibits glioma malignancy, including cell proliferation, colony formation, migration, invasion in vitro, and the xenograft tumor formation in vivo. In addition, ATB was confirmed to target miR-200a, and miR-200a inhibition reversed the malignant characteristics of ATB knockdown on glioma cells. In particular, ATB may act as a ceRNA, effectively becoming a sink for miR-200a, thereby modulating the derepression of TGF-ß2. CONCLUSIONS: Our findings suggest that ATB plays an oncogenic role of glioma cells by inhibiting miR-200a and facilitating TGF-ß2 in glioma, thereby may represent a potential therapeutic target for the treatment of human glioma.
Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Regulación hacia Arriba , Adolescente , Adulto , Anciano , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Humanos , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Trasplante de Neoplasias , Pronóstico , Factor de Crecimiento Transformador beta2/genética , Adulto JovenRESUMEN
Epigenetic regulation plays a significant role in gliomas. However, how methylation and long non-coding RNA (lncRNA) cooperates to regulate gliomas progression is largely unknown. In this investigation we showed that the downregulation of MEG3 expression due to hypermethylation of MEG3 was observed in gliomas tissues. Treatment of glioma cells with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) decreased aberrant hypermethylation of the MEG3 promoter and prevented the loss of MEG3 expression. In addition, DNMT1 was involved in MEG3 promoter methylation, and was inversely correlated with MEG3 expression in gliomas. The inhibition of DNMT1 repressed the proliferation, clone formation, and induced apoptosis in glioma cells. Importantly, the inhibition of DNMT1 contributed to the activation of p53 pathways in gliomas cells. These results suggest that DNMT1-mediated MEG3 hypermethylation caused the loss of MEG3 expression, followed by the inhibition of the p53 pathways in gliomas.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Epigénesis Genética/genética , Represión Epigenética/genética , Glioma/genética , ARN Largo no Codificante/genética , Proteína p53 Supresora de Tumor/genética , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , ADN (Citosina-5-)-Metiltransferasa 1 , Metilación de ADN/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Regiones Promotoras Genéticas/genéticaRESUMEN
Melittin is a water-soluble toxic peptide derived from the venom of the bee. Although many studies show the anti-tumor activity of melittin in human cancer including glioma cells, the underlying mechanisms remain elusive. Here the effect of melittin on human hepatocelluar carcinoma HepG2 cell proliferation in vitro and further mechanisms was investigated. We found melittin could inhibit cell proliferation in vitro using Flow cytometry and MTT method. Besides, we discovered that melittin significantly downregulated the expressions of CyclinD1 and CDK4. Results of western Blot and Real-time PCR analysis indicated that melittin was capable to upregulate the expression of PTEN and attenuate histone deacetylase 2 (HDAC2) expression. Further studies demonstrated that knockdown of HDAC2 completely mimicked the effects of melittin on PTEN gene expression. Conversely, it was that the potential utility of melittin on PTEN expression was reversed in cells treated with a recombinant pEGFP-C2-HDAC2 plasmid. In addition, treatment with melittin caused a downregulation of Akt phosphorylation, while overexpression of HDAC2 promoted Akt phosphorylation. These findings suggested that the inhibitory of cell growth by melittin might be led by HDAC2-mediated PTEN upregulation, Akt inactivation, and inhibition of the PI3K/Akt signaling pathways.
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Carcinoma Hepatocelular/patología , Regulación hacia Abajo/efectos de los fármacos , Histona Desacetilasa 2/metabolismo , Neoplasias Hepáticas/patología , Meliteno/farmacología , Fosfohidrolasa PTEN/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Histona Desacetilasa 2/genética , Humanos , Fosfohidrolasa PTEN/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
INTRODUCTION: Gliomas are characterized by increased anaplasia, malignization, proliferation and invasion. They exhibit high resistance to standard treatment with combinations of radiotherapy and chemotherapy. They are currently the most common primary malignancy tumors in the brain that is related to a high mortality rate. Recently, increasing evidence suggests that EZH2 is involved in a number of glioma cell processes, including proliferation, apoptosis, invasion and angiogenesis. AREAS COVERED: In this review, we emphasize the role of EZH2 in gliomas. We also address that EZH2 interacting with DNA methylation mediates transcriptional repression of specific genes in gliomas, and the regulation of EZH2 by microRNAs in gliomas. EXPERT OPINION: Although the exact role of EZH2 in gliomas has not been fully elucidated, to understand the role of EZH2 proteins in epigenetic modification will provide valuable insights into the causes of gliomas, and pave the way to the potential future applications of EZH2 in the treatment of gliomas.
