Suppression of miR-203-3p inhibits lipopolysaccharide induced human intervertebral disc inflammation and degeneration through upregulating estrogen receptor α

Cai, Zhongxu; Li, Kunpeng; Yang, Keshi; Luo, Dawei; Xu, Hui

doi:10.1038/s41434-019-0118-z

Cited by 16 publications

(12 citation statements)

References 23 publications

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“…The Kyoto Encyclopedia of Genes and Genomes analysis of the estrogen signaling pathway revealed that ESR1 might regulate the expression of related genes (Figure 1C) to mediate various signaling pathways, including canonical mitogen-activated protein kinase, PI3K-Akt, and estrogen pathways, thereby affecting cell cycle progression, growth, apoptosis, and other pathological processes (Figure 1D). Furthermore, Cai et al (2020) demonstrated that the mRNA and protein expression levels of ESR1 were significantly decreased in patients with IDD diseases. Collectively, these results predicted that ESR1 might be one of the most KDEGs in IDD.…”

Section: Prediction Of Esr1 Was One Of the Most Critical Differentially Expressed Genes In Iddmentioning

confidence: 97%

“…Upregulation of ESR1 was demonstrated to protect TNF-αinduced NPC degeneration through the activation of CCN5 by binding to its promoter (Song et al, 2021). Moreover, ESR1 has a negative correlation with the severity of IDD, and its mRNA and protein levels are downregulated in the NP tissues of patients with high-grade IDD compared with patients with low-grade IDD (Song et al, 2014;Cai et al, 2020). A series of studies demonstrated that the activity and biofunction of ESR1 could be regulated by circRNAs and miRNAs (Sheng et al, 2018;Cai et al, 2020;Taheri et al, 2020).…”

Section: Biofunction Of Circ_0040039 In Npcsmentioning

confidence: 99%

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Circ_0040039 May Aggravate Intervertebral Disk Degeneration by Regulating the MiR-874-3p-ESR1 Pathway

Wang

et al. 2021

Front. Genet.

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The functional alteration of nucleus pulposus cells (NPCs) exerts a crucial role in the occurrence and progression of intervertebral disk degeneration (IDD). Circular RNAs and microRNAs (miRs) are critical regulators of NPC metabolic processes such as growth and apoptosis. In this study, bioinformatics tools, encompassing Gene Ontology pathway and Venn diagrams analysis, and protein–protein interaction (PPI) network construction were used to identify functional molecules related to IDD. PPI network unveiled that ESR1 was one of the most critical genes in IDD. Then, a key IDD-related circ_0040039-miR-874-3p-ESR1 interaction network was predicted and constructed. Circ_0040039 promoted miR-874-3p and repressed ESR1 expression, and miR-874-3p repressed ESR1 expression in NPCs, suggesting ESR1 might be a direct target of miR-874-3p. Functionally, circ_0040039 could enhance NPC apoptosis and inhibit NPC growth, revealing that circ_0040039 might aggravate IDD by stabilizing miR-874-3p and further upregulating the miR-874-3p-ESR1 pathway. This signaling pathway might provide a novel therapeutic strategy and targets for the diagnosis and therapy of IDD-related diseases.

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Section: Prediction Of Esr1 Was One Of the Most Critical Differentially Expressed Genes In Iddmentioning

confidence: 97%

Section: Biofunction Of Circ_0040039 In Npcsmentioning

confidence: 99%

Circ_0040039 May Aggravate Intervertebral Disk Degeneration by Regulating the MiR-874-3p-ESR1 Pathway

Wang

et al. 2021

Front. Genet.

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“…Notably, the expression of this miRNA has been negatively correlated with ERα expression. miR-203-3p has been shown to directly target ERα in the NP cells of IDD patients [97]. The role of miR-203 in the regulation of ERα and cartilage degradation in IL-1β-stimulated chondrocytes has been verified in another study [98].…”

Section: Mirnas and Er Function In Other Disordersmentioning

confidence: 85%

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

Taheri

Shoorei

Dinger

et al. 2020

Cancers

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Estrogen receptors (ERs) comprise several nuclear and membrane-bound receptors with different tissue-specific functions. ERα and ERβ are two nuclear members of this family, whereas G protein-coupled estrogen receptor (GPER), ER-X, and Gq-coupled membrane estrogen receptor (Gq-mER) are membrane-bound G protein-coupled proteins. ERα participates in the development and function of several body organs such as the reproductive system, brain, heart and musculoskeletal systems. ERβ has a highly tissue-specific expression pattern, particularly in the female reproductive system, and exerts tumor-suppressive roles in some tissues. Recent studies have revealed functional links between both nuclear and membrane-bound ERs and non-coding RNAs. Several oncogenic lncRNAs and miRNAs have been shown to exert their effects through the modulation of the expression of ERs. Moreover, treatment with estradiol has been shown to alter the malignant behavior of cancer cells through functional axes composed of non-coding RNAs and ERs. The interaction between ERs and non-coding RNAs has functional relevance in several human pathologies associated with estrogen regulation, such as cancers, intervertebral disc degeneration, coronary heart disease and diabetes. In the current review, we summarize scientific literature on the role of miRNAs and lncRNAs on ER-associated signaling and related disorders.

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“…For instance, both miR-203 induced promotion and inhibition of cell proliferation were observed, in hepatocytes and pancreatic cancer cells, respectively, via targeting PTEN and SLUG [ 31 , 32 ]. Similarly, both pro-and anti-inflammatory functions were ascribed to miR-203 via modulating negative and positive regulators of cytokine signaling [ 33 – 35 ].…”

Section: Discussionmentioning

confidence: 99%

miR-203, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling

et al. 2022

J Neuroinflammation

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Background miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA. Methods Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3ʹUTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test. Results Akirin2, an activator of NF‐κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF‐κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF‐κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF‐κB, IL-1β and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus. Conclusion A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF‐κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling.

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Suppression of miR-203-3p inhibits lipopolysaccharide induced human intervertebral disc inflammation and degeneration through upregulating estrogen receptor α

Cited by 16 publications

References 23 publications

Circ_0040039 May Aggravate Intervertebral Disk Degeneration by Regulating the MiR-874-3p-ESR1 Pathway

Circ_0040039 May Aggravate Intervertebral Disk Degeneration by Regulating the MiR-874-3p-ESR1 Pathway

Perspectives on the Role of Non-Coding RNAs in the Regulation of Expression and Function of the Estrogen Receptor

miR-203, fine-tunning neuroinflammation by juggling different components of NF‐κB signaling

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