Overexpression of miR-378 Alleviates Chronic Sciatic Nerve Injury by Targeting EZH2

Gao, Pengfei; Zeng, Xin; Zhang, Lin; Wang, Long; Shen, Lanxiao; Hou, Ya-Yun; Zhou, Fang; Zhang, Xianlong

doi:10.1007/s11064-021-03424-9

Cited by 11 publications

(11 citation statements)

References 41 publications

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“…CA1 treatment with siEZH2 downregulated CA1 LTP, visceral hypersensitivity, and anxiety in IBS-like rats. EZH2 is a target gene of miR-124-3p and other miRNAs (Li et al, 2020 ; Gao P. et al, 2021 ; Zhang et al, 2021 ). It is reasonable to consider that EZH2 is the common cellular pathway involved in many disorders, including cancer (Anwar et al, 2018 ), chronic pain (Yadav and Weng, 2017 ), and negative emotions (Yan et al, 2019 ; Li et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Role of hippocampal circKcnk9 in visceral hypersensitivity and anxiety comorbidity of irritable bowel syndrome

Liu

Chen

Lin

et al. 2022

Front. Cell. Neurosci.

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Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by recurrent visceral pain and altered bowel habits (diarrhea or constipation). However, the molecular and pathological mechanisms are poorly understood. This study found neonatal colorectal distension to induce visceral hypersensitivity and anxiety. The expression of hippocampal circKcnk9, a novel circRNA, was significantly increased in IBS-like rats. Interestingly, CA1 shcircKcnk9 treatment inhibited long-term potentiation (LTP) and alleviated visceral hypersensitivity and anxiety in IBS-like rats, whereas overexpression of CA1 circKcnk9 induced LTP, visceral hypersensitivity, and anxiety in controls. Several experiments indicated that increased CA1 circKcnk9 acted as a miR-124-3p sponge, which resulted in the inhibitory effect of miR-124-3p on gene silencing. There was a negative correlation between circKcnk9 and miR-124-3p expression. As expected, CA1 administration of agomiR-124-3p decreased CA1 LTP, visceral hypersensitivity, and anxiety in the IBS-like rats. In contrast, CA1 treatment with antagomiR-124-3p induced LTP, visceral hypersensitivity, and anxiety in the controls. Furthermore, bioinformatic analysis and experimental data showed that EZH2 is a circKcnk9/miR-124-3p target gene, and increased EZH2 expression was involved in visceral hypersensitivity and anxiety in IBS-like rats by enhancing hippocampal synaptic plasticity. In conclusion, early life stress induces increased expression of circKcnk9 in the CA1 of IBS-like rats. Increased circKcnk9 expression regulates synaptic transmission and enhances LTP, leading to visceral hypersensitivity and anxiety in IBS-like rats. The underlying circKcnk9 signaling pathway is miR124-3p/EZH2. Increased circKcnk9 reinforces its sponging of miR124-3p and strongly suppresses miR124-3p activity, resulting in increased expression of the target gene EZH2. This study provides a new epigenetic mechanism for visceral hypersensitivity and anxiety in IBS-like rats.

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Section: Discussionmentioning

confidence: 99%

Role of hippocampal circKcnk9 in visceral hypersensitivity and anxiety comorbidity of irritable bowel syndrome

Liu

Chen

Lin

et al. 2022

Front. Cell. Neurosci.

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“…However, in our study of GC patients with CIPN, we observed no difference in the expression levels of these miRNAs between the analyzed groups. On the other hand, it has been reported that miR-378 reduces neuropathic aches by negatively targeting enhancer of zeste homolog 2 (EZH2), and the miR-378/EZH2 axis plays an important role in the development of neuropathic pain [ 32 ]. Moreover, it has been reported that miR-378 is downregulated in rats with chronic constriction injury, and the overexpression of miR-378 reduces pain [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Expression Profiles of Circulating MicroRNAs in XELOX-Chemotherapy-Induced Peripheral Neuropathy in Patients with Advanced Gastric Cancer

Seol

Kim

et al. 2022

IJMS

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Gastric cancer (GC) is one of the most common cancers and a leading cause of cancer deaths around the world. Chemotherapy is one of the most effective treatments for cancer patients, and has remarkably enhanced survival rates. However, it has many side effects. Recently, microRNAs (miRNAs) have been intensively studied as potential biomarkers for cancer diagnosis and treatment monitoring. However, definitive biomarkers in chemotherapy-induced peripheral neuropathy (CIPN) are still lacking. The aim of this study was to identify the factors significant for neurological adverse events in GC patients receiving XELOX (oxaliplatin and capecitabine) chemotherapy. The results show that XELOX chemotherapy induces changes in the expression of hsa-miR-200c-3p, hsa-miR-885-5p, and hsa-miR-378f. Validation by qRT-PCR demonstrated that hsa-miR-378f was significantly downregulated in CIPN. Hsa-miR-378f was identified as showing a statistically significant correlation in GC patients receiving XELOX chemotherapy according to the analysis of differentially expressed (DE) miRNAs. Furthermore, 34 potential target genes were predicted using a web-based database for miRNA target prognostication and functional annotations. The identified genes are related to the peptidyl-serine phosphorylation and regulation of alternative mRNA splicing with enrichment in the gastric cancer, neurotrophin, MAPK, and AMPK signaling pathways. Collectively, these results provide information useful for developing promising strategies for the treatment of XELOX-chemotherapy-induced peripheral neuropathy.

