RESUMO
Asthma is an inflammatory disease of the airways, characterized by lung eosinophilia, mucus hypersecretion by goblet cells and airway hyperresponsiveness to inhaled allergens. The present study aimed to identify the function of microRNA (miR/miRNA)106b5p in TGFß1induced pulmonary fibrosis and epithelialmesenchymal transition (EMT) via targeting sine oculis homeobox homolog 1 (SIX1) through regulation of E2F transcription factor 1 (E2F1) in asthma. Asthmatic mouse models were induced with ovalbumin. miRNA expression was evaluated using reverse transcriptionquantitative PCR. Transfection experiments using bronchial epithelial cells were performed to determine the target genes. A luciferase reporter assay system was applied to identify the target gene of miR106b5p. The present study revealed downregulated miR106b5p expression and upregulated SIX1 expression in asthmatic mice and TGFß1induced BEAS2B cells. Moreover, miR106b5p overexpression inhibited TGFß1induced fibrosis and EMT in BEAS2B cells, while miR106b5pknockdown produced the opposite effects. Subsequently, miR106b5p was found to regulate SIX1 through indirect regulation of E2F1. Additionally, E2F1 and SIX1knockdown blocked TGFß1induced fibrosis and EMT in BEAS2B cells. In addition, miR106b5p negatively regulated SIX1 via E2F1 in BEAS2B cells. The present study demonstrated that the miR106b5p/E2F1/SIX1 signaling pathway may provide potential therapeutic targets for asthma.
Assuntos
Asma/metabolismo , Fator de Transcrição E2F1/metabolismo , Transição Epitelial-Mesenquimal , Proteínas de Homeodomínio/metabolismo , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Asma/patologia , Linhagem Celular , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/patologiaRESUMO
Microglial cells are key component of central nervous system (CNS) and mediate the immune response of the brain under physiological or pathological conditions. It tends to activate into a pro-inflammatory M1 phenotype after traumatic brain injury (TBI) and promote secondary brain damage. Recently, necroptosis was found to promote microglial activation and neuroinflammation after TBI. However, the mechanism and specific interventions of microglial necroptosis after TBI remain poorly investigated. Here, we reported that overexpress the charged multivesicular body protein 4b (CHMP4B) which is a core member of the endosomal sorting required for transport complex III (ESCRT-III) significantly decreased the level of necroptosis in microglia, improved neurological function recovery and protected against cell death after TBI. Further investigation showed that forkhead transcription factor O1 (FOXO1) was a crucial transcription factor that increased CHMP4B transcription by binding to the promoter region, thereby inhibiting necroptosis in microglia. Collectively, our findings demonstrated that CHMP4B relieved microglial necroptosis and neuroinflammation after TBI, and promote the recovery of nerve function. FOXO1 is an important factor in promoting CHMP4B expression. This study provides the novel viewpoint for TBI prevention and treatment.
Assuntos
Lesões Encefálicas Traumáticas/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Microglia/patologia , Necroptose/genética , Regulação para Cima/genética , Adulto , Idoso , Animais , Encéfalo/patologia , Lesões Encefálicas Traumáticas/patologia , Linhagem Celular , Feminino , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/genética , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Adulto JovemRESUMO
Tumour invasion is closely related to the prognosis and recurrence of glioblastoma multiforme and partially attributes to epithelial-mesenchymal transition. Long intergenic non-coding RNA 00511 (LINC00511) plays a pivotal role in tumour; however, the role of LINC00511 in GBM, especially in the epigenetic molecular regulation mechanism of EMT, is still unclear. Here, we found that LINC00511 was up-regulated in GBM tissues and relatively high LINC00511 expression predicted poorer prognosis. Moreover, ectopic LINC00511 enhanced GBM cells proliferation, EMT, migration and invasion, whereas LINC00511 knockdown had the opposite effects. Mechanistically, we confirmed that ZEB1 acted as a transcription factor for LINC00511 in GBM cells. Subsequently, we found that LINC00511 served as a competing endogenous RNA that sponged miR-524-5p to indirectly regulate YB1, whereas, up-regulated YB1 promoted ZEB1 expression, which inversely facilitated LINC00511 expression. Finally, orthotopic xenograft models were performed to further demonstrate the LINC00511 on GBM tumorigenesis. This study demonstrates that a LINC00511/miR-524-5p/YB1/ZEB1 positive feedback loop provides potential therapeutic targets for GBM progression.
Assuntos
Carcinogênese/genética , Transição Epitelial-Mesenquimal/genética , Retroalimentação Fisiológica , Glioblastoma/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Sequência de Bases , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Prognóstico , RNA Longo não Codificante/genética , Transcrição Gênica , Regulação para Cima/genéticaRESUMO
Glioblastoma (GBM) is the most universal type of primary brain malignant tumour, and the prognosis of patients with GBM is poor. S100A11 plays an essential role in tumour. However, the role and molecular mechanism of S100A11 in GBM are not clear. Here, we found that S100A11 was up-regulated in GBM tissues and higher S100A11 expression indicated poor prognosis of GBM patients. Overexpression of S100A11 promoted GBM cell growth, epithelial-mesenchymal transition (EMT), migration, invasion and generation of glioma stem cells (GSCs), whereas its knockdown inhibited these activities. More importantly, S100A11 interacted with ANXA2 and regulated NF-κB signalling pathway through decreasing ubiquitination and degradation of ANXA2. Additionally, NF-κB regulated S100A11 at transcriptional level as a positive feedback. We also demonstrated the S100A11 on tumour growth in GBM using an orthotopic tumour xenografting. These data demonstrate that S100A11/ANXA2/NF-κB positive feedback loop in GBM cells that promote the progression of GBM.
