脊髓
Notch信号通路
基因敲除
医学
细胞
癌症研究
化学
内科学
细胞凋亡
受体
生物化学
精神科
作者
Jie Fu,Baoxia Zhao,Ge Luo,Huadong Ni,Longsheng Xu,Qing He,Miao Xu,Chengfei Xu,Yahui Wang,Chaobo Ni,Ming Yao
摘要
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
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