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1.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188353, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32112817

RESUMO

Glioma is the most common primary malignant tumor in the human brain. Although there are a variety of treatments, such as surgery, radiation and chemotherapy, glioma is still an incurable disease. Super-enhancers (SEs) are implicated in the control of tumor cell identity, and they promote oncogenic transcription, which supports tumor cells. Inhibition of the SE complex, which is required for the assembly and maintenance of SEs, may repress oncogenic transcription and impede tumor growth. In this review, we discuss the unique characteristics of SEs compared to typical enhancers, and we summarize the recent advances in the understanding of their properties and biological role in gene regulation. Additionally, we highlight that SE-driven lncRNAs, miRNAs and genes are involved in the malignant phenotype of glioma. Most importantly, the application of SE inhibitors in different cancer subtypes has introduced new directions in glioma treatment.

2.
Int J Biol Sci ; 16(4): 671-681, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32025214

RESUMO

Background: Activation of macrophages and infiltration are key events in acute liver injury (ALI). Kv1.3 plays an important role in regulating immunologic functions of macrophages and is extensively recognized as a potential ion channel for immunological diseases. Objective: We hypothesized that blockage of Kv1.3 may influence ALI by inhibiting macrophages infiltration in damaged liver tissues. Methods: Margatoxin was administered into the peritoneal cavity of ALI mice. The impact of this treatment on ALI and macrophage migration in vivo and in vitro was determined using immunohistochemistry, transwell migration, and wound healing assays. Results: MgTX treatment alleviated ALI in mice, as evidenced by reduced macrophage infiltration in liver tissues and lower serum levels of liver ALT and AST. RNA-seq profiling analysis showed that the most obvious change by MgTX treatment was downregulation of δ-catenin, a protein known to be associated with macrophage migration. The effect of MgTX on macrophage migration and involvement of δ-catenin was confirmed by transwell and wound healing assays. Overexpression of δ-catenin in RAW264.7 cells promoted migration, an event that was suppressed upon silencing of δ-catenin. Mechanistically, the expression of RhoA was regulated by the overexpression or knockdown of δ-catenin. Conclusion: These findings suggest a role for blockage of Kv1.3 channel in macrophage migration and reveal a new target in the treatment of ALI.

3.
Mol Biol Rep ; 47(1): 433-441, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31637620

RESUMO

Glioma is the most aggressive primary brain tumor. We have previously provided evidence that IFITM3 promoted glioma cells migration. However, the mechanism of how IFITM3 regulates glioma cells invasion and whether IFITM3 participates in TGF-ß-mediated glioma invasion are still unknown. In this paper, we proved that IFITM3 was notably up-regulated in glioma tissues. Knockdown of IFITM3 suppressed STAT3 phosphorylation in vitro, and a specific STAT3 inhibitor AG490 reversed IFITM3-induced invasion of glioma cells. Furthermore, IFITM3 expression was induced by TGF-ß in glioma and IFITM3 knockdown abolished TGF-ß-mediated glioma cells invasion. Collectively, the results indicate that IFITM3/STAT3 axis may promote TGF-ß-induced glioma cells invasion. This study provided some suggestions for the clinical treatment of the brain tumor.

4.
Cell Signal ; 65: 109460, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31678253

RESUMO

BACKGROUND: Although gankyrin has been identified as a vital regulator of tumorigenesis, its role and regulatory mechanism in osteosarcoma (OS) remain unclear. METHODS: QRT-PCR, western blot and IHC staining were conducted to detect the expression of gankyrin in OS. Pearson's χ² test was adopted to examine the associations between gankyrin expression and clinicopathologic characteristics. Kaplan-Meier method was used to investigate the relationship between gankyrin expression and overall survival of patients with OS. Next, a series of in vitro and in vivo assays were performed to determine the positive feedback loop between gankyrin and YAP in OS. RESULTS: We first reported that gankyrin is upregulated in human OS specimens and cell lines and predicts OS progression and poor prognosis. Furthermore, we demonstrated that gankyrin protects miR-200a-mediated yes-associated protein (YAP) downregulation through p53 and establishes a positive feedback loop to regulate YAP signaling in U2OS and MG63 cells. Intriguingly, gankyrin interacts with YAP to promote OS cell growth in vitro. In addition, our results showed that gankyrin promotes OS tumor growth and regulates YAP levels in vivo. Notably, we also observed a positive correlation between gankyrin and YAP expression in human OS tissues, and co-upregulation of gankyrin and YAP indicated a poor prognosis. CONCLUSIONS: Our results identify that gankyrin acts as an oncogene in OS by forming a positive feedback loop with YAP, and disrupting the gankyrin-YAP regulation may be beneficial for controlling OS tumorigenesis.

