JAG‐1/Notch signaling axis in the spinal cord contributes to bone cancer pain in rats

Abstract

Notch signal plays an important role in regulating cell–cell interactions with the adjacent cells. However, it remains unknown whether Jagged1 (JAG‐1) mediated Notch signaling regulates bone cancer pain (BCP) via the spinal cell interactions mechanism. Here, we showed that intramedullary injection of Walker 256 breast cancer cells increased the expression of JAG‐1 in spinal astrocytes and knockdown of JAG‐1 reduced BCP. The supplementation of exogenous JAG‐1 to the spinal cord induced BCP‐like behavior and promoted expression of c‐Fos and hairy and enhancer of split homolog‐1 (Hes‐1) in the spinal cord of the naïve rats. These effects were reversed when the rats were administered intrathecal injections of N‐[N‐(3,5‐difluorophenacetyl)‐l‐alanyl]‐S‐phenylglycine t‐butyl ester (DAPT). The intrathecal injection of DAPT reduced BCP and inhibited Hes‐1 and c‐Fos expression in the spinal cord. Furthermore, our results showed that JAG‐1 up‐regulated Hes‐1 expression by inducing the recruitment of Notch intracellular domain (NICD) to the RBP‐J/CSL‐binding site located within the Hes‐1 promoter sequence. Finally, the intrathecal injection of c‐Fos‐antisense oligonucleotides (c‐Fos‐ASO) and administration of sh‐Hes‐1 to the spinal dorsal horn also alleviated BCP. The study indicates that inhibition of the JAG‐1/Notch signaling axis may be a potential strategy for the treatment of BCP.image

N4-acetylcytidine acetylation of neurexin 2 in the spinal dorsal horn regulates hypersensitivity in a rat model of cancer-induced bone pain

“…A CIBP model was created by injecting 10 μL Walker-256 breast cancer cell suspension into the bone marrow cavity of the left tibia of Sprague-Dawley rats. 22 , 23 , 24 Our previous research identified the widespread distribution of ac4C in the spinal dorsal horn (SDH) L4–L6 transcriptome of rats by ac4C-specific RNA immunoprecipitation assay (acRIP-seq). The differential genes with ac4C mRNA modification and mRNA expression in CIBP rats revealed a significant correlation, suggesting that ac4C is involved in the development of CIBP.…”