Asunto(s)
Epigénesis Genética , Glioma/genética , Complejo Represivo Polycomb 2/genética , Animales , Apoptosis/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Proliferación Celular/genética , Metilación de ADN/genética , Proteína Potenciadora del Homólogo Zeste 2 , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Glioma/terapia , Humanos , MicroARNs/genética , Invasividad NeoplásicaRESUMEN
Macrophages activation which releases the pro-inflammatory cytokines is an essential event in the process of inflammation. SOCS1 has been shown to act as a negative regulator of cytokine signals and plays a key role in the suppression of tissue injury and inflammatory diseases. DNA methylation mediated by specific DNA methyltransferases1 (DNMT1) which contributes to the epigenetic silencing of multiple genes. SOCS1 promoter hypermethylation is by far the best categorized epigenetic change in tumors. Our study with a view to investigate whether the loss of SOCS1 due to SOCS1 promoter methylation was involved in the course of inflammatory cytokines released from lipopolysaccharide (LPS)-stimulated macrophages. Here, we found that treatment of LPS-induced RAW264.7 macrophage cells with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-azadC) reduced aberrant promoter hypermethylation of SOCS1 and prevented the loss of the expression of SOCS1 in macrophages which secret inflammatory cytokines. Knockdown of DNMT1 gene not only attenuated the SOCS1 gene promoter methylation but also up-regulated the expression of SOCS1 in activated RAW264.7 cells. Furthermore, silencing of DNMT1 prevented the activation of JAK2/STAT3 pathway in LPS-induced RAW264.7 cells. These studies demonstrated that DNMT1-mediated SOCS1 hypermethylation caused the loss of SOCS1 expression results in negative regulation of activation of the JAK2/STAT3 pathway, and enhanced the release of LPS-induced pro-inflammatory cytokines such as TNF-α and IL-6 in macrophages.
Asunto(s)
Citocinas/inmunología , Metilación de ADN , Inflamación/inmunología , Macrófagos/inmunología , Transducción de Señal/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Animales , Azacitidina/análogos & derivados , Azacitidina/farmacología , Western Blotting , Línea Celular , Citocinas/análisis , Citocinas/genética , Decitabina , Epigénesis Genética/inmunología , Inflamación/genética , Activación de Macrófagos/inmunología , Ratones , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
Conversion of hepatic stellate cells (HSCs) into hepatic myofibroblasts is a necessary event during the development of liver fibrosis. DNA methyltransferase 1 (DNMT1), which catalyzes DNA methylation and subsequently leads to the transcriptional repression of profibrotic genes, is selectively induced in myofibroblasts from diseased livers. Treatment of HSC with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-azadC), prevented TGF-ß1-induced proliferation and alpha-smooth muscle actin (α-SMA) and collagen expression. 5-AzadC also rescued TGF-ß1-induced suppression of Smad7 expression which occurs during HSC activation. Similarly, silencing the expression of the DNMT1 gene ameliorated the suppression of Smad7 expression by TGF-ß1. In addition, DNMT1 inhibition, by 5-azadC or DNMT1 silencing, prevented the phosphorylation of Smad2 and Smad3. These studies suggest that epigenetic repression of Smad7 promotes the phosphorylation of Smad2 and Smad3 that may be an important molecular mechanism for perpetuated HSC activation and liver fibrosis.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/fisiología , Células Estrelladas Hepáticas/fisiología , Cirrosis Hepática Experimental/etiología , Proteína smad7/fisiología , Animales , ADN (Citosina-5-)-Metiltransferasa 1 , Epigénesis Genética , Masculino , Fosforilación , Ratas , Ratas Sprague-Dawley , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Proteína smad7/genética , Factor de Crecimiento Transformador beta1/farmacología , Cicatrización de HeridasRESUMEN
DNA methylation refers to a heritable alteration in the pattern of gene expression that is regulated by a mechanism specifically not owing to changes in the primary nucleotide sequence. The transcriptional silencing caused by DNA methylation affects genes involved in the main cellular pathways: cell cycle control, Ras signaling, apoptosis, and detoxification. Recent studies have shown that methylation modifications orchestrate the activation of hepatic stellate cells (HSCs) characterized by excessive accumulation of extracellular matrices (ECMs). The activation of HSCs is mediated by multiple signal transduction pathways and is generally regarded as the major ECM producer responsible for liver fibrosis. In addition, aberrant methylation of specific gene involved in the activation of multiple signal transduction pathways in liver fibrosis. The aim of this review is to compile recent information on aberrant DNA methylation in hepatic fibrosis and to highlight key genes and molecular pathways in hepatic fibrosis formation.
