外泌体circ-PLXDC2结合HuR蛋白激活Wnt/整合素β1通路促进前列腺癌骨转移的机制

骨转移是前列腺癌(PC)致死的重要原因，但机制不明。我们前期通过高通量测序在PC患者血浆外泌体中筛选出骨转移相关环状RNA (circ-PLXDC2)，临床验证血浆外泌体circ-PLXDC2高表达者骨转移进展率明显高于低表达者；进一步实验证实，circ-PLXDC2可与HuR蛋白结合，沉默PC细胞系 circ-PLXDC2明显抑制增殖和侵袭；circ-PLXDC2转染后，β-catenin上调，整合素β1上调。鉴于整合素β1与骨转移存在密切关联，我们提出外泌体circ-PLXDC2促进PC骨转移新机制：外泌体circ-PLXDC2转运至PC细胞，与HuR蛋白结合，激活wnt/β-catenin通路，上调整合素β1表达，促进PC骨转移。本项目拟通过分子、细胞、动物和临床标本等水平的一系列实验，力图解析外泌体circ-PLXDC2促进PC骨转移的机理，为干预PC骨转移提供新的分子靶点。

Bone metastasis is the major cause of mortality in prostate cancer (PC), however its mechanism remains unclear. In our previous study, we found a bone metastasis-related circular RNA (circ-PLXDC2) via high-throughput RNA sequencing from plasma exosomes of PC patients. Patients with high level of plasma exosomal circ-PLXDC2 had shorter bone metastasis-free survival than those with low level of plasma exosomal circ-PLXDC2. Further experiments confirmed that circ-PLXDC2 could bind to HuR protein. Silencing circ-PLXDC2 in PC cell lines could significantly inhibit cell proliferation and invasion in vitro and in vivo. The expression of β-catenin and β1 integrin was up-regulated in circ-PLXDC2 transfected PC cells. Considering the close relationship between β1 integrin and bone metastasis, we propose a new mechanism of exosomal circ-PLXDC2 promoting bone metastasis in PC: exosomal circ-PLXDC2 could be transported to low malignant PC cells. It binds to HuR protein, activates wnt/β-catenin pathway, up-regulates the expression of β1 integrin, thus promotes bone metastasis. This present project aims to elucidate the mechanism by which exosomal circ-PLXDC2 promoting bone metastasis and may provide a new target for clinical intervention.