Spinal circRNA-9119 Suppresses Nociception by Mediating the miR-26a-TLR3 Axis in a Bone Cancer Pain Mouse Model
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Altered expression of circular RNA (circRNA) is recognized as a contributor to malignant pain where microRNA (miRNA) exerts an essential effect. We generated a murine model for bone malignancy pain in which 2472 osteolytic sarcoma cells were injected into the femurs of mice. CircRNA microarray and quantitative PCR (qPCR) and revealed that circ9119 expression was repressed in the spinal cord of bone malignancy pain model mice, which is the first relay site involved in the transmission of nociceptive information to the cerebrum of mice that receive spinal analgesics for malignancy pain. Overexpression of circ9119 by plasmid injection in the model mice reduced progressive thermal hyperalgesia and mechanical hyperalgesia. Bioinformatics prediction and dual-luciferase reporter assay showed that circ9119 functions as a sponge of miR-26a, which targets the TLR3 3′-untranslated region. Furthermore, expression of miR-26a was elevated and TLR3 level was repressed in bone malignancy pain model mice, which were counteracted by circ9119 in the spinal cord of tumor-bearing mice. Moreover, excessive expression of miR-26a was involved in the recovery of mice from progressive thermal hyperalgesia and mechanical hyperalgesia triggered via circ9119. TLR3 knockdown in bone malignancy pain model mice thoroughly impaired pain in the initial stages and reduced the effects of circ9119 on hyperalgesia. Our research findings indicate that targeting the circ9119-miR-26a-TLR3 axis may be a promising analgesic strategy to manage malignancy pain.
KeywordsBone cancer pain Hyperalgesia Circular RNA-9119 miR-26a TLR3
This work was supported by the Key Specialist Project of Clinical Medicine of Foshan City (Grant Number FSZDZK135049); Distinguished Youth Talent Fund Project of the First Medical Science Center of Foshan City in 2018; and Guangdong Medical Research Fund Project in 2019 (Grant Number A2019045). We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
Compliance with Ethical Standards
This study was approved by the Committee on the Ethics of Animal Experiments of Shunde Hospital of Southern Medical University.
Conflict of Interest
The authors declare that they have no conflict of interest.
- Coleman RE (1997) Skeletal complications of malignancy cancer: interdisciplinary. Int J Am Cancer Soc 80:1588–1594Google Scholar
- Fujii T, Shimada K, Nakai T, Ohbayashi C (2018) MicroRNAs in smoking-related carcinogenesis: biomarkers, functions, and therapy. J Clin Med:7. https://doi.org/10.3390/jcm7050098
- Jeck WR et al. (2013) Circular RNAs are abundant, conserved, and associated with ALU repeats RNA 19:141-157 doi: https://doi.org/10.1261/rna.035667.112
- Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method methods 25:402–408Google Scholar
- Luger NM et al (2001) Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res 61:4038–4047Google Scholar
- Njoo C, Heinl C, Kuner R (2014) In vivo SiRNA transfection and gene knockdown in spinal cord via rapid noninvasive lumbar intrathecal injections in mice JoVE (Journal of Visualized Experiments):e51229Google Scholar
- Rybak-Wolf A, Stottmeister C, Glažar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, Herzog M, Schreyer L, Papavasileiou P, Ivanov A, Öhman M, Refojo D, Kadener S, Rajewsky N (2015) Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell 58:870–885. https://doi.org/10.1016/j.molcel.2015.03.027 CrossRefGoogle Scholar
- Sabino MAC et al. (2002) Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2 62:7343-7349Google Scholar
- Zhang L et al (2018a) CircRNA-9119 regulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) by sponging miR-26a in the endometrial epithelial cells of dairy goat. Reprod Fertil Dev. https://doi.org/10.1071/RD18074
- Zhang L et al (2018b) CircRNA-9119 regulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) by sponging miR-26a in the endometrial epithelial cells of dairy goat. 30:1759–1769Google Scholar