Asunto(s)
Metilación de ADN , ADN/metabolismo , Cirrosis Hepática/terapia , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Epigénesis Genética , Matriz Extracelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Inhibidor NF-kappaB alfa , Transducción de SeñalRESUMEN
Ion channels are important for the functions of excitable and non-excitable cells. Using the whole-cell patch clamp technique, we analyzed the electrophysiological and pharmacological properties of voltage-gated potassium channels in primary rat peritoneal macrophages. With intracellular solution contained K(+) as the main charge carrier, all cells showed outward currents in response to membrane depolarization. The currents can be inhibited by TEA (10 mM), a non-selective blocker for voltage-gated K(+) channels, and attenuated when intracellular K(+) was substituted with Cs(+). Changing holding potential from -80 to -30 mV or -10 mV also inhibited the outward currents. In contrast, increasing the concentration of ATP in the intracellular solution decreased the amplitude of the outward currents. Thus, rat peritoneal macrophages express several types of functional voltage-gated K(+) channels.
RESUMEN
Liver injury is induced by various insults such as alcohol abuse, if insults persist, may result in the formation of liver fibrosis. Hepatic stellate cell (HSC) activation and transdifferentiation into hepatic myofibroblast, accompanied with potent pro-inflammatory and pro-fibrogenic activities and the down-regulation of anti-inflammatory anti-fibrogenic in gene expression in coordination with epigenetic modifications at the level of the chromatin structure, are pivotal events in liver fibrogenesis. In this review we focus on the role of the methyl-CpG binding protein 2 (MeCP2) transcriptional regulation of different target genes and the interaction MeCP2 with microRNAs (miRNAs) during liver fibrosis. In addition, we address different signaling pathways interacted with MeCP2 regulated HSC activation. Such approaches provide valuable insights into the potential targets of liver fibrosis, and are useful pointers for the development of future therapeutic strategies.
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Cirrosis Hepática/metabolismo , Proteína 2 de Unión a Metil-CpG/fisiología , Animales , Humanos , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Transducción de Señal/genética , Transcripción Genética/genéticaRESUMEN
Epigenetics refers to the study of heritable changes in the pattern of gene expression that is controlled by a mechanism specifically not due to changes the primary DNA sequence. Well-known epigenetic mechanisms include DNA methylation, post-translational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (miRNAs). Recent studies have shown that epigenetic modifications orchestrate the hepatic stellate cell (HSC) activation and liver fibrosis. In this review we focus on the aberrant methylation of CpG island promoters of select genes is the prominent epigenetic mechanism to effectively silence gene transcription facilitating HSC activation and liver fibrosis. Furthermore, we also discuss epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation and the interaction of DNA methylation with miRNAs involved in the regulation of HSC activation and liver fibrosis. Recent advances in epigenetics alterations in the pathogenesis of liver fibrosis and their possible use as new therapeutic targets and biomarkers.