5.
J Exp Clin Cancer Res ; 38(1): 366, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429770

RESUMO

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) has been linked to the regulation of glioma progression. However, the underlying signaling mechanisms that regulate EMT are poorly understood. METHODS: Quantitative real-time PCR (RT-qPCR) and western blot were performed to detect the expression of MeCP2 in glioma tissues and cell lines. MeCP2 functions were tested with cell immunofluorescence staining and western blot. For in vivo experiments, mouse xenograft model was used to investigate the effects of MeCP2 on glioma. ChIP and Co-IP were used to detect the relationships among MeCP2, miR-200c and Suv39H1. RESULTS: In this study, we found that MeCP2 was frequently up-regulated in human glioma tissues and cell lines. MeCP2 knockdown remarkably induced cell epithelial phenotype and inhibited mesenchymal marker ZEB1 and ZEB2 in vitro and in vivo. In addition, MeCP2 in glioma tissues was negatively correlated with miR-200c expression, and miR-200c overexpression partially abrogated mesenchymal phenotype induced by MeCP2. More importantly, we showed that MeCP2 recruited H3K9 to the promoter of miR-200c by interacting with SUV39H1, resulting in EMT of glioma cells. CONCLUSIONS: This study for the first time reveals MeCP2 as a novel regulator of EMT in glioma and suggest that MeCP2 inhibition may represent a promising therapeutic option for suppressing EMT in glioma.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Repressão Epigenética , Transição Epitelial-Mesenquimal , Glioma/patologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , MicroRNAs/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Cell Physiol ; 234(12): 23302-23314, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31140621

RESUMO

Glioma constitutes the most aggressive primary intracranial malignancy in adults. We previously showed that long noncoding RNA activated by TGF-ß (lncRNA-ATB) promoted the glioma cells invasion. However, whether lncRNA-ATB is involved in TGF-ß-mediated invasion of glioma cells remains unknown. In this study, quantitative real-time polymerase chain reaction and western blot analysis were used for detecting the mRNA and protein expression of related genes, respectively. Transwell assay was performed to assess the impact of lncRNA-ATB on TGF-ß-induced glioma cells migration and invasion. Immunofluorescence staining was utilized to characterize related protein distribution. Results showed that TGF-ß upregulated lncRNA-ATB expression in glioma LN-18 and U251 cells. Overexpression of lncRNA-ATB activated nuclear factor-κB (NF-κB) pathway and promoted P65 translocation into the nucleus, thus facilitated glioma cells invasion stimulated by TGF-ß. Similarly, lncRNA-ATB markedly enhanced TGF-ß-mediated invasion of glioma cells through activation P38 mitogen-activated protein kinase (P38/MAPK) pathway. Moreover, both the NF-κB selected inhibitor pyrrolidinedithiocarbamate ammonium and P38/MAPK specific inhibitor SB203580 partly reversed lncRNA-ATB induced glioma cells invasion mediated by TGF-ß. Collectively, this study revealed that lncRNA-ATB promotes TGF-ß-induced glioma cell invasion through NF-κB and P38/MAPK pathway and established a detailed framework for understanding the way how lncRNA-ATB performs its function in TGF-ß-mediated glioma invasion.

7.
J Cell Physiol ; 234(3): 2194-2203, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30229908

RESUMO

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.


Assuntos
Cirrose Hepática/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Biomarcadores/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Cirrose Hepática/patologia
8.
Int J Oncol ; 54(2): 713-721, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30483768

RESUMO

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.


Assuntos
Exossomos/genética , Glioma/genética , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/genética , Astrócitos/metabolismo , Astrócitos/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , MicroRNAs/genética , Microscopia Eletrônica , Invasividade Neoplásica/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Microambiente Tumoral/genética
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 34(10): 931-936, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30554587

RESUMO

Objective To investigate the clinical application value of circulating miR-29a in diagnosis and prognosis monitoring in acute pancreatitis (AP) patients, and to preliminary explore the molecular pathology significance of high expression of miR-29a. Methods 30 cases of mild acute pancreatitis (MAP) patients (MAP group) and 30 cases of moderately serve acute pancreatitis (MSAP) or serve acute pancreatitis (SAP) patients ( M-SAP group) were randomly selected, and 30 cases of healthy adults were used as control group. The general clinical data of each group were compared, and miR-29a levels in peripheral blood were measured by real tome quantitative PCR, then the correlation between miR-29a levels and Ranson score or APACHEIIscore were analyzed. The clinical usefulness of miR-29a for AP patients was assessed by ROC curve analysis. AR42J cells were treated with deoxycholic acid (DCA) to establish AP cell model, the expression levels of miR-29a and caspase-3 were detected. AR42J cells were transfected by lentiviral vector contain miR-29a mimic or miR-29a AMO and measured of expression levels of miR-29a and caspase-3. Results In acute phase, the expression of circulating miR-20a was up-regulated in MAP and M-SAP group patients, and miR-20a levels of M-SAP group patients were higher than MAP group patients. In same group, miR-20a levels in acute phase were higher than recovery phase. Correlation analysis indicated the positive correlation between miR-20a levels and Ranson score or APACHEII score. ROC curve analysis indicated that the AUC of miR-29a for diagnosis MAP patients was 0.961 ( 95%CI: 0.921~ 1.002), cut-off value was 1.460. The AUC of miR-29a for diagnosis M-SAP patients was 0.972 ( 95%CI: 0.939 ~ 1.004), cut-off value was 1.340. The expression levels of miR-29a and caspase 3 were increased in AP cell model. Moreover, caspase 3 levels in AP cell model were increased than vector control after overexpression of miR-29a, and caspase-3 levels were reduced than vector control after suppressing of miR-29a expression. Conclusion Circulating miR-29a is high expression in MAP and M-SAP patients, and high expression of miR-29a may relate to pancreatic acinar cell apoptosis, and this biomarkers has high clinical value in AP diagnosis and prognosis monitoring.