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“…miR‐130a‐3p targets and downregulates insulin‐like growth factor‐1/insulin‐like growth factor‐1 receptor (IGF‐1/IGF‐1R) expression to alleviate SCI‐induced neuropathic pain by mitigating microglial activation and NF‐κB phosphorylation 45 . miR‐378 was decreased in CCI rats, inhibiting neuropathic pain development by targeting the enhancer of zeste homolog 2 (EZH2) 46 . EZH2 promotes neuropathic pain by increasing tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐1β, and monocyte chemoattractant protein‐1 (MCP‐1) production.…”

Section: Studying Mirna Neuropathic Pain Mechanismsmentioning

confidence: 99%

“… 45 miR‐378 was decreased in CCI rats, inhibiting neuropathic pain development by targeting the enhancer of zeste homolog 2 (EZH2). 46 EZH2 promotes neuropathic pain by increasing tumor necrosis factor‐alpha (TNF‐α), interleukin (IL)‐1β, and monocyte chemoattractant protein‐1 (MCP‐1) production. Intrathecally injecting miRNA‐138 lentivirus can remarkably alleviate neuropathic pain in partial sciatic nerve ligation (pSNL) rats by suppressing toll‐like receptor 4 (TLR4) and macrophage inflammatory protein‐1 alpha (MIP‐1α)/C‐C chemokine receptor 1 (CCR1) signaling pathways.…”

Section: Studying Mirna Neuropathic Pain Mechanismsmentioning

confidence: 99%

The etiological roles of miRNAs, lncRNAs, and circRNAs in neuropathic pain: A narrative review

Jiang

Wang

et al. 2022

Clinical Laboratory Analysis

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Background Non‐coding RNAs (ncRNAs) are involved in neuropathic pain development. Herein, we systematically searched for neuropathic pain‐related ncRNAs expression changes, including microRNAs (miRNAs), long non‐coding RNAs (lncRNAs), and circular non‐coding RNAs (circRNAs). Methods We searched two databases, PubMed and GeenMedical, for relevant studies. Results Peripheral nerve injury or noxious stimuli can induce extensive changes in the expression of ncRNAs. For example, higher serum miR‐132‐3p, ‐146b‐5p, and ‐384 was observed in neuropathic pain patients. Either sciatic nerve ligation, dorsal root ganglion (DRG) transaction, or ventral root transection (VRT) could upregulate miR‐21 and miR‐31 while downregulating miR‐668 and miR‐672 in the injured DRG. lncRNAs, such as early growth response 2‐antisense‐RNA (Egr2‐AS‐RNA) and Kcna2‐AS‐RNA, were upregulated in Schwann cells and inflicted DRG after nerve injury, respectively. Dysregulated circRNA homeodomain‐interacting protein kinase 3 (circHIPK3) in serum and the DRG, abnormally expressed lncRNAs X‐inactive specific transcript (XIST), nuclear enriched abundant transcript 1 (NEAT1), small nucleolar RNA host gene 1 (SNHG1), as well as ciRS‐7, zinc finger protein 609 (cirZNF609), circ_0005075, and circAnks1a in the spinal cord were suggested to participate in neuropathic pain development. Dysregulated miRNAs contribute to neuropathic pain via neuroinflammation, autophagy, abnormal ion channel expression, regulating pain‐related mediators, protein kinases, structural proteins, neurotransmission excitatory–inhibitory imbalances, or exosome miRNA‐mediated neuron–glia communication. In addition, lncRNAs and circRNAs are essential in neuropathic pain by acting as antisense RNA and miRNA sponges, epigenetically regulating pain‐related molecules expression, or modulating miRNA processing. Conclusions Numerous dysregulated ncRNAs have been suggested to participate in neuropathic pain development. However, there is much work to be done before ncRNA‐based analgesics can be clinically used for various reasons such as conservation among species, proper delivery, stability, and off‐target effects.

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Overexpression of miR-378 Alleviates Chronic Sciatic Nerve Injury by Targeting EZH2

Cited by 11 publications

References 41 publications

Role of hippocampal circKcnk9 in visceral hypersensitivity and anxiety comorbidity of irritable bowel syndrome

Role of hippocampal circKcnk9 in visceral hypersensitivity and anxiety comorbidity of irritable bowel syndrome

Expression Profiles of Circulating MicroRNAs in XELOX-Chemotherapy-Induced Peripheral Neuropathy in Patients with Advanced Gastric Cancer

The etiological roles of miRNAs, lncRNAs, and circRNAs in neuropathic pain: A narrative review

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