Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer deaths among American men. Androgen deprivation therapy (ADT) has been systemically applied as a first-line therapy for PCa patients. Despite the initial responses, the majority of patients under ADT eventually experienced tumor progression to castration-resistant prostate cancer (CRPC), further leading to tumor metastasis to distant organs. Therefore, identifying the key molecular mechanisms underlying PCa progression remains crucial for the development of novel therapies for metastatic PCa. Previously, we identified that tumor-suppressive miR-99b-5p is frequently downregulated in aggressive African American (AA) PCa and European American (EA) CRPC, leading to upregulation of mTOR, androgen receptor (AR), and HIF-1α signaling. Given the fact that mTOR and HIF-1α signaling are critical upstream pathways that trigger the activation of epithelial–mesenchymal transition (EMT), we hypothesized that miR-99b-5p may play a critical functional role in regulating EMT-mediated PCa metastasis. To test this hypothesis, a series of cell biology, biochemical, and in vitro functional assays (wound healing, transwell migration, cell/ECM adhesion, and capillary-like tube formation assays) were performed to examine the effects of miR-99b-5p mimic on regulating EMT-mediated PCa metastasis processes. Our results have demonstrated that miR-99b-5p simultaneously targets MTOR and AR signaling, leading to upregulation of E-cadherin, downregulation of Snail/N-cadherin/Vimentin, and suppression of EMT-mediated PCa metastasis. MiR-99b-5p alone and in combination with enzalutamide or abiraterone significantly inhibits the EMT-mediated metastasis of AA PCa and EA CRPC.
前列腺癌（PCa）是美国男性中诊断率最高的癌症，也是癌症死亡的第二大原因。雄激素剥夺疗法（ADT）已作为前列腺癌患者的一线治疗方案被系统应用。尽管初期治疗有效，但大多数接受ADT的患者最终会经历肿瘤进展为去势抵抗性前列腺癌（CRPC），并进一步导致肿瘤向远处器官转移。因此，明确前列腺癌进展的关键分子机制对于开发针对转移性前列腺癌的新型疗法至关重要。先前研究发现，具有肿瘤抑制作用的miR-99b-5p在侵袭性非裔美国人（AA）前列腺癌和欧裔美国人（EA）CRPC中常出现表达下调，导致mTOR、雄激素受体（AR）和HIF-1α信号通路上调。鉴于mTOR和HIF-1α信号通路是触发上皮-间质转化（EMT）激活的关键上游通路，我们推测miR-99b-5p可能在调控EMT介导的前列腺癌转移中发挥关键功能作用。为验证这一假设，我们通过一系列细胞生物学、生物化学及体外功能实验（包括伤口愈合实验、Transwell迁移实验、细胞/细胞外基质黏附实验和毛细血管样管形成实验），检测了miR-99b-5p模拟物对EMT介导的前列腺癌转移过程的调控作用。研究结果表明，miR-99b-5p同时靶向MTOR和AR信号通路，导致E-钙黏蛋白表达上调、Snail/N-钙黏蛋白/波形蛋白表达下调，从而抑制EMT介导的前列腺癌转移。单独使用miR-99b-5p或联合恩杂鲁胺/阿比特龙治疗，均能显著抑制AA前列腺癌和EA CRPC中EMT介导的转移过程。
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