Annexin A3介导HIF-1α/VEGF信号通路参与骨癌痛形成的分子机制研究

The mechanisms of cancer-induced bone pain are pooly understood. Our previous study,for the first time,discovered that Annexin A3 (ANXA3) was upregulated with bone cancer pain（BCP）rats, and immunofluorescence staining showed that ANXA3 was located in the microglia of the spinal cord.Then we further intrathecal injection of LV-shANXA3, the reduction of Annexin A3 was correlated with the relief of mechanical allodynia and thermal hyperalgesia induced by BCP rats.Previous study showed that ANXA3 is a novel angiogenic factor that induces VEGF production through the HIF-1α signaling pathway. So we hypothesized that ANXA3 may involed in the development and maintenance of BCP. ANXA3 was activated and up-regulated in the dorsal horn of spinal cord by BCP, Annexin A3 further activate transcription factor HIF-1α, activated HIF-1α act on VEGF, VEGF bind to VEGFR1, so PI3K was activated and nociceptor TRPV1 was sensitized, resut in development and maintance of BCP. Our proposed study will unveil the mechanisms of ANXA3 involvement in the development and maintenance of BCP, and provide experimental basis for the molecular machanisms of bone cancer pain, and provide new target for developing new analgesia and anticancer drugs, which has important potential clinical translational significance.

骨癌痛的分子机制尚不完全清楚，且缺乏有效的治疗手段。我们前期研究中发现骨癌痛大鼠脊髓小胶质细胞的膜联蛋白Annexin A3(ANXA3)表达上调，鞘内注射慢病毒载体介导ANXA3 shRNA对骨癌痛大鼠有显著的镇痛作用。有研究报道ANXA3作为一个新的血管生成因子，通过HIF-1α途径诱导VEGF的表达。因此我们提出假说：骨癌痛引起的伤害性信息通过背根神经节传入至脊髓背角，激活ANXA3，ANXA3进一步激活转录因子HIF-1α，活化的HIF-1α激活VEGF信号通路，VEGF作用于VEGFR1，导致下游PI3K及TRPV1通道激活，介导骨癌痛的发生发展。本项目从分子-细胞-整体动物行为学的研究角度揭示骨癌痛发生发展的新机制，以期为阐明ANXA3介导HIF-1α/VEGF信号通路参与骨癌痛发生发展的分子机制提供理论及实验依据，为开发新型镇痛药物提供新的有益靶点，具有重要的临床转化意义。

骨癌痛的分子机制尚不完全清楚，且缺乏有效的治疗手段。我们在本项目中发现骨癌痛大鼠脊髓小胶质细胞的膜联蛋白Annexin A3（ANXA3）表达上调，鞘内注射慢病毒载体介导ANXA3 shRNA对骨癌痛大鼠有显著的镇痛作用。有研究报道ANXA3作为一个新的血管生成因子，通过HIF-1α途径诱导VEGF的表达。本项目中我们证实了：骨癌痛引起的伤害性信息通过背根神经节传入至脊髓背角，激活ANXA3，ANXA3进一步激活转录因子HIF-1α，活化的HIF-1α激活VEGF信号通路，VEGF作用于VEGFR1，导致下游PI3K及TRPV1通道激活，介导骨癌痛的发生发展。本项目从分子-细胞-整体动物行为学的研究角度揭示骨癌痛发生发展的新机制，为阐明ANXA3介导HIF-1α/VEGF信号通路参与骨癌痛发生发展的分子机制提供理论及实验依据，为开发新型镇痛药物提供了新的有益靶点，具有重要的临床转化意义。