Bicalutamide (BIC) resistance impedes the treatment of prostate cancer (PCa) and seems to involve ferroptosis; however, the underlying mechanism remains unclear. Our study aimed to explore how miR-15b-3p modulates ferroptosis in response to BIC resistance and determine whether the miRNA is suitable for early screening of PCa. Here, we found that PCa tissues had significantly higher miR-15b-3p expression than adjacent normal tissues. Analysis of blood samples in patients who underwent prostate-specific antigen (PSA) screening revealed that miR-15b-3p was a more accurate diagnostic than PSA (miR-15b-3p area under the curve [AUC] = 0.941, PSA AUC = 0.815). In vitro experiments then demonstrated that miR-15b-3p expression was markedly higher in LNCaP, PC-3, and DU145 cells than in RWPE-1 cells. Treatment with BIC decreased miR-15b-3p expression and progressive ferroptosis. Mechanistically, we identified KLF2 as the downstream target of miR-15b-3p. Overexpressing KLF2 facilitated ferroptosis via augmenting MDA and iron concentrations, in turn inhibiting the SLC7A11/GPX4 axis and decreasing GSH concentration. Through modulating ferroptosis, miR-15b-3p mimic and inhibitor weakened and enhanced BIC sensitivity, respectively. Furthermore, BIC treatment limited xenograft tumor volume in vivo, whereas agomir-15b-3p promoted tumor growth, indicating that miR-15b-3p attenuated the tumor-suppressive effects of BIC. Taken together, our results suggested that miR-15b-3p is crucial to BIC resistance, specifically via targeting KLF2 and thereby suppressing ferroptosis. High miR-15b-3p expression in early PCa screening should reflect a higher probability of cancer. In conclusion, miR-15b-3p has strong potential as a screening and diagnostic biomarker with reliable prospects for clinical application. Furthermore, because patients with high miR-15b-3p and low KLF2 expression have a greater risk of BIC resistance and malignant progression, targeting the miRNA and its downstream protein may be a new treatment strategy.

中文翻译：

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MiR-15b-3p 通过靶向 KLF2 抑制铁死亡，削弱前列腺癌中比卡鲁胺的敏感性

比卡鲁胺 (BIC) 耐药性会阻碍前列腺癌 (PCa) 的治疗，并且似乎会导致铁死亡；然而，其根本机制仍不清楚。我们的研究旨在探索 miR-15b-3p 如何调节铁死亡以应对 BIC 耐药，并确定 miRNA 是否适合 PCa 的早期筛查。在这里，我们发现 PCa 组织的 miR-15b-3p 表达显着高于邻近正常组织。对接受前列腺特异性抗原 (PSA) 筛查的患者血液样本的分析表明，miR-15b-3p 的诊断比 PSA 更准确（miR-15b-3p 曲线下面积 [AUC] = 0.941，PSA AUC = 0.815 ）。体外实验表明，LNCaP、PC-3 和 DU145 细胞中 miR-15b-3p 的表达显着高于 RWPE-1 细胞。BIC 治疗可降低 miR-15b-3p 表达和进行性铁死亡。从机制上讲，我们确定 KLF2 是 miR-15b-3p 的下游靶标。过表达 KLF2 通过增加 MDA 和铁浓度促进铁死亡，进而抑制 SLC7A11/GPX4 轴并降低 GSH 浓度。通过调节铁死亡，miR-15b-3p 模拟物和抑制剂分别减弱和增强 BIC 敏感性。此外，BIC 治疗限制了体内异种移植肿瘤的体积，而 agomir-15b-3p 促进了肿瘤生长，表明 miR-15b-3p 减弱了 BIC 的肿瘤抑制作用。综上所述，我们的结果表明 miR-15b-3p 对于 BIC 抗性至关重要，特别是通过靶向 KLF2 从而抑制铁死亡。早期 PCa 筛查中 miR-15b-3p 的高表达应反映癌症的可能性较高。总之，miR-15b-3p作为筛选和诊断生物标志物具有强大的潜力，具有可靠的临床应用前景。此外，由于miR-15b-3p高表达和KLF2低表达的患者出现BIC耐药和恶性进展的风险更大，因此靶向miRNA及其下游蛋白可能是一种新的治疗策略。