Yuan Shuai, Bi Xing, Shayiti Furhati, Niu Yue, Chen Peng
Department of Urology, Affiliated Cancer Hospital of Xinjiang Medical University, No. 789 Suzhou East Street, Urumqi，Xinjiang, 830011, P.R. China.
BMC Urol. 2024 Dec 21;24(1):275. doi: 10.1186/s12894-024-01666-7.
Metastatic castration-resistant prostate cancer is the most dangerous stage of prostate cancer, with a high mortality rate. Docetaxel chemotherapy is one of the most effective treatment methods currently, but some patients do not respond to chemotherapy. To avoid unnecessary toxicity in non-responders, this study explores the potential of circulating microRNAs as early biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer.
PC3 cells and DU145 cells were divided into the control, NC mimics, and miRNA-136-5p-mimics groups. Cell viability was measured using the CCK-8 assay. Cell apoptosis was determined by flow cytometry. Cell migration and invasion abilities were evaluated using the Transwell assay. Real-time quantitative PCR was used to measure the miRNA levels in cells and peripheral blood of patients. The miRNA-136-5p target genes were predicted by using the PITA, TargetScan, and miRanda databases. The target genes were analyzed with KEGG pathway analysis.
In both PC3 and DU145 cells, the miRNA-136-5p-mimics group exhibited significantly increased cell survival rates, migration and invasion numbers, and significantly decreased apoptosis rates than the control group (p < 0.05). The miRNA-222-3p and miRNA-136-5p levels were significantly increased in docetaxel-resistant PC3 and DU145 cells (p < 0.05). The levels of circulating miRNA-222-3p and miRNA-136-5p were significantly associated with docetaxel treatment (p < 0.05). Higher levels of miRNA-222-3p were observed in non-responsive patients (p < 0.05). The area under the curve for miRNA-222-3p was 0.76 (95%CI: 0.55-0.97), indicating its effectiveness as a predictive factor for non-responsive patients to docetaxel. Patients with high expression of miRNA-34c-5p after docetaxel chemotherapy had shorter overall survival times (P < 0.05). Bioinformatics analysis identified 110 potential target genes of miRNA-136-5p. KEGG revealed that these genes were mainly distributed in three pathways. Among them, the PI3K-AKT pathway was closely related to the metastasis of prostate cancer cells.
Our study demonstrates that miRNA-136-5p promotes the proliferation and invasion of PC3 and DU145 cells while inhibiting apoptosis. Circulating miRNA-222-3p may serve as a biomarker for early therapeutic response to docetaxel, and further clinical investigation is warranted. Additionally, miRNA-136-5p may have anti-cancer effects during docetaxel chemotherapy in metastatic castration-resistant prostate cancer.
转移性去势抵抗性前列腺癌是前列腺癌最危险的阶段，死亡率很高。多西他赛化疗是目前最有效的治疗方法之一，但一些患者对化疗无反应。为避免无反应者出现不必要的毒性，本研究探讨循环微RNA作为转移性去势抵抗性前列腺癌患者多西他赛反应早期生物标志物的潜力。
将PC3细胞和DU145细胞分为对照组、NC模拟物组和miRNA - 136 - 5p模拟物组。使用CCK - 8法检测细胞活力。通过流式细胞术测定细胞凋亡。使用Transwell法评估细胞迁移和侵袭能力。采用实时定量PCR检测细胞和患者外周血中的miRNA水平。使用PITA、TargetScan和miRanda数据库预测miRNA - 136 - 5p的靶基因。通过KEGG通路分析对靶基因进行分析。
在PC3和DU145细胞中，与对照组相比，miRNA - 136 -5p模拟物组的细胞存活率、迁移和侵袭数量显著增加，凋亡率显著降低（p < 0.05）。多西他赛耐药的PC3和DU145细胞中miRNA - 222 - 3p和miRNA - 136 - 5p水平显著升高（p < 0.05）。循环miRNA - 222 - 3p和miRNA - 136 - 5p水平与多西他赛治疗显著相关（p < 0.05）。在无反应患者中观察到较高水平的miRNA - 222 - 3p（p < 0.05）。miRNA - 222 - 3p的曲线下面积为0.76（95%CI：0.55 - 0.97），表明其作为多西他赛无反应患者预测因子的有效性。多西他赛化疗后miRNA - 34c - 5p高表达的患者总生存时间较短（P < 0.05）。生物信息学分析确定了miRNA - 136 - 5p的110个潜在靶基因。KEGG显示这些基因主要分布在三条通路中。其中，PI3K - AKT通路与前列腺癌细胞的转移密切相关。
我们的研究表明，miRNA - 136 - 5p促进PC3和DU145细胞的增殖和侵袭，同时抑制凋亡。循环miRNA - 222 - 3p可能作为多西他赛早期治疗反应的生物标志物，值得进一步进行临床研究。此外，miRNA - 136 - 5p在转移性去势抵抗性前列腺癌的多西他赛化疗期间可能具有抗癌作用。
