Effects of XIST/miR‐137 axis on neuropathic pain by targeting TNFAIP1 in a rat model

Abstract

Non-coding RNAs have been reported to participate in the pathophysiology of neuropathic pain. The objective of our study was to investigate the biological role of XIST in neuropathic pain development. In our study, we identify and validate that lncRNA XIST was markedly increased and miR-137 was significantly decreased in chronic constriction injury (CCI) rats. XIST silencing alleviated pain behaviors including both mechanical and thermal hyperalgesia in the CCI rats. XIST was predicted to interact with miR-137 by bioinformatics technology and dual-luciferase reporter assays confirmed the correlation between XIST and miR-137. miR-137 was negatively modulated by XIST and upregulation of miR-137 greatly reduced neuropathic pain development in CCI rats. Moreover, we observed that tumor necrosis factor alpha-induced protein 1 (TNFAIP1) was enhanced in CCI rats and 3'-untranslated region (UTR) of TNFAIP1 was exhibited to be a target of miR-137 by bioinformatics prediction. TNFAIP1 can act as a crucial inflammation regulator by activating NF-kB activity. Overexpression of miR-137 significantly suppressed TNFAIP1 both in vitro and in vivo. Furthermore, upregulation of XIST reversed the inhibitory role of miR-137 in neuropathic pain development by inhibiting TNFAIP1. In conclusion, our current study indicates that XIST can positively regulate neuropathic pain in rats through regulating the expression of miR-137 and TNFAIP1. Our results imply that XIST/miR-137/TNFAIP1 axis may serve as a novel therapeutic target in neuropathic pain.

miR-34a-mediated regulation of XIST in female cells under inflammation

“…A recent report showed upregulation of Xist in spinal cord from rat chronic constriction injury model of neuropathic pain, and silencing Xist alleviated both mechanical and thermal hyperalgesia. 41 …”

“…miRNAs are fine tuners of gene regulation and can induce nuanced knockdown of its target mRNAs. Downregulation of Xist by siRNAs was recently shown to decrease pain hypersensitivity 41 in mouse model of neuropathic pain. miR-34a is a tumor suppressor and currently in Phase 1 clinical trials for cancer.…”

Targeting XIST induced apoptosis of human osteosarcoma cells by activation of NF-kB/PUMA signal

“…It has recently found that the expression of XIST was promoted by activated NF-κB pathway and, in turn, XIST generated a negative feedback loop to regulate NF-κB/NLRP3 inflammasome pathway for mediating the process of inflammation [38]. Zhao et al also reported that targeting XIST inhibited NF-kB activity, which serving as a therapeutic target in neuropathic pain [39]. In our study, we found that targeting XIST results in constitutive activation of NF-κB and p65 nucleus translocation and PUMA signal pathway, whereas P65 inhibition could attenuate the PUMA signal expression in the XIST shRNA transfected U2OS cells, demonstrating that XIST could modulate PUMA signaling through activation of P65.…”

The rs1625579 T&gt;G polymorphism in the <em>miRNA-137</em> gene confers a risk of early-onset Kawasaki disease in a southern Chinese population

“…This study is the first to examine miRNA-13 rs1625579 polymorphisms in patients with KD. Recent research showed that overexpression of miRNA-13 significantly inhibited tumor necrosis factor alpha-induced protein 1 (TNFAIP1) production both in vivo and in vitro, 30 and miRNA-13 suppressed vascular smooth muscle cell proliferation and migration. 31 Overexpression of miR-137 inhibited upregulation of the inflammatory cytokines IL-6, VCAM-1 and ICAM-1, and human umbilical vein endothelial cell angiogenesis in vitro.…”