Assuntos
MicroRNAs/sangue , Pancreatite/sangue , Doença Aguda , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Caspase 3/sangue , Humanos , Pancreatite/diagnóstico , Prognóstico , Índice de Gravidade de Doença , Regulação para Cima
10.
Biomed Pharmacother ; 106: 678-685, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29990858

RESUMO

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.


Assuntos
Neoplasias Encefálicas/enzimologia , Proliferação de Células , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Glioma/enzimologia , Proteínas Musculares/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA , Epigênese Genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Musculares/genética , Regiões Promotoras Genéticas , Transdução de Sinais , Fatores de Tempo , Carga Tumoral
11.
Oncol Lett ; 15(3): 3977-3984, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29467908

RESUMO

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.

12.
Biomed Pharmacother ; 94: 774-780, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28802229

RESUMO

Human gliomas are related to high rates of morbidity and mortality. TGF-ß promotes the growth of glioma cells, and correlate with the degree of malignancy of human gliomas. However, the molecular mechanisms involved in the malignant function of TGF-ß are not fully elucidated. Here, we showed that TGF-ß induced the downregulation of MST1 expression in U87 and U251 glioma cells. Treatment of glioma cells with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-AzadC) prevented the loss of MST1 expression. Addition of 5-AzadC also reduced the TGF-ß-stimulated proliferation, migration and invasiveness of glioma cells. Furthermore, Knockdown of DNMT1 upregulated MST1 expression in gliomas cells. In addition, the inhibition of DNMT1 blocked TGF-ß-induced proliferation, migration and invasiveness in glioma cells. These results suggest that TGF-ß promotes glioma malignancy through DNMT1-mediated loss of MST1 expression.


Assuntos
Azacitidina/análogos & derivados , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferase 1/genética , Decitabina , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioma/genética , Glioma/patologia , Fator de Crescimento de Hepatócito/genética , Humanos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas/genética , Regulação para Cima
13.
J Clin Neurosci ; 44: 133-142, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28666652

RESUMO

BACKGROUND: Osteosarcoma of the skull base is rarely observed; most published studies comprise case reports. The clinical features and optimal treatments have not been clearly established. The purpose of this article is to present 19 cases of skull base osteosarcoma and review the literature to analyse the clinical features and treatment of skull base osteosarcoma. METHODS: The clinical data of 19 patients with skull base osteosarcoma from January 2005 to December 2016 were retrospectively analysed; pertinent English literature from 1976 to 2016 was reviewed. RESULTS: Six female and 13 male patients were included. The ages ranged from 11 to 55years (mean 34years). Gross-total resection of the tumour was achieved in 13 cases, and nearly total resection was achieved in 6 cases. Five cases were treated with surgery alone, whereas 14 cases received comprehensive treatment. The follow-up period ranged from 3 to 132months (mean 33months) with 17 patients who underwent follow-up. The median survival durations of the patients who underwent surgery alone and who received comprehensive treatment were 18 and 50months, respectively. The literature results were similar to the current findings. Overall, the 5-year survival rates of the patients in our series and in the literature were 30.5% and 37.8%, respectively. CONCLUSIONS: Skull base osteosarcoma had a low complete resection rate, a high recurrence rate and a poor prognosis because of the complex anatomy and vital structures involved. Radical surgery with comprehensive treatment is most appropriate for this disease.


