LncRNA NONRATT014888.2负向调控SOCS3信号通路介导癌性痛的分子机制研究

Cancer-induced pain (CIP), often seen among breast cancer patients, is one of the most severe types of chronic pain, which clinical treatment remains challenging and the involved mechanisms are largely unknown. It’s urgent to study its mechanisms and to find new therapeutic targets. More and more evidence proves that peripheral tissue injuries result in sensitization of primary sensory neurons, which their cell bodies located in the dorsal root ganglion (DRG). LncRNAs has been reported to play an important role in pain progress, but its role in CIP hasn’t been reported. Previous study has showed that lncRNA NONRATT014888.2 was upregulated and associated with suppressor of cytokine signaling 3 (SOCS3), which is an important intracellular protein and provides a classical negative feedback loop, thus involving in a wide variety of processes including inflammation and nociception. In our preliminary studies, we have demonstrated that the protein level of SOCS3 was decreased and SOCS3-overexpression relieved CIP. Based on these exciting data, firstly we are aimed to define the roles of lncRNA NONRATT014888.2 in CIP. And then we are aimed to identify the possible downstream molecules such as SOCS3 in rats with CIP and to investigate the epigenetic and neuronal mechanisms by which lncRNA NONRATT014888.2 expression was up-regulated. We hope our studies will shed the light into the mechanism of CIP and eventually provide potential therapeutic targets for the treatment for patients with cancer pain.

癌痛是临床难题，研究其分子机制、寻找治疗靶点是临床上亟待解决的问题。文献报导外周组织损伤导致的初级神经元（DRG）敏化是机械痛敏、热痛敏的主要原因。LncRNA在疼痛中的作用已经越来越受到重视,而在癌痛中的作用和分子机制目前还未有报道。我们的前期基因芯片结果发现lncRNA NONRATT014888.2异常升高且与细胞信号传导抑制因子SOCS3的表达负相关；SOCS3在骨癌痛大鼠中表达降低，过表达SOCS3可以缓解骨癌痛大鼠的痛觉过敏。本项目拟在骨癌大鼠模型上着重开展二方面的研究：首先阐明lncRNA NONRATT014888.2对癌骨转移疼痛的影响，然后深入探讨其通过负向调节SOCS3参与癌痛调控的机制及其异常表达的上游靶分子。该项目的实施，有望为癌痛的治疗提供科学依据及新的治疗靶点。

癌痛是临床难题，多发于乳腺癌、肺癌等病人中，研究其分子机制、寻找治疗靶点是临床上亟待解决的问题。LncRNA在疼痛中的作用已经越来越受到重视，而在癌痛中的作用和分子机制目前还未有报道。文献报导外周组织损伤导致的初级神经元（DRG）敏化是机械痛敏、热痛敏的主要原因。我们前期基因芯片结果发现lncRNA NONRATT014888.2在癌痛大鼠的DRG组织中异常升高，构建慢病毒shRNA敲降该lncRNA的表达后，能有效缓解癌痛大鼠的痛觉过敏。本项目首先阐明lncRNA NONRATT014888.2在癌痛中的表达、定位及对癌痛的影响，发现其具有组织和疾病特异性；然后通过mRNA测序，质谱分析，FISH等技术重点研究lncRNA NONRATT014888.2发挥作用的机制，结果发现该lncRNA可激活TNF等通路，调控炎症反应、对细胞因子的反应过程等发挥功能作用。另外，我们重点发现了lncRNA NONRATT014888.2可调控下游的SOCS3、NPR3等疼痛相关分子的表达，从而进一步参与癌痛的调控。LncRNA NONRATT014888.2可能有望为癌痛的治疗提供科学依据及新的治疗靶点。