成骨细胞外泌体miRNA-223通过β-catenin通路促进前列腺癌骨转移的作用与机制研究

The metastasis of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer require improved molecular understanding of the mechanisms underlying the specific osteogenesis metastasis. Published data have demonstrated that bone microenvironment including prostate cancer cells and osteoblasts is of great importance to the development of osteogenesis metastasis. Exosomes have been found to be involved in intercellular communication by delivering their contents to recipient cells and thereby influence physiological and pathological processes. Molecular components in exosomes have been found to be related to certain diseases and treatment responses. Of note, most of recent studies have focused on miRNAs in exosomes. In the preliminary study, we found that osteoblast exosomes can increase colony formation of prostate cancer cells. After high-throughput screening, the key molecule miR-223 was identified, and further experiments confirmed that miR-223 can promote bone metastasis of prostate cancer. In mechanism studies, it was found that miR-223 can affect the activity of β-catenin pathway in prostate cancer cells. With these results, we will further investigate the upstream mechanism of miR-223 production, as well as the process by which exosomes mediate the transfer of miR-223 from osteoblasts to PCa cells, and mechanisms of miR-223 affects the β-catenin pathway of prostate cancer. And to assess whether the osteoblast-exosomal miR-223-β-catenin pathway can serve as a predictive marker and therapeutic target for prostate cancer bone metastasis. The research will provide new ideas for the comprehensive understanding of the mechanism of bone metastasis and novel targets for treatment of prostate cancer bone metastases.

前列腺癌（PCa）特异性骨转移机制不清，缺乏有效治疗手段。骨微环境中被肿瘤所激活的成骨细胞对PCa细胞的反馈，可能发挥了重要作用。外泌体介导miRNAs传递是新近发现的细胞间通讯方式。前期研究发现成骨细胞能够经外泌体向PCa细胞传递miRNAs，并促进前列腺癌细胞克隆形成。经高通量筛选鉴定出关键作用分子miR-223，实验证实miR-223能够促进前列腺癌骨转移。机制研究发现miR-223能够影响PCa细胞内β-catenin通路活性。在此基础之上，拟进一步研究miR-223生成及经外泌体由成骨细胞传递至PCa细胞的机制，和miR-223影响PCa β-catenin通路的机制，并评估成骨细胞-外泌体miR-223-β-catenin通路这一作用链作为前列腺癌骨转移治疗靶点和预警标志的潜能。研究为全面解析前列腺癌骨转移机制和骨转移的治疗提供新思路、新靶点。

前列腺癌（PCa）特异性骨转移机制不清，缺乏有效治疗手段。骨微环境中被肿瘤所激活的成骨细胞对PCa细胞的反馈，可能发挥了重要作用。外泌体介导miRNAs传递是新近发现的细胞间通讯方式。研究发现成骨细胞能够经外泌体向PCa细胞传递miRNAs，并促进前列腺癌细胞克隆形成。通过高通量筛选对比加入成骨细胞外泌体后前列腺癌细胞内miRNAs的表达变化，我们发现miR-223的变化最为显著。通过细胞实验证实了miR-223能够促进前列腺癌细胞的生长，抵抗凋亡。从miR-223的预测靶基因交集中提取的分子组合能够在多个队列中预测前列腺癌的生化复发进展风险。从miR-223的预测靶基因中我们注意到β-catenin通路的抑制分子APC。随后在实验中证实了miR-223通过APC影响β-catenin通路活性，并以此促进前列腺癌细胞的增殖和抵抗凋亡。研究结果为全面解析前列腺癌骨转移机制和前列腺癌骨转移的治疗提供新思路、新靶点。