Zhang Chunlin, Yu Haitao, Bai Xuesong, Zhou Xiang, Feng Zhenwei, Li Yang, Peng Xiang, Mei Yuhua, Li Li, Gou Xin, Deng Yuanzhong, Chen Guo
Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, China.
J Cancer. 2024 Mar 2;15(8):2306-2317. doi: 10.7150/jca.92379. eCollection 2024.
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.
比卡鲁胺（BIC）耐药阻碍了前列腺癌（PCa）的治疗，且似乎与铁死亡有关；然而，其潜在机制仍不清楚。我们的研究旨在探讨miR-15b-3p如何调节对BIC耐药的铁死亡，并确定该微小RNA是否适用于PCa的早期筛查。在此，我们发现PCa组织中miR-15b-3p的表达显著高于相邻正常组织。对接受前列腺特异性抗原（PSA）筛查的患者血液样本进行分析发现，miR-15b-3p是比PSA更准确的诊断指标（miR-15b-3p曲线下面积[AUC]=0.941，PSA AUC=0.815）。随后的体外实验表明，LNCaP、PC-3和DU145细胞中miR-15b-3p的表达明显高于RWPE-1细胞。用BIC处理可降低miR-15b-3p的表达并诱导进行性铁死亡。从机制上讲，我们确定KLF2是miR-15b-3p的下游靶点。过表达KLF2通过增加丙二醛（MDA）和铁的浓度促进铁死亡，进而抑制溶质载体家族7成员11（SLC7A11）/谷胱甘肽过氧化物酶4（GPX4）轴并降低谷胱甘肽（GSH）浓度。通过调节铁死亡，miR-15b-3p模拟物和抑制剂分别削弱和增强了BIC敏感性。此外，BIC处理在体内限制了异种移植瘤的体积，而miR-15b-3p激动剂促进了肿瘤生长，表明miR-15b-3p减弱了BIC的抑癌作用。综上所述，我们的结果表明，miR-15b-3p对BIC耐药至关重要，具体是通过靶向KLF2从而抑制铁死亡。早期PCa筛查中miR-15b-3p高表达应反映出更高的癌症发生概率。总之，miR-15b-3p作为一种筛查和诊断生物标志物具有很强的潜力，临床应用前景可靠。此外，由于miR-15b-3p高表达和KLF2低表达的患者发生BIC耐药和恶性进展的风险更大，靶向该微小RNA及其下游蛋白可能是一种新的治疗策略。
