摘要
骨转移引起的疼痛对癌症患者生活质量有很大影响,但因为各种不良反应目前对骨癌痛的治疗不能达到满意的治疗目标。当前,需要先进的监控来阐明其发病机制,以便开发出更有效的治疗方法。我们构建了针对CNTF (HSV-siCNTF)的单纯疱疹病毒携带的小分子干扰RNA,并建立了胫骨内注射MRMT-1细胞的癌症诱发骨癌痛模型。在治疗后不同时间点,测定了由热痛觉过敏和无意识痛觉来表达的感觉功能。也测定了由CNTF调控的感觉功能的基本机制。在注射骨癌细胞的大鼠上有明显的机械和热痛觉过敏。通过普通放射在胫骨注射肿瘤细胞的区域中检测到骨损坏。在胫骨部分发现苏木精和曙红的染色,显示了MRMT -1细胞和破骨细胞的数量增加。鞘内注射吗啡或HSV - siCNTF能显著降低异常性疼痛和热痛觉过敏,并伴随着星形胶质细胞肥大。呈P物质阳性神经纤维和降钙素基因相关肽(CGRP )数量的显著下降,这与CNTF, ERK/pERK, AKT/pAKT 和 c-fos表达下降一致。这些结果表明, HSV- siCNTF基因疗法表明通过阻断AKT- ERK信号通路治疗骨癌引发的疼痛的效果。我们的数据表明,CNTF干扰可被视为一个新的靶标来发展成为骨癌痛的一个有效方案。
关键词: 骨癌痛,CNTF
Current Gene Therapy
Title:Reversal of Bone Cancer Pain by HSV-1-Mediated Silencing of CNTF in an Afferent Area of the Spinal Cord Associated with AKT-ERK Signal Inhibition
Volume: 14 Issue: 5
Author(s): Xu Yang, Jia Liu, Zun-Jing Liu, Qing-Jie Xia, Mu He, Ran Liu, Wei Liu, Wei Wang, Jin Liu, Xin-Fu Zhou, Yun-Hui Zhang and Ting-Hua Wang
Affiliation:
关键词: 骨癌痛,CNTF
摘要: Pain induced by bone metastases has a strong impact on the quality of life of patients with cancer, but current therapies for bone cancer pain cannot attain a satisfactory therapeutic goal because of various adverse reactions. Currently, advanced monitoring is required to clarify pathogenic mechanisms, so as to develop more effective treatments. We constructed herpes simplex virus carrying small interference RNA for CNTF (HSV-siCNTF) and established cancer-induced bone cancer pain models with intra-tibial injection of MRMT-1 cells. At different time points after treatment, sensory function indicated by thermal hyperalgesia and mechanical allodynia was measured. The mechanism underlying sensory function regulated by CNTF was also determined. There was apparent mechanical and thermal hyperalgesia in rats injected with bone cancer cells. Bone destruction was detected in the area of tibia injected with tumor cells by the plain radiography. MRMT-1 cells and the increased number of osteoclasts were found in tibia sections stained with hematoxylin and eosin. Intrathecal injection of morphine or HSV-siCNTF significantly reduced the mechanical allodynia and thermal hyperalgesia, which was accompanied by astrocyte hypertrophy. The number of nerve fibers positive for substance P (SP) and calcitonin gene related peptide (CGRP) was significantly decreased, which was consistent with the decrease of CNTF, ERK/pERK, AKT/pAKT and c-fos expression. These results demonstrate that the HSV-siCNTF gene therapy appears beneficial for the treatment of pain induced by bone cancer via blocking the AKT-ERK signaling pathway. Our data suggest that CNTF interference may be considered a new target to develop an effective management for bone cancer pain.
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Yang Xu, Liu Jia, Liu Zun-Jing, Xia Qing-Jie, He Mu, Liu Ran, Liu Wei, Wang Wei, Liu Jin, Zhou Xin-Fu, Zhang Yun-Hui and Wang Ting-Hua, Reversal of Bone Cancer Pain by HSV-1-Mediated Silencing of CNTF in an Afferent Area of the Spinal Cord Associated with AKT-ERK Signal Inhibition, Current Gene Therapy 2014; 14 (5) . https://dx.doi.org/10.2174/156652321405140926162236
DOI https://dx.doi.org/10.2174/156652321405140926162236 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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