CircSMARCC1经外泌体靶向作用肿瘤相关巨噬细胞调控HMGB1分泌促进前列腺癌骨转移的机制研究

骨转移是前列腺癌最常见远处转移。近来研究表明circRNA在肿瘤转移中起重要作用。我们前期研究发现血浆外泌体中circSMARCC1在前列腺癌显著上调，沉默其表达显著抑制肿瘤增殖转移；同时发现其可经外泌体被肿瘤相关巨噬细胞（TAM）摄取并促进TAM分泌HMGB1；相关机制可能是circSMARCC1海绵吸附miR-582-5p调控HMGB1。而我们此前已证实HMGB1与前列腺癌转移和不良预后相关。据此提出科学假说：circSMARCC1经外泌体靶向作用TAM，通过ceRNA机制调控HMGB1分泌，介导成骨细胞释放CCL2，促进前列腺癌骨转移。课题组拟从体内外和临床标本多个层面探讨circSMARCC1/miR-582-5p/HMGB1轴在前列腺癌骨转移中的作用及机制，并探索将外泌体circSMARCC1作为前列腺癌骨转移生物标志物的可能性，为其诊治和预后评估提供新的分子靶点。

Bone metastasis is the most common distant metastasis of prostate cancer, but the underlying mechanism remains unclear. Recent studies have shown that circRNA plays an important role in tumor metastasis. Our previous study demonstrated that circSMARCC1 was significantly up-regulated in plasma exosomes from prostate cancer, and silencing of circSMARCC1 remarkably suppressed tumor proliferation and metastasis. Furthermore, the upregulated circSMARCC1 in exosomes could be taken up by tumor-associated macrophages and then promote HMGB1 secretion. Mechanistically, circSMARCC1 executed the function by sponging miR-582-5p to regulate HMGB1. In addition, we have previously proved that HMGB1 is associated with prostate cancer metastasis and poor prognosis. Considering these， we proposed the scientific hypothesis that circSMARCC1 derived from exosomes can upregulate the HMGB1 secretion in macrophages through ceRNA mechanism and the secreted HMGB1 may facilitate the metastasis of prostate cancer cells to bone through improving the release of CCL2 from osteoblast. The purpose of this study was to explore the role and mechanism of circSMARCC1/ mir-582-5p /HMGB1 axis in bone metastasis of prostate cancer through in vivo and in vitro experiments as well as in clinical specimens. Moreover, we will explore the possibility of using exosomes circSMARCC1 as biomarkers to predict bone metastasis of prostate cancer. This study will provide a novel molecular target for the diagnosis, treatment and prognosis evaluation of bone metastasis of prostate cancer.