CREB-regulated transcription coactivator 1 enhances CREB-dependent gene expression in spinal cord to maintain the bone cancer pain in mice.
CREB-regulated transcription coactivator 1 enhances CREB-dependent gene expression in spinal cord to maintain the bone cancer pain in mice.
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CREB调节的转录共激活因子1增强脊髓中CREB依赖性基因表达以维持小鼠骨癌疼痛
DOI：
10.1177/1744806916641679
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发表时间：
2016
期刊：
影响因子：
3.3
通讯作者：
Gu X
中科院分区：
文献类型：
--
作者：
Liang Y;Liu Y;Hou B;Zhang W;Liu M;Sun YE;Ma Z;Gu X
背景cAMP反应元件结合蛋白（CREB）依赖的基因表达在中枢致敏中起重要作用。CREB调节的转录辅激活因子1（CRTC 1）显著增加CREB介导的转录活性。脑源性神经营养因子、N-甲基-d-天冬氨酸受体亚基2B和miRNA-212/132是高度CREB反应性的，它们在CREB/CRTC 1下游起作用，介导活性依赖性突触可塑性，并反过来环回放大CREB/CRTC 1信号传导。本研究旨在利用RNA干扰方法研究脊髓CRTC 1在骨癌疼痛维持中的作用。结果将骨肉瘤细胞植入C3 H/HeNCrlVr小鼠右侧股骨髓内，诱导骨癌痛。Western blotting检测脊髓磷酸化Ser 133 CREB和CRTC 1的表达。我们进一步研究了重复鞘内注射表达CRTC 1-小干扰RNA（siRNA）的腺病毒对伤害性行为和与骨癌疼痛相关的CREB/CRTC 1靶基因上调的影响。骨肉瘤细胞的接种诱导进行性机械异常性疼痛和自发性疼痛，并导致脊髓p-CREB和CRTC 1的上调。重复鞘内注射表达CRTC 1-siRNA的腺病毒可减弱骨癌诱发的疼痛行为，并降低脊髓中CREB/CRTC 1靶基因（包括BDNF、NR 2B和miR-212/132）的表达。结论脊髓CRTC 1表达上调，CREB依赖基因转录增加，可能在骨癌痛中起重要作用。抑制脊髓CRTC 1表达可减轻骨癌疼痛。阻断CREB/CRTC 1与其靶点之间的正反馈回路可能有助于镇痛作用。这些发现可能为骨癌疼痛的机制和治疗提供进一步的见解。
Background cAMP response element binding protein (CREB)-dependent gene expression plays an important role in central sensitization. CREB-regulated transcription coactivator 1 (CRTC1) dramatically increases CREB-mediated transcriptional activity. Brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, and miRNA-212/132, which are highly CREB responsive, function downstream from CREB/CRTC1 to mediate activity-dependent synaptic plasticity and in turn loops back to amplify CREB/CRTC1 signaling. This study aimed to investigate the role of spinal CRTC1 in the maintenance of bone cancer pain using an RNA interference method. Results Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeNCrlVr mice to induce bone cancer pain. Western blotting was applied to examine the expression of spinal phospho-Ser133 CREB and CRTC1. We further investigated effects of repeated intrathecal administration with Adenoviruses expressing CRTC1-small interfering RNA (siRNA) on nociceptive behaviors and on the upregulation of CREB/CRTC1-target genes associated with bone cancer pain. Inoculation of osteosarcoma cells induced progressive mechanical allodynia and spontaneous pain, and resulted in upregulation of spinal p-CREB and CRTC1. Repeated intrathecal administration with Adenoviruses expressing CRTC1-siRNA attenuated bone cancer–evoked pain behaviors, and reduced CREB/CRTC1-target genes expression in spinal cord, including BDNF, NR2B, and miR-212/132. Conclusions Upregulation of CRTC1 enhancing CREB-dependent gene transcription in spinal cord may play an important role in bone cancer pain. Inhibition of spinal CRTC1 expression reduced bone cancer pain. Interruption to the positive feedback circuit between CREB/CRTC1 and its targets may contribute to the analgesic effects. These findings may provide further insight into the mechanisms and treatment of bone cancer pain.