Studies have found that RNA-binding proteins (RBPs) are dysfunctional and play a significant regulatory role in the development of glioma. Based on The Cancer Genome Atlas database and the previous studies, we selected heterogeneous nuclear ribonucleoprotein (HNRNPD) as the research candidate and sought its downstream targeted genes. In the present study, HNRNPD, linc00707, and specific protein 2 (SP2) were highly expressed, while zinc fingers and homeboxes 2 (ZHX2) and miR-651-3p were remarkedly downregulated in glioma tissues and cells. HNRNPD, linc00707, and SP2 knockdown or ZHX2 and miR-651-3p overexpression suppressed glioma cells proliferation, migration, and invasion and vasculogenic mimicry (VM) formation. Knockdown of HNRNPD increased the stability of ZHX2 mRNA. ZHX2 bound to the promoter region of linc00707 and negatively regulate its expression. Linc00707 could bind with miR-651-3p, while miR-651-3p bound to the 3′ untranslated region (3′UTR) of SP2 mRNA to negatively regulate its expression. The transcription factor SP2 directly bound to the promoter regions of the VM formation-related proteins MMP2, MMP9, and VE-cadherin, playing a role in promoting transcription in order to regulate the VM formation ability of glioma cells.
The blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.
The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are involved in the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the expressions of tight junction-related proteins. ELK4 was lower expressed in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by increasing the tight junction-related proteins expressions. TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.
The blood-brain barrier (BBB) plays a pivotal role in maintenance and regulation of the neural microenvironment. The occurrence of BBB disruption is the pathological change of early Alzheimer’s disease (AD). RNA-binding proteins and long non-coding RNAs are involved in the regulation of BBB permeability. Our study was performed to demonstrate TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ1-42-incubated microvascular endothelial cells (ECs) of BBB model in vitro, TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased the BBB permeability via upregulating the expressions of tight junction-related proteins. ELK4 was lower expressed in BBB model in vitro in AD microenvironment. LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. The downregulated ELK4 increased the permeability of BTB by increasing the tight junction-related proteins expressions. TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.
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