PDF(Pubmed)
Abstract：
Cancer-induced bone pain (CIBP) significantly impacts the quality of life and survival of patients with advanced cancer. Despite the established role of neurexins in synaptic structure and function, their involvement in sensory processing during injury has not been extensively studied. In this study using a rat model of CIBP, we observed increased neurexin 2 expression in spinal cord neurons. Knockdown of neurexin 2 in the spinal cord reversed CIBP-related behaviors, sensitization of spinal c-Fos neurons, and pain-related negative emotional behaviors. Additionally, increased acetylation of neurexin 2 mRNA was identified in the spinal dorsal horn of CIBP rats. Decreasing the expression of N-acetyltransferase 10 (NAT10) reduced neurexin 2 mRNA acetylation and neurexin 2 expression. In PC12 cells, we confirmed that neurexin 2 mRNA acetylation enhanced its stability, and neurexin 2 expression was regulated by NAT10. Finally, we discovered that the NAT10/ac4C-neurexin 2 axis modulated neuronal synaptogenesis. This study demonstrated that the NAT10/ac4C-mediated posttranscriptional modulation of neurexin 2 expression led to the remodeling of spinal synapses and the development of conscious hypersensitivity in CIBP rats. Therefore, targeting the epigenetic modification of neurexin 2 mRNA ac4C may offer a new therapeutic approach for the treatment of nociceptive hypersensitivity in CIBP.
摘要：
癌症引起的骨痛（CIBP）显着影响晚期癌症患者的生活质量和生存率。尽管神经素在突触结构和功能中的作用已经确立，它们在损伤过程中的感官处理中的参与尚未得到广泛研究。在这项研究中使用CIBP的大鼠模型，我们观察到脊髓神经元中Neurexin2的表达增加。脊髓神经肽2的敲减逆转CIBP相关行为，脊髓c-Fos神经元致敏，和疼痛相关的负面情绪行为。此外,在CIBP大鼠的脊髓背角中发现了Neurexin2mRNA的乙酰化增加。降低N-乙酰转移酶10（NAT10）的表达会降低Neurexin2的mRNA乙酰化和Neurexin2的表达。在PC12单元格中，我们证实Neurexin2mRNA乙酰化增强了其稳定性，NAT10调控Nurexin2的表达。最后,我们发现NAT10/ac4C-neurexin2轴调节神经元突触发生。这项研究表明，NAT10/ac4C介导的neurexin2表达的转录后调节导致了脊髓突触的重塑和意识超敏反应的发展。因此,靶向neurexin2mRNAac4C的表观遗传修饰可能为CIBP伤害性超敏反应的治疗提供新的治疗方法。
