The Transcription Factor IRF6 Co-Represses PPARγ-Mediated Cytoprotection in Ischemic Cerebrovascular Endothelial Cells

Huang, Rongzhong; Hu, Zicheng; Feng, Yuxing; Yu, Lehua; Li, Xingsheng

doi:10.1038/s41598-017-02095-3

Cited by 5 publications

(6 citation statements)

References 33 publications

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“…Interestingly, amongst all microRNAs, both miR-424 and miR-503 are predominantly regulated by estrogen [ 60 , 61 ] while miR-503 is known to control female CD4 + T cell activation and as such the acute inflammatory response in women [ 62 ]. More support for elevated X-linked miR expression and potential sex-specific downstream effects in brain ECs was demonstrated in OGD cultured cerebral ECs which increased miR-106a expression, thereby decreasing cell viability, leading to cell death due to an increased and pro-inflammatory caspase-3 expression [ 63 ]. Also, murine cerebrovascular endothelial cells displayed less cell viability upon transient MCA occlusion in C57BL/6 J male mice ( n = 24, 8–10 weeks old), a phenotype induced by elevated miR-106a expression [ 63 ].…”

Section: Stroke Promoting Mechanismsmentioning

confidence: 99%

Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

Florijn

Bijkerk

Kruyt

et al. 2021

IJMS

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Accumulating evidence pinpoints sex differences in stroke incidence, etiology and outcome. Therefore, more understanding of the sex-specific mechanisms that lead to ischemic stroke and aggravation of secondary damage after stroke is needed. Our current mechanistic understanding of cerebral ischemia states that endothelial quiescence in neurovascular units (NVUs) is a major physiological parameter affecting the cellular response to neuron, astrocyte and vascular smooth muscle cell (VSMC) injury. Although a hallmark of the response to injury in these cells is transcriptional activation, noncoding RNAs such as microRNAs exhibit cell-type and context dependent regulation of gene expression at the post-transcriptional level. This review assesses whether sex-specific microRNA expression (either derived from X-chromosome loci following incomplete X-chromosome inactivation or regulated by estrogen in their biogenesis) in these cells controls NVU quiescence, and as such, could differentiate stroke pathophysiology in women compared to men. Their adverse expression was found to decrease tight junction affinity in endothelial cells and activate VSMC proliferation, while their regulation of paracrine astrocyte signaling was shown to neutralize sex-specific apoptotic pathways in neurons. As such, these microRNAs have cell type-specific functions in astrocytes and vascular cells which act on one another, thereby affecting the cell viability of neurons. Furthermore, these microRNAs display actual and potential clinical implications as diagnostic and prognostic biomarkers in ischemic stroke and in predicting therapeutic response to antiplatelet therapy. In conclusion, this review improves the current mechanistic understanding of the molecular mechanisms leading to ischemic stroke in women and highlights the clinical promise of sex-specific microRNAs as novel diagnostic biomarkers for (silent) ischemic stroke.

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Section: Stroke Promoting Mechanismsmentioning

confidence: 99%

Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

Florijn

Bijkerk

Kruyt

et al. 2021

IJMS

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“…Two previous reports also showed that IRF6 regulates Pparγ gene in macrophages and endothelial cells. (31,32) These studies, combined with our findings, suggest a more generalized transcriptional target gene for IRF6; however, we investigated a unique function of IRF6 in regulating different disease from the current report with different molecular mechanism. Moreover, each IRF member may have a wide spectrum of direct target genes depending on the disease setting.…”

Section: Discussionmentioning

confidence: 68%

“…Our data show that IRF6 directly binds to the promoter of the PPARγ gene and inhibits its transcription in hepatocytes. Two previous reports also showed that IRF6 regulates Pparγ gene in macrophages and endothelial cells . These studies, combined with our findings, suggest a more generalized transcriptional target gene for IRF6; however, we investigated a unique function of IRF6 in regulating different disease from the current report with different molecular mechanism.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Interferon Regulatory Factor 6 Alleviates Liver Steatosis and Metabolic Disorder by Transcriptionally Suppressing Peroxisome Proliferator‐Activated Receptor γ in Mice

