Pseudogene RPL32P3 regulates the blood-tumor barrier permeability via the YBX2/HNF4G axis.
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ABSTRACT:
SUBMITTER: Ding Y
PROVIDER: S-EPMC8613260 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The blood-tumor barrier (BTB) restricts the efficient delivery of anti-glioma drugs to cranial glioma tissues. Increased BTB permeability may allow greater delivery of the therapeutic agents. Increasing evidence has revealed that PIWI proteins and PIWI-interacting RNAs (piRNAs) play an important role in tumor progression. However, whether PIWI proteins and piRNAs regulate BTB permeability remains unclear. In the present study, we demonstrated that the PIWIL1/piRNA-DQ593109 (piR-DQ593109) complex was the predominant regulator of BTB permeability. Briefly, PIWIL1 was upregulated in glioma endothelial cells (GECs). Furthermore, piR-DQ593109 was also overexpressed in GECs, as revealed via a piRNA microarray. Downregulation of PIWIL1 or piR-DQ593109 increased the permeability of the BTB. Moreover, PIWIL1 and piR-DQ593109, which formed a piRNA-induced silencing complex, degraded the long non-coding RNA maternally expressed 3 (MEG3) in a sequenced-dependent manner. Furthermore, restoring MEG3 released post-transcriptional inhibition of Runt related transcription factor 3 (RUNX3) by sponging miR-330-5p. In addition, RUNX3 bounded to the promoter regions and reduced the promoter activities of ZO-1, occludin, and claudin-5, which significantly impaired the expression levels of ZO-1, occludin, and claudin-5. In conclusion, downregulating PIWIL1 and piR-DQ593109 increased BTB permeability through the MEG3/miR-330-5p/RUNX3 axis. These data may provide insight into glioma treatment.
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Project description:The blood-tumor barrier limits the delivery of therapeutic drugs to brain tumor tissues. Selectively opening the blood-tumor barrier is considered crucial for effective chemotherapy of glioma. RNA-binding proteins have emerged as crucial regulators in various biologic processes. This study found that RNA-binding Fox-1 homolog 1 (RBFOX1) was downregulated in glioma vascular endothelial cells derived from glioma tissues, and in glioma endothelial cells obtained by co-culturing endothelial cells with glioma cells. Overexpression of RBFOX1 impaired the integrity of the blood-tumor barrier and increased its permeability. Additionally, RBFOX1 overexpression decreased the expression of tight junction proteins ZO-1, occludin, and claudin-5. Subsequent analysis of the mechanism indicated that the overexpression of RBFOX1 increased musculoaponeurotic fibrosarcoma protein basic leucine zipper [bZIP] transcription factor F (MAFF) expression by downregulating LINC00673, which stabilized MAFF messenger RNA (mRNA) through Staufen1-mediated mRNA decay. Moreover, MAFF could bind to the promoter region and inhibit the promoter activities of ZO-1, occludin, and claudin-5, which reduced its expression. The combination of RBFOX1 upregulation and LINC00673 downregulation promoted doxorubicin delivery across the blood-tumor barrier, resulting in apoptosis of glioma cells. In conclusion, this study indicated that overexpression of RBFOX1 increased blood-tumor barrier permeability through the LINC00673/MAFF pathway, which might provide a new useful target for future enhancement of blood-tumor barrier permeability.
