DNMT3a contributes to the development and maintenance of bone cancer pain by silencing Kv1.2 expression in spinal cord dorsal horn.
DNMT3a contributes to the development and maintenance of bone cancer pain by silencing Kv1.2 expression in spinal cord dorsal horn.
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DOI：
10.1177/1744806917740681
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发表时间：
2017-01
期刊：
影响因子：
3.3
通讯作者：
Tao YX
中科院分区：
文献类型：
--
作者：
Miao XR;Fan LC;Wu S;Mao Q;Li Z;Lutz B;Xu JT;Lu Z;Tao YX
转移性骨肿瘤引起的神经系统疼痛相关区域基因转录和翻译的改变可能参与骨癌疼痛的发生和维持。包括DNA甲基化在内的表观遗传修饰调节基因转录。在这里，我们报告说，鞘内注射地西他滨，DNA甲基转移酶（DNMT）抑制剂，剂量依赖性衰减的发展和维持骨癌疼痛注射前列腺癌细胞到胫骨。在前列腺癌细胞注射后，在同侧L4/5背角（而不是L4/5背根神经节）中从头DNMT 3a而不是DNMT 3b的水平时间依赖性地增加。通过将表达Dnmt 3a shRNA的重组腺相关病毒5（AAV 5）显微注射到背角中来阻断这种增加，挽救了前列腺癌细胞诱导的背角Kv1.2表达下调和受损的前列腺癌细胞诱导的疼痛超敏反应。反过来，通过将表达全长Dnmt 3a的AAV 5显微注射到背角中来模拟这种增加，减少了背角Kv1.2表达，并在没有前列腺癌细胞注射的情况下产生疼痛超敏反应。地西他滨和病毒的管理都不影响运动功能和对机械、热或冷刺激的急性反应。鉴于Dnmt 3a mRNA与Kcna 2 mRNA（编码Kv1.2）在单个背角神经元中共表达，我们的研究结果表明，增加背角DNMT 3a通过沉默背角Kv1.2表达而导致骨癌疼痛。DNMT 3a可能是癌症疼痛管理的潜在新靶点。
Metastatic bone tumor-induced changes in gene transcription and translation in pain-related regions of the nervous system may participate in the development and maintenance of bone cancer pain. Epigenetic modifications including DNA methylation regulate gene transcription. Here, we report that intrathecal injection of decitabine, a DNA methyltransferase (DNMT) inhibitor, dose dependently attenuated the development and maintenance of bone cancer pain induced by injecting prostate cancer cells into the tibia. The level of the de novo DNMT3a, but not DNMT3b, time dependently increased in the ipsilateral L4/5 dorsal horn (not L4/5 dorsal root ganglion) after prostate cancer cells injection. Blocking this increase through microinjection of recombinant adeno-associated virus 5 (AAV5) expressing Dnmt3a shRNA into dorsal horn rescued prostate cancer cells-induced downregulation of dorsal horn Kv1.2 expression and impaired prostate cancer cells-induced pain hypersensitivity. In turn, mimicking this increase through microinjection of AAV5 expressing full-length Dnmt3a into dorsal horn reduced dorsal horn Kv1.2 expression and produced pain hypersensitivity in the absence of prostate cancer cells injection. Administration of neither decitabine nor virus affected locomotor function and acute responses to mechanical, thermal, or cold stimuli. Given that Dnmt3a mRNA is co-expressed with Kcna2 mRNA (encoding Kv1.2) in individual dorsal horn neurons, our findings suggest that increased dorsal horn DNMT3a contributes to bone cancer pain through silencing dorsal horn Kv1.2 expression. DNMT3a may represent a potential new target for cancer pain management.
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影响因子：
3.3
作者：
Fan L;Guan X;Wang W;Zhao JY;Zhang H;Tiwari V;Hoffman PN;Li M;Tao YX
通讯作者：
Tao YX
影响因子：
2.9
作者：
Wang, Ying;Liu, Chang;Zou, Wang-Yuan
通讯作者：
Zou, Wang-Yuan
靶向初级感觉神经元中的 A 型 K 通道治疗大鼠模型中的骨癌疼痛
影响因子：
7.4
作者：
Duan, Kai-Zheng;Xu, Qian;Zhang, Yu-Qiu
通讯作者：
Zhang, Yu-Qiu
影响因子：
4.6
作者：
Liang L;Gu X;Zhao JY;Wu S;Miao X;Xiao J;Mo K;Zhang J;Lutz BM;Bekker A;Tao YX
通讯作者：
Tao YX
影响因子：
4
作者：
Gaskin, Darrell J.;Richard, Patrick
通讯作者：
Richard, Patrick