Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion
Upregulation of TRPC6 Mediated by PAX6 Hypomethylation Is Involved in the Mechanical Allodynia Induced by Chemotherapeutics in Dorsal Root Ganglion
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PAX6 低甲基化介导的 TRPC6 上调与化疗药物引起的背根神经节机械性异常性疼痛有关
DOI：
10.1093/ijnp/pyaa014
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发表时间：
2020-03
影响因子：
4.8
通讯作者：
Xu Ting
中科院分区：
文献类型：
--
作者：
Zhang Xiang-Zhong;Luo De-Xing;Bai Xiao-Hui;Ding Huan-Huan;Liu Meng;Deng Jie;Mai Jing-Wen;Yang Yan-Ling;Zhang Su-Bo;Ruan Xiang-Cai;Zhang Xue-Qin;Xin Wen-Jun;Xu Ting
摘要背景：虽然抗神经病药物的作用机制各不相同，但奥沙利铂、紫杉醇或硼替佐米作为一线抗神经病药物均可引起疼痛性神经病。在啮齿类动物中，机械性异常性疼痛是3种化疗药物疼痛性神经病变的常见表型。然而，是否有一个共同的分子参与不同的化疗药物引起的疼痛性周围神经病变仍不清楚。方法在Sprague-Dawley大鼠中腹膜内注射溶剂、奥沙利铂、紫杉醇或硼替佐米后，通过von Frey毛发测试机械性异常性疼痛。采用还原亚硫酸氢盐测序法和甲基化DNA免疫沉淀法检测DNA甲基化的变化。采用免疫印迹、定量聚合酶链反应、染色质免疫沉淀和免疫组化等方法探讨其分子机制。结果奥沙利铂、紫杉醇、硼替佐米3种化疗药物均上调DRG瞬时受体电位阳离子通道、C6亚家族（TRPC 6）mRNA和蛋白的表达，但不影响TRPC 6基因甲基化水平。通过使用TRPC 6 siRNA（i.t.，连续10天）在应用化疗剂后显著缓解了机械性异常性疼痛。此外，在配对盒蛋白6（PAX 6）基因处的DNA甲基转移酶3 β（DNMT 3b）的下调募集导致PAX 6基因的低甲基化和PAX 6表达的增加。最后，通过与TPRC 6启动子结合而增加的PAX 6有助于TRPC 6增加和化疗药物治疗后的机械异常性疼痛。结论DNMT 3b介导的PAX 6基因低甲基化导致TRPC 6表达上调参与了不同化疗药物引起的机械性痛觉超敏反应。
Abstract Background Although the action mechanism of antineoplastic agents is different, oxaliplatin, paclitaxel, or bortezomib as first-line antineoplastic drugs can induce painful neuropathy. In rodents, mechanical allodynia is a common phenotype of painful neuropathy for 3 chemotherapeutics. However, whether there is a common molecular involved in the different chemotherapeutics-induced painful peripheral neuropathy remains unclear. Methods Mechanical allodynia was tested by von Frey hairs following i.p. injection of vehicle, oxaliplatin, paclitaxel, or bortezomib in Sprague-Dawley rats. Reduced representation bisulfite sequencing and methylated DNA immunoprecipitation were used to detect the change of DNA methylation. Western blot, quantitative polymerase chain reaction, chromatin immunoprecipitation, and immunohistochemistry were employed to explore the molecular mechanisms. Results In 3 chemotherapeutic models, oxaliplatin, paclitaxel, or bortezomib accordantly upregulated the expression of transient receptor potential cation channel, subfamily C6 (TRPC6) mRNA and protein without affecting the DNA methylation level of TRPC6 gene in DRG. Inhibition of TRPC6 by using TRPC6 siRNA (i.t., 10 consecutive days) relieved mechanical allodynia significantly following application of chemotherapeutics. Furthermore, the downregulated recruitment of DNA methyltransferase 3 beta (DNMT3b) at paired box protein 6 (PAX6) gene led to the hypomethylation of PAX6 gene and increased PAX6 expression. Finally, the increased PAX6 via binding to the TPRC6 promoter contributes to the TRPC6 increase and mechanical allodynia following chemotherapeutics treatment. Conclusions The TRPC6 upregulation through DNMT3b-mediated PAX6 gene hypomethylation participated in mechanical allodynia following application of different chemotherapeutic drugs.
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影响因子：
16.6
作者：
Sakai A;Saitow F;Maruyama M;Miyake N;Miyake K;Shimada T;Okada T;Suzuki H
通讯作者：
Suzuki H
脑脊液奥沙利铂会导致奥沙利铂全身给药引起的急性疼痛
影响因子：
8.8
作者：
Huang, Zhen-Zhen;Li, Dai;Xin, Wen-Jun
通讯作者：
Xin, Wen-Jun
DOI：
10.1523/jneurosci.0893-09.2009
发表时间：
2009-05-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Alessandri-Haber N;Dina OA;Chen X;Levine JD
通讯作者：
Levine JD
影响因子：
7.4
作者：
SIMONE, DA;BAUMANN, TK;LAMOTTE, RH
通讯作者：
LAMOTTE, RH
DOI：
10.1523/jneurosci.22-15-06408.2002
发表时间：
2002-08
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
A. D. Güler;Hyosang Lee;Tohko Iida;I. Shimizu;M. Tominaga;M. Caterina
通讯作者：
A. D. Güler;Hyosang Lee;Tohko Iida;I. Shimizu;M. Tominaga;M. Caterina