Assuntos
Osteossarcoma/patologia , Neoplasias da Base do Crânio/patologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/cirurgia , Osteossarcoma/terapia , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/cirurgia , Neoplasias da Base do Crânio/terapia , Taxa de Sobrevida
14.
Int J Biol Macromol ; 96: 578-588, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28041914

RESUMO

Pulmonary fibrosis (PF) is a severe inflammatory disease with limited effective treatments. It is known that the transdifferentiation of human embryo lung fibroblast (HELF) cells from pulmonary fibroblasts into myofibroblasts, contributes to the progression of pulmonary fibrogenesis. The tuberous sclerosis proteins TSC1 and TSC2 are two key signaling factors which can suppress cell growth and proliferation. However, the roles of TSC1 and TSC2 in lung fibroblast are unclear. Here, we developed a PF model with bleomycin (BLM) in mice and conducted several simulation experiments in HELF cells. Our study shows that the expression of TSC1 and TSC2 in fibrotic mice lung was reduced and stimulation of HELF cells with TGF-ß1 resulted in a down-regulation of TSC1 and TSC2. In addition, overexpression of TSC1 or TSC2 decreased cell proliferation and differentiation. Furthermore, we found that reduced expression of TSC1 and TSC2 caused by TGF-ß1 is associated with the promoter methylation status of TSC1 and TSC2. MeCP2, controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. We found that expression of TSC1 and TSC2 can be repressed by MeCP2, which regulates HELF cell differentiation and proliferation as myofibroblasts and lead to PF ultimately.


Assuntos
Diferenciação Celular , Regulação para Baixo , Fibroblastos/citologia , Pulmão/citologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteínas Supressoras de Tumor/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Embrião de Mamíferos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose , Humanos , Pulmão/patologia , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Regiões Promotoras Genéticas/genética , Fator de Crescimento Transformador beta1/farmacologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
15.
Biochim Biophys Acta Mol Basis Dis ; 1863(3): 674-686, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27979710

RESUMO

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.


Assuntos
Células Estreladas do Fígado/metabolismo , Cirrose Hepática/genética , RNA Longo não Codificante/genética , Regulação para Cima , Animais , Linhagem Celular , DNA (Citosina-5-)-Metiltransferase 1/genética , Epigênese Genética , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética
16.
J Exp Clin Cancer Res ; 35(1): 90, 2016 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-27267902

RESUMO

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.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Regulação para Cima , Adolescente , Adulto , Idoso , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Prognóstico , Fator de Crescimento Transformador beta2/genética , Adulto Jovem
17.
Oncotarget ; 7(21): 30610-25, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27121316

RESUMO

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.


Assuntos
Neoplasias Encefálicas/genética , Proteínas Cromossômicas não Histona/genética , Metilação de DNA , Glioma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Regiões 3' não Traduzidas/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas Cromossômicas não Histona/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas/genética , Transplante Heterólogo , Carga Tumoral/genética
18.
Int J Oncol ; 48(2): 723-33, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26676363

RESUMO

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.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Epigênese Genética/genética , Repressão Epigenética/genética , Glioma/genética , RNA Longo não Codificante/genética , Proteína Supressora de Tumor p53/genética , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Regiões Promotoras Genéticas/genética
19.
Int J Mol Med ; 36(4): 1012-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26310274

RESUMO

Ubiquitin-associated protein 2-like (UBAP2L), which contains a ubiquitin-associated (UBA) domain near its N-terminus, has been indicated in the pathogenesis of several human cancers, including multiple myeloma, hepatocellular carcinoma and malignant ovarian tumors. However, the role of UBAP2L in human glioma remains unknown. In the present study, UBAP2L was widely expressed in multiple glioma cell lines. To further examine the effects of UBAP2L on glioma growth, lentivirus­mediated short hairpin RNA (shRNA) was employed to knockdown UBAP2L expression in the glioblastoma cell lines. Depletion of UBAP2L significantly inhibited the proliferation and colony formation ability, as determined by MTT and colony formation assays. Cell cycle analysis showed that UBAP2L knockdown induced G0/G1 phase arrest in U251 and U373 cells, while S phase arrest was induced in A172 cells. These results suggest that UBAP2L has a key role in glioma cell growth, and may act as an oncogene to promote malignant glioma development.


Assuntos
Proteínas de Transporte/biossíntese , Pontos de Checagem da Fase G1 do Ciclo Celular , Proteínas de Neoplasias/biossíntese , Fase de Repouso do Ciclo Celular , Pontos de Checagem da Fase S do Ciclo Celular , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes/métodos , Glioma , Humanos , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia
20.
J Cell Physiol ; 230(3): 496-503, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24403021

RESUMO

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.


Assuntos
Glioma/genética , Terapia de Alvo Molecular , Complexo Repressor Polycomb 2/genética , RNA Longo não Codificante/genética , Apoptose/genética , Proliferação de Células/genética , Metilação de DNA/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Glioma/patologia , Humanos , Invasividade Neoplásica/genética , Neovascularização Patológica/genética , Complexo Repressor Polycomb 2/biossíntese , RNA Longo não Codificante/metabolismo , Transdução de Sinais
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