XIST/miR‐544 axis induces neuropathic pain by activating STAT3 in a rat model

Abstract

An increasing number of studies have reported that lncRNAs are responsible for the development of neuropathic pain. In our current study, chronic constriction injury (CCI) rat models were established and we observed that lncRNA XIST was greatly increased. Knockdown of XIST can relieve pain characteristics including both mechanical and thermal hyperalgesia in CCI rats. Meanwhile, XIST down-regulation could inhibit neuro-inflammation by reducing expression of inflammatory cytokines including tumor necrosis factor (TNF)-α, IL-1β, and IL-6 and in CCI rats. By performing bioinformatics technology, miR-544 was predicted to have interactions with XIST and dual-luciferase reporter assays validated the correlation between them. A negative correlation between miR-544 and XIST was observed by carrying out XIST loss or gain of function tests. miR-544 markedly alleviated neuropathic pain development in CCI rats via targeting inflammatory cytokines, which was reversed by XIST over-expression. Moreover, STAT3 was manifested to be a target gene of miR-544 by bioinformatics predictions and it was activated in CCI rats. Over-expression of STAT3 was able to induce neuropathic pain and miR-544 inhibited this process in vivo. Furthermore, XIST increased STAT3 expression by sponging miR-544 in neuropathic pain development. To conclude, our present study indicated that XIST can contribute to neuropathic pain progression in rats through down-regulating miR-544 and up-regulating STAT3. Our results suggested that XIST/miR-544/STAT3 axis can serve as a novel therapeutic target in neuropathic pain development.

Knockdown XIST alleviates LPS‐induced WI‐38 cell apoptosis and inflammation injury via targeting miR‐370‐3p/TLR4 in acute pneumonia

“…Sun et al showed that XIST inhibition could reduce inflammatory pain through inhibiting Nav1.7 by acting as a sponge for miR‐146a, suggesting a promising strategy for fighting inflammatory pain . Moreover, XIST knockdown inhibited neuroinflammation by suppressing TNF‐α, COX‐2, and IL‐6 expression in CCI rats . However, there are few literature studies on the function and mechanism of XIST in pneumonia.…”

“…XIST was reported to promote cancer development and could cause inflammation response in chronic constriction injury, neuropathic pain, and chronic pain . To profile the expression of XIST in LPS‐injured WI‐38 cells, qRT‐RCR analysis was evaluated.…”

“…The lncRNA X inactivate‐specific transcript (XIST), which is located on the X chromosome, is enriched in multiple cancers and regulates tumorigenesis and development as a potential oncogene gene through competing RNA mechanisms . Of note, XIST is proved to regulate the inflammatory response in neuropathic pain and peripheral nerve injury . Hence, it was hypothesized that XIST might function to modify the inflammation response in pneumonia.…”

LncRNA Xist Contributes to Endogenous Neurological Repair After Chronic Compressive Spinal Cord Injury by Promoting Angiogenesis Through the miR-32-5p/Notch-1 Axis

“…For miR-32-5p and Notch-1 interaction, the putative and mutated miR-32-5p target binding sequences in Notch-1 were synthesized and cells were co-transfected with the WT or MUT Notch-1 reporter gene plasmid or pmirGlo plasmids using Lipofectamine ® 2000 (Invitrogen). At 48 h post-transfection, cells were harvested and the firefly luciferase activity was measured using a dual-luciferase reporter assay system (Promega) and normalized to Renilla luciferase activity ( Jin et al, 2018 ; Hu et al, 2019 ).…”

Functional roles of lncRNAs and its potential mechanisms in neuropathic pain

“…1b). In recent studies, XIST appeared to function as miRNA sponge sequestering miR-137, miR-150, miR-544, and miR-154-5p, then regulating the expression of relevant binding proteins or the release of inflammatory cytokines that accelerated NP progression [36][37][38][39][40]. In addition, Gu et al [41] demonstrated that XIST effectively becomes a miRNA sponge for miR-494, also acting as a competitive endogenous RNA (ceRNA), and contributed to neuronal apoptosis through the downregulation of AKT phosphorylation in the SCI model.…”