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Project description:ObjectiveThe primary goals of this study were to investigate the potential roles of ZNF22 and HDAC3 as a histone deacetylase in regulating an increases in blood-tumor barrier (BTB) permeability and some of the possible molecular mechanisms associated with this effect.MethodsThe expression of ZNF22 and HDAC3 in glioma-exposed endothelial cells (GECs) of BTB were detected transcription real-time PCR or western blot. The interaction of ZNF22 and HDAC3 in GECs associated with transcript effect was analyzed by means of Co-Immunoprecipitation and luciferase reporter assay.ResultsIn the present investigation, GECs expressed higher levels of ZNF22 as a zinc finger transcription factor and HDAC3 than endothelial cells. We then affirmed that silencing HDAC3 or ZNF22 led to a reduction in BTB permeability. By bioinformatics analysis, chromatin immunoprecipitation (ChIP) assays and luciferase assay, we found that ZNF22 had a target binding relationship with the promoter regions of ZO-1, Occludin, and Claudin-5 and negatively regulated the expression of ZO-1, Occludin, and Claudin-5. Furthermore, we revealed that HDAC3, as a co-transcript repressor with histone deacetylase activity, could interact with ZNF22 to hinder the expression of TJ-associated proteins, thereby further facilitating the permeability of BTB.ConclusionZNF22 acted as a transcription factor in conjunction with HDAC3 to modulate the expression of TJ-associated proteins, which was correlated with an increase in BTB permeability. These results may provide new strategies and targets for the chemotherapy of gliomas as well as intracranial infections.
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Project description:Blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that impairs the delivery of therapeutic drugs. However, the methods and molecular mechanisms underlying the BTB opening remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of various biologic processes and therapeutic targets. In this study, we have identified microRNA-181a (miR-181a) as a critical miRNA in opening BTB. MicroRNA-181a expression was upregulated in glioma endothelial cells (GECs), which were obtained by coculturing endothelial cells (ECs) with glioma cells. Overexpression of miR-181a resulted in an impaired and permeability increased BTB, and meanwhile reduced the expression of zonula occluden (ZO)-1, occludin, and claudin-5. Kruppel-like factor 6 (KLF6), a transcription factor of the zinc-finger family, was downregulated in GECs. Mechanistic investigations defined it as a direct and functional downstream target of miR-181a, which was involved in the regulation of BTB permeability and the expression of ZO-1, occludin, and claudin-5. Furthermore, luciferase assays and chromatin immunoprecipitation assays showed that KLF6 upregulated the promoter activities and interacted with the promoters of ZO-1, occludin, and claudin-5 in GECs. Collectively, we showed the possibility that overexpression of miR-181a contributes to the increased permeability of BTB by targeting KLF6, thereby revealing potential therapeutic targets for the treatment of brain gliomas.
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Project description:The primary goals of this study were to investigate the potential roles of miR-200b in regulating RMP7-induced increases in blood-tumor barrier (BTB) permeability and some of the possible molecular mechanisms associated with this effect. Microarray analysis revealed 34 significantly deregulated miRNAs including miR-200b in the BTB as induced by RMP7 and 8 significantly up-regulated miRNAs in the BTB by RMP7. RMP7 induced tight junction (TJ) opening of the BTB, thereby increasing BTB permeability. Associated with this effect of RMP7 was a decrease in miR-200b expression within the human cerebral microvascular endothelial cells line hCMEC/D3 (ECs) of the BTB. Overexpression of miR-200b inhibited endothelial leakage and restored normal transendothelial electric resistance values. A simultaneous shift in occludin and claudin-5 distributions from insoluble to soluble fractions were observed to be significantly reduced. In addition, overexpression of miR-200b inhibited the relocation of occludin and claudin-5 from cellular borders into the cytoplasm as well as the production of stress fiber formation in GECs (ECs with U87 glioma cells co-culturing) of the BTB. MiR-200b silencing produced opposite results as that obtained from that of the miR-200b overexpression group. Overexpression of miR-200b was also associated with a down-regulation in RhoA and ROCKII expression, concomitant with a decrease in BTB permeability. Again, results which were opposite to that obtained with the miR-200b silencing group. We further found that miR-200b regulated BTB permeability by directly targeting RhoA and ROCKII. Collectively, these results suggest that miR-200b's contribution to the RMP7-induced increase in BTB permeability was associated with stress fiber formation and TJ disassembly as achieved by directly targeting RhoA and ROCKII.
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