CircDUSP22