Department of Medical Services and Techniques, Vocational School of Health Services, Adiyaman University, Adiyaman, Turkey.
Department of Physiology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey.
Mol Biol Rep. 2022 Jul;49(7):6803-6815. doi: 10.1007/s11033-021-06996-5. Epub 2021 Nov 27.
Prostate cancer antigen 3 (PCA3) is the most promising diagnostic biomarker for the differential diagnosis of prostate cancer identified to date. As a dominant-negative oncogene, PCA3 negatively regulates the expression of tumor suppressor PRUNE2 (a human homolog of the Drosophila prune gene) gene. Although interaction between PCA3-PRUNE2 was clearly reported, the precise mechanism how PCA3 is upregulated in prostate cancer remained highly elusive. Accordingly, here we aimed demonstrate the role of microRNAs in PCA3 upregulation and interplay between these miRNAs and PCA3-PRUNE2 axis.
We evaluated expression of PCA3, PRUNE2 and miRNAs by quantitative reverse transcription polymerase chain reaction. Overexpression and silencing of miRNAs were achieved by synthetic miRNA mimics and inhibitors, respectively. Colony formation, migration, apoptosis, and cell cycle assays were performed to reveal the effects of miRNA modulation. We identified that PCA3 expression was significantly downregulated in both prostate cancer tissues and cells and inversely correlated with the expressions of miR-19a and miR-421. Restoring the functions of miR-19a and miR-421 by miRNA mimics significantly downregulated the expression of PCA3 and promoted apoptosis and cell cycle blockade and interfered with the proliferation and migration in prostate cancer cells. Conversely, silencing the expressions of these miRNAs yielded the opposite effect.
Collectively, our results uncover a previously unrecognized novel mechanism on PCA3 upregulation in prostate cancer and proved that miR-19a and miR-421 might be responsible for the increased expression of PCA3, indicating that both miRNAs might be novel candidates for prostate cancer diagnosis and therapy.
前列腺癌抗原 3（PCA3）是迄今为止发现的用于鉴别诊断前列腺癌的最有希望的诊断生物标志物。作为一种显性负致癌基因，PCA3 负调控肿瘤抑制基因 PRUNE2（果蝇 prune 基因的人类同源物）的表达。尽管 PCA3-PRUNE2 之间的相互作用已被明确报道，但 PCA3 在前列腺癌中上调的确切机制仍难以捉摸。因此，我们旨在证明 microRNAs 在 PCA3 上调中的作用以及这些 microRNAs 与 PCA3-PRUNE2 轴之间的相互作用。
我们通过定量逆转录聚合酶链反应评估 PCA3、PRUNE2 和 microRNAs 的表达。通过合成 microRNA 模拟物和抑制剂分别实现 microRNAs 的过表达和沉默。进行集落形成、迁移、凋亡和细胞周期测定以揭示 microRNA 调节的影响。我们发现 PCA3 在前列腺癌组织和细胞中的表达均显著下调，与 miR-19a 和 miR-421 的表达呈负相关。通过 microRNA 模拟物恢复 miR-19a 和 miR-421 的功能可显著下调 PCA3 的表达，促进前列腺癌细胞的凋亡和细胞周期阻滞，并干扰其增殖和迁移。相反，沉默这些 microRNAs 的表达则产生相反的效果。
总之，我们的研究结果揭示了前列腺癌中 PCA3 上调的一种先前未知的新机制，并证明了 miR-19a 和 miR-421 可能是 PCA3 表达增加的原因，这表明这两种 microRNAs 可能是前列腺癌诊断和治疗的新候选物。
