Metastasis is the main cause of deaths in prostate cancer (PCa). However, the exact mechanisms underlying PCa metastasis are not fully understood. In this study, we discovered pronounced hypoxia in primary lesions of metastatic PCa(mPCa). The exosomes secreted by cancer-associated fibroblasts (CAFs) under hypoxic conditions significantly enhance PCa metastasis both in vitro and in vivo. Through miRNA sequencing and reverse transcription quantitative PCR (RT-qPCR), we found that hypoxia elevated miR-500a-3p levels in CAFs exosomes. Subsequent RT-qPCR, western blotting, and dual luciferase reporter assays identified F-box and WD repeat domain-containing 7(FBXW7) as a target of miR-500a-3p. In addition, immunohistochemistry revealed that FBXW7 expression decreased with the progression of PCa, while heat shock transcription factor 1(HSF1) expression increased. Introducing an FBXW7 plasmid into PCa cells reduced their metastatic potential and significantly lowered HSF1 expression. These findings suggest that CAFs exosomes drive PCa metastasis via the miR-500a-3p/FBXW7/HSF1 axis in a hypoxic microenvironment. Targeting either hypoxia or exosomal miR-500a-3p could be a promising strategy for PCa management.

转移是前列腺癌（PCa）死亡的主要原因。然而，PCa 转移的确切机制尚不完全清楚。在这项研究中，我们发现转移性前列腺癌（mPCa）的原发灶存在明显的缺氧。癌症相关成纤维细胞（CAF）在缺氧条件下分泌的外泌体在体外和体内均显着增强 PCa 转移。通过 miRNA 测序和逆转录定量 PCR (RT-qPCR)，我们发现缺氧会升高 CAF 外泌体中的 miR-500a-3p 水平。随后的 RT-qPCR、蛋白质印迹和双荧光素酶报告基因测定将 F-box 和含有 WD 重复结构域的 7 (FBXW7) 确定为 miR-500a-3p 的靶标。此外，免疫组织化学显示FBXW7表达随着PCa的进展而减少，而热休克转录因子1（HSF1）表达增加。将 FBXW7 质粒引入 PCa 细胞可降低其转移潜力并显着降低 HSF1 表达。这些发现表明，CAF 外泌体在缺氧微环境中通过 miR-500a-3p/FBXW7/HSF1 轴驱动 PCa 转移。针对缺氧或外泌体 miR-500a-3p 可能是治疗 PCa 的一种有前途的策略。