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic. A large and growing unmet therapeutic need has inspired numerous studies in the field. Integrating the published genomic data available in the Gene Expression Omnibus (GEO) with NAFLD samples from rodents, we discovered that interferon regulatory factor 6 (IRF6) is significantly downregulated in high‐fat diet (HFD)‐induced fatty liver. In the current study, we identified IRF6 in hepatocytes as a protective factor in liver steatosis (LS). During HFD challenge, hepatic Irf6 was suppressed by promoter hypermethylation. Severity of HFD‐induced LS was exacerbated in hepatocyte‐specific Irf6 knockout mice, whereas hepatocyte‐specific transgenic mice overexpressing Irf6 (IRF6‐HTG) exhibited alleviated steatosis and metabolic disorder in response to HFD feeding. Mechanistic studies in vitro demonstrated that hepatocyte IRF6 directly binds to the promoter of the peroxisome proliferator‐activated receptor γ (PPARγ) gene and subsequently halts the transcription of Pparγ and its target genes (e.g., genes that regulate lipogenesis and lipid acid uptake) under physiological conditions. Conclusion: Irf6 is downregulated by promoter hypermethylation upon metabolic stimulus exposure, which fail to inhibit Pparγ and its targets, driving abnormalities of lipid metabolism.

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“…Ardenne and Reitnauer (27) demonstrated that hsa-miR-106a suppressed proliferation and induced apoptosis. Application of miR-106a mimics induced cerebrovascular endothelial cell death under oxygen-glucose deprivation conditions (28). Therefore, DGCR8 promoting hsa-miR-106a transcription might be one of the important reasons for enhancing radiation sensitivity.…”

Section: Discussionmentioning

confidence: 99%

DGCR8/miR-106 Axis Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinomas by Downregulating RUNX3

et al. 2020

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Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignant tumor worldwide, and the radiotherapy effect is strongly associated with human papillomavirus (HPV) infection. Therefore, the aim of our study was to analyze the mechanism of HPV E7 and its effects on radiosensitivity in HNSCC cells.Methods: The mRNA expression of DiGeorge syndrome critical region gene 8 (DGCR8), has-miR-106a, and Runt-related transcription factor 3 (RUNX3) was examined by quantitative real-time PCR (RT-qPCR). The protein expression of DGCR8, E7, RUNX3, caspase-3/cleaved caspase-3, poly(ADP-ribose) polymerase (PARP)/cleaved PARP, and γH2AX was measured by Western blot. The expression level of DGCR8 was measured by immunofluorescence assay. Starbase database (http://starbase.sysu.edu.cn/) was used to analyze the correlation between has-miR-106a-5p and DGCR8. TargetScan database (http://www.targetscan.org/vert_72/) was adopted to calculate the prediction of binding sites. Radiosensitivity was evaluated through clone formation assays and Cell Counting Kit-8 (CCK-8) assays.Results: In our study, we found that the mRNA and protein expression levels of HPV E7 and DGCR8 in HPV-positive HNSCC cells were higher than those in HPV-negative cells. The expression of DGCR8 was increased in FaDu and UM-SCC-4 with E7 overexpression, while the expression of DGCR8 was decreased in UM-SCC-47 and UPCI-SCC-090 with E7 silence. The miR-106a expression was increased after DGCR8 overexpression in FaDu and UM-SCC-4. However, the miR-106a expression was decreased in UM-SCC-47 and UPCI-SCC-090 with E7 silence. In radiation conditions, clone formation assays found that less clones formed in FaDu and UM-SCC-4 cells subsequent to silencing DGCR8 or miR-106a than that in the control group, and more clones were formed in UM-SCC-47 and UPCI-SCC-090 cells overexpressing DGCR8 or miR-106a than that in the control group. Luciferase reporter gene assays verified that miR-106a targeted the 3′ untranslated region (UTR) of RUNX3 mRNA. MiR-106a overexpression resulted in a decrease in RUNX3 expression, and miR-106a silence increased RUNX3 expression. Rescue experiments conducted with miR-106a inhibitor restored radiation resistance and reduced DNA damage in radiation condition.Conclusions: Our study indicated that HPV E7 activated DGCR8/miR-106a/RUNX3 axis to enhance radiation sensitivity and provided directions for targeted therapeutic interventions.

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The Transcription Factor IRF6 Co-Represses PPARγ-Mediated Cytoprotection in Ischemic Cerebrovascular Endothelial Cells

Cited by 5 publications

References 33 publications

Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

Sex-Specific MicroRNAs in Neurovascular Units in Ischemic Stroke

Hepatic Interferon Regulatory Factor 6 Alleviates Liver Steatosis and Metabolic Disorder by Transcriptionally Suppressing Peroxisome Proliferator‐Activated Receptor γ in Mice

DGCR8/miR-106 Axis Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinomas by Downregulating RUNX3

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