State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Cancer Lett. 2022 Feb 1;526:76-90. doi: 10.1016/j.canlet.2021.11.017. Epub 2021 Nov 19.
Most prostate cancer (PCa)-related deaths are caused by progression to bone metastasis. Recently, the importance of extracellular vesicles (EVs) in pre-metastatic niche formation has been reported. However, whether and how tumor-derived EVs interact with bone marrow macrophages (BMMs) to release EV-delivered microRNAs to promote osteolysis and induce pre-metastatic niche formation for PCa bone metastasis remain unclear. Our in vitro and in vivo functional and mechanistic assays revealed that EV-mediated release of miR-378a-3p from tumor cells was upregulated in bone-metastatic PCa, maintaining low intracellular miR-378a-3p concentration to promote proliferation and MAOA-mediated epithelial-to-mesenchymal transition. Moreover, miR-378a-3p enrichment in tumor-derived EVs was induced by hnRNPA2B1 (a transfer chaperone) overexpression. After tumor-derived EVs were taken in by BMMs, enriched miR-378a-3p promoted osteolytic progression by inhibiting Dyrk1a to improve Nfatc1 (an osteolysis-related transcription factor) nuclear translocation, to activate the expression of downstream target gene Angptl2. As a feedback, increased Angptl2 secretion into the tumor environment promoted PCa progression. In conclusion, tumor-derived miR-378a-3p-containing EVs play a significant role in PCa bone metastasis by activating the Dyrk1a/Nfatc1/Angptl2 axis in BMMs to induce osteolytic progression, making miR-378a-3p a potential predictor of metastatic PCa. Reducing the release of miR-378a-3p-containing EVs or inhibiting the recruitment of miR-378a-3p into EVs can be a therapeutic strategy against PCa metastasis.
大多数前列腺癌（PCa）相关死亡是由转移到骨转移引起的。最近，细胞外囊泡（EVs）在转移前生态位形成中的重要性已被报道。然而，肿瘤衍生的 EV 是否以及如何与骨髓巨噬细胞（BMMs）相互作用，释放 EV 递送的 microRNAs 以促进溶骨性，并诱导 PCa 骨转移的转移前生态位形成仍不清楚。我们的体外和体内功能和机制研究表明，肿瘤细胞中 EV 介导的 miR-378a-3p 的释放在骨转移 PCa 中上调，维持低细胞内 miR-378a-3p 浓度以促进增殖和 MAOA 介导的上皮-间充质转化。此外，hnRNPA2B1（转移伴侣）过表达诱导肿瘤衍生 EV 中 miR-378a-3p 的富集。肿瘤衍生 EV 被 BMMs 摄取后，富含 miR-378a-3p 通过抑制 Dyrk1a 来促进溶骨性进展，改善 Nfatc1（与溶骨性相关的转录因子）核易位，激活下游靶基因 Angptl2 的表达。作为反馈，增加 Angptl2 分泌到肿瘤环境中促进了 PCa 的进展。总之，肿瘤衍生的含 miR-378a-3p 的 EV 通过在 BMMs 中激活 Dyrk1a/Nfatc1/Angptl2 轴来促进溶骨性进展，在 PCa 骨转移中发挥重要作用，使 miR-378a-3p 成为转移性 PCa 的潜在预测因子。减少含 miR-378a-3p 的 EV 的释放或抑制 miR-378a-3p 招募到 EV 中可能是对抗 PCa 转移的治疗策略。
