Enhanced binding capability of nuclear factor-κB with demethylated P2X3 receptor gene contributes to cancer pain in rats.
Enhanced binding capability of nuclear factor-κB with demethylated P2X3 receptor gene contributes to cancer pain in rats.
复制标题
核因子-kappaB 与去甲基化 P2X3 受体基因的结合能力增强有助于大鼠的癌痛。
DOI：
10.1097/j.pain.0000000000000248
复制
发表时间：
2015-10
期刊：
影响因子：
7.4
通讯作者：
Xu GY
中科院分区：
文献类型：
--
作者：
Zhou YL;Jiang GQ;Wei J;Zhang HH;Chen W;Zhu H;Hu S;Jiang X;Xu GY
补充数字内容可在正文中找到。P2X3受体的表观遗传调控在癌症疼痛中起着至关重要的作用。靶向p65结合去甲基化的P2X3受体基因可抑制癌痛。核因子-kappaB(NF-κB)信号转导与肿瘤的发生和炎症过程密切相关。然而，核因子-κB信号在癌变疼痛中的作用和机制仍不清楚。本研究旨在探讨核因子-κB的p65亚单位在调控大鼠背根神经节嘌呤能受体可塑性中的作用。我们在这里显示，肿瘤细胞注射产生机械和热过敏，以及增强的体重差异，这与腰椎DRG中P65和P2X3R的表达上调以及胫骨神经支配的DRG神经元的ATP诱发反应增强有关。用p65抑制剂吡咯烷二硫代氨基甲酸酯、BAY-11-7082或慢病毒p65短发夹状核糖核酸抑制NF-κB信号转导显著减弱CIP并逆转P2X3R的活性。有趣的是，肿瘤细胞注射导致p2x3r基因启动子的CpG岛显著去甲基化，并增强了p65与p2x3r基因启动子的结合能力。我们的研究结果提示，p65与p2x3r基因去甲基化启动子结合能力的增强是导致P2X3R表达上调的原因之一。NF-κBp65可能是治疗CIP的潜在靶点，CIP是一种神经病理性疼痛，由肿瘤细胞对支配皮肤的神经造成损伤而产生。
Supplemental Digital Content is Available in the Text. Epigenetic regulations of P2X3 receptors play a crucial role in cancer pain. Targeting p65 binding to demethylated P2X3 receptor gene suppresses cancer pain. Nuclear factor-kappa B (NF-κB) signaling is implicated in both cancer development and inflammation processes. However, the roles and mechanisms of NF-κB signaling in the development of cancer-induced pain (CIP) remain unknown. This study was designed to investigate the roles of the p65 subunit of NF-κB in regulation of the purinergic receptor (P2X3R) plasticity in dorsal root ganglion (DRG) of CIP rats. We showed here that tumor cell injection produced mechanical and thermal hyperalgesia, and an enhanced body weight–bearing difference, which was correlated with an upregulation of p65 and P2X3R expression in lumber DRGs and a potentiation of ATP-evoked responses of tibia-innervating DRG neurons. Inhibition of NF-κB signaling using p65 inhibitor pyrrolidine dithiocarbamate, BAY-11-7082, or lentiviral-p65 short-hairpin RNA significantly attenuated CIP and reversed the activities of P2X3R. Interestingly, tumor cell injection led to a significant demethylation of CpG island in p2x3r gene promoter and enhanced ability of p65 to bind the promoter of p2x3r gene. Our findings suggest that upregulation of P2X3R expression was mediated by the enhanced binding capability of p65 with demethylated promoter of p2x3r gene, thus contributing to CIP. NF-κBp65 might be a potential target for treating CIP, a neuropathic pain generated by tumor cell–induced injury to nerves that innervate the skin.