尽管雄激素剥夺疗法具有临床益处，但大多数晚期雄激素依赖性前列腺癌（ADPC）患者最终会复发并发展为致命的雄激素非依赖性前列腺癌（AIPC），也称为去势抵抗性前列腺癌（CRPC）。MiRNA可以被包装进外泌体（Exos）并在细胞之间传递。然而，与CRPC进展相关的外泌体miRNA的作用和机制尚未完全阐明。在这里，我们发现miR-222-3p在AIPC细胞中升高，导致细胞增殖、迁移和侵袭能力显著增强。此外，AIPC细胞释放的外泌体可以被ADPC细胞摄取，从而通过miR-222-3p的外泌体转移使ADPC细胞在体外和体内适应进展为更具侵袭性的细胞类型。机械上，外泌体中的miR-222-3p通过靶向MIDN激活mTOR信号通路，促使ADPC细胞转化为类似AIPC细胞。我们的结果显示，AIPC细胞分泌含有miRNA的外泌体，这些载体可以通过旁分泌机制转移给ADPC细胞，对细胞功能重塑产生重大影响。当前工作突出了靶向外泌体miRNA作为单一药物或与雄激素受体通路抑制剂联合应用的治疗CRPC的巨大潜力。© 2023 The Authors. 由John Wiley & Sons Australia, Ltd代表日本癌症协会发表的《癌症科学》

Despite the clinical benefits of androgen deprivation therapy, most patients with advanced androgen-dependent prostate cancer (ADPC) eventually relapse and progress to lethal androgen-independent prostate cancer (AIPC), also termed castration-resistant prostate cancer (CRPC). MiRNAs can be packaged into exosomes (Exos) and shuttled between cells. However, the roles and mechanisms of exosomal miRNAs involved in CRPC progression have not yet been fully elucidated. Here, we find that miR-222-3p is elevated in AIPC cells, which results in remarkable enhancement of cell proliferation, migration, and invasion ability. Furthermore, Exos released by AIPC cells can be uptaken by ADPC cells, thus acclimating ADPC cells to progressing to more aggressive cell types in vitro and in vivo through exosomal transfer of miR-222-3p. Mechanistically, Exos-miR-222-3p promoted ADPC cells transformed to AIPC-like cells, at least in part, by activating mTOR signaling through targeting MIDN. Our results show that AIPC cells secrete Exos containing miRNA cargo. These cargos can be transferred to ADPC cells through paracrine mechanisms that have a strong impact on cellular functional remodeling. The current work underscores the great therapeutic potential of targeting Exo miRNAs, either as a single agent or combined with androgen receptor pathway inhibitors for CRPC treatment.© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.