Medical College of Guizhou University, Guiyang, Guizhou Province 550025, China.
Department of Urology, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province 550002, China.
Oxid Med Cell Longev. 2022 Sep 6;2022:3611540. doi: 10.1155/2022/3611540. eCollection 2022.
The expression of ZFP36 in previous study was reduced in prostate cancer (PCa) tissues as compared to benign prostate tissues, indicating the potential of ZFP36 as an auxiliary marker for PCa. Further evaluation was conducted in clinical samples for in vitro and in vivo experiments, to prove the potential possibility that ZFP36 dysregulation participated in the malignant phenotype of PCa, to determine its potential mechanism for tumor regulation, and to provide a new theoretical basis for gene therapy of PCa.
First, the expression of ZFP36 in prostate tissue and PCa tissue was explored, and the relationship between ZFP36 and clinical features of PCa patients was illustrated. Subsequently, the impact of ZFP36 on the biology of PCa cells and relevant downstream pathways of ZFP36's biological impact on PCa were elucidated. Finally, whether oxidative stress mediated the regulation of ZFP36 in PCa was verified by the determination of oxidative stress-related indicators and bioinformatics analysis.
The downregulation of ZFP36 in PCa tissue had a positive correlation with high Gleason scores, advanced pathological stage, and biochemical recurrence. ZFP36 was identified as an independent prognostic factor for PCa patients' BCR-free survival ( = 0.022) by survival analysis. Following a subsequent experiment of function gain and loss, ZFP36 inhibited the proliferation, invasion, and migration in DU145 and 22RV1 cells and inhibits tumor growth in the mouse model. Additionally, high-throughput sequencing screened out CDK6 as the downstream target gene of ZFP36. Western blot/Q-PCR demonstrated that overexpression of ZFP36 could reduce the expression of CDK6 at both cellular and animal levels, and the dual-luciferase experiment and RIP experiment proved that CDK6 was the downstream target of ZFP36, indicating that CDK6 was a downstream target of ZFP36, which mediated tumor cell growth by blocking cell cycle at the G1 stage. Furthermore, ZFP36 inhibited oxidative stress in PCa cells.
In PCa, ZFP36 might be a tumor suppressor that regulated growth, invasion, and migration of PCa cells. The lately discovered ZFP36-CDK6 axis demonstrated the molecular mechanism of PCa progression to a certain extent which might act as a new possible therapeutic target of PCa therapy.
先前的研究表明，ZFP36 在前列腺癌（PCa）组织中的表达低于良性前列腺组织，表明 ZFP36 有作为辅助标记物用于 PCa 的潜力。进一步在临床样本中进行了体外和体内实验的评估，以证明 ZFP36 失调参与 PCa 恶性表型的可能性，确定其肿瘤调节的潜在机制，并为 PCa 的基因治疗提供新的理论基础。
首先，研究了 ZFP36 在前列腺组织和 PCa 组织中的表达，并说明了 ZFP36 与 PCa 患者临床特征的关系。随后，阐明了 ZFP36 对 PCa 细胞生物学的影响及其对 PCa 生物学的下游途径。最后，通过测定氧化应激相关指标和生物信息学分析，验证了氧化应激是否介导了 ZFP36 在 PCa 中的调节作用。
PCa 组织中 ZFP36 的下调与高 Gleason 评分、晚期病理分期和生化复发呈正相关。生存分析表明，ZFP36 是 PCa 患者无生化复发生存的独立预后因素（ = 0.022）。随后进行的功能增益和缺失实验表明，ZFP36 抑制了 DU145 和 22RV1 细胞的增殖、侵袭和迁移，并抑制了小鼠模型中的肿瘤生长。此外，高通量测序筛选出 CDK6 作为 ZFP36 的下游靶基因。Western blot/Q-PCR 表明，ZFP36 的过表达可降低细胞和动物水平的 CDK6 表达，双荧光素酶实验和 RIP 实验证明 CDK6 是 ZFP36 的下游靶基因，表明 CDK6 是 ZFP36 的下游靶基因，通过阻断细胞周期在 G1 期介导肿瘤细胞生长。此外，ZFP36 抑制了 PCa 细胞中的氧化应激。
在 PCa 中，ZFP36 可能是一种肿瘤抑制因子，可调节 PCa 细胞的生长、侵袭和迁移。最近发现的 ZFP36-CDK6 轴在一定程度上说明了 PCa 进展的分子机制，可能作为 PCa 治疗的新的潜在治疗靶点。
