Department of Anesthesiology, Shunde Hospital of Southern Medical University, No. 1 Lunjiaojiazi Road, Shunde District, Foshan, 528308, Guangdong, China.
J Mol Neurosci. 2020 Jan;70(1):9-18. doi: 10.1007/s12031-019-01378-w. Epub 2019 Jul 31.
Altered expression of circular RNA (circRNA) is recognized as a contributor to malignant pain where microRNA (miRNA) exerts an essential effect. We generated a murine model for bone malignancy pain in which 2472 osteolytic sarcoma cells were injected into the femurs of mice. CircRNA microarray and quantitative PCR (qPCR) and revealed that circ9119 expression was repressed in the spinal cord of bone malignancy pain model mice, which is the first relay site involved in the transmission of nociceptive information to the cerebrum of mice that receive spinal analgesics for malignancy pain. Overexpression of circ9119 by plasmid injection in the model mice reduced progressive thermal hyperalgesia and mechanical hyperalgesia. Bioinformatics prediction and dual-luciferase reporter assay showed that circ9119 functions as a sponge of miR-26a, which targets the TLR3 3'-untranslated region. Furthermore, expression of miR-26a was elevated and TLR3 level was repressed in bone malignancy pain model mice, which were counteracted by circ9119 in the spinal cord of tumor-bearing mice. Moreover, excessive expression of miR-26a was involved in the recovery of mice from progressive thermal hyperalgesia and mechanical hyperalgesia triggered via circ9119. TLR3 knockdown in bone malignancy pain model mice thoroughly impaired pain in the initial stages and reduced the effects of circ9119 on hyperalgesia. Our research findings indicate that targeting the circ9119-miR-26a-TLR3 axis may be a promising analgesic strategy to manage malignancy pain.
环状 RNA（circRNA）表达的改变被认为是恶性疼痛的一个促成因素，其中 microRNA（miRNA）发挥着重要作用。我们构建了一种骨恶性疼痛的小鼠模型，其中将 2472 个骨肉瘤细胞注射到小鼠的股骨中。circRNA 微阵列和定量 PCR（qPCR）显示，circ9119 在骨恶性疼痛模型小鼠的脊髓中表达受到抑制，这是涉及向接受脊髓镇痛治疗的恶性疼痛小鼠大脑传递伤害性信息的第一级中继站。在模型小鼠中通过质粒注射过表达 circ9119 可减轻进行性热痛觉过敏和机械性痛觉过敏。生物信息学预测和双荧光素酶报告基因测定显示，circ9119 作为 miR-26a 的海绵体发挥作用，后者靶向 TLR3 的 3'-非翻译区。此外，miR-26a 的表达在骨恶性疼痛模型小鼠中升高，TLR3 水平受到抑制，而在肿瘤小鼠的脊髓中，circ9119 则逆转了这种情况。此外，miR-26a 的过度表达参与了由 circ9119 引发的小鼠进行性热痛觉过敏和机械性痛觉过敏的恢复。在骨恶性疼痛模型小鼠中敲低 TLR3 可完全损害早期疼痛，并减轻 circ9119 对痛觉过敏的影响。我们的研究结果表明，靶向 circ9119-miR-26a-TLR3 轴可能是一种有前途的治疗恶性疼痛的镇痛策略。
