Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.
Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.
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DOI：
10.1002/emmm.201302797
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发表时间：
2013-11
影响因子：
11.1
通讯作者：
Kuner, Rohini
中科院分区：
文献类型：
--
作者：
Bali, Kiran Kumar;Selvaraj, Deepitha;Satagopam, Venkata P.;Lu, Jianning;Schneider, Reinhard;Kuner, Rohini
癌症疼痛仍然是一个主要的挑战，迫切需要开发基于特定机制的治疗方法。各种疾病都与microRNAs(MiRNAs)表达的独特特征有关，这揭示了对疾病病理学的深刻见解。在小鼠转移性骨癌疼痛的临床相关模型中，使用结合全基因组miRNA筛选、分子和电子计算机分析与行为方法的综合方法，我们现在表明，肿瘤诱发条件与肿瘤受影响区域对应的感觉神经元中57个miRNAs的显著失调有关。通过在体内建立干扰疾病诱导的外周感觉神经元miRNA失调的方案，我们从功能上验证了六个调控失调的miRNAs是肿瘤相关超敏反应的重要调节器。在计算机分析中发现，他们预测的靶点包括关键的疼痛相关基因，我们发现Clcn3，一个编码氯离子通道的基因，是感觉神经元中的一个关键的miRNA靶点，在体内肿瘤诱导的伤害性超敏中具有重要的功能。我们的结果为癌症疼痛的内源性基因调控机制提供了新的见解，并开辟了有吸引力和可行的治疗方案。
Cancer pain remains a major challenge and there is an urgent demand for the development of specific mechanism-based therapies. Various diseases are associated with unique signatures of expression of microRNAs (miRNAs), which reveal deep insights into disease pathology. Using a comprehensive approach combining genome-wide miRNA screening, molecular and in silico analyses with behavioural approaches in a clinically relevant model of metastatic bone-cancer pain in mice, we now show that tumour-induced conditions are associated with a marked dysregulation of 57 miRNAs in sensory neurons corresponding to tumour-affected areas. By establishing protocols for interference with disease-induced miRNA dysregulation in peripheral sensory neurons in vivo, we functionally validate six dysregulated miRNAs as significant modulators of tumour-associated hypersensitivity. In silico analyses revealed that their predicted targets include key pain-related genes and we identified Clcn3, a gene encoding a chloride channel, as a key miRNA target in sensory neurons, which is functionally important in tumour-induced nociceptive hypersensitivity in vivo. Our results provide new insights into endogenous gene regulatory mechanisms in cancer pain and open up attractive and viable therapeutic options.
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影响因子：
1.7
作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.1206432109
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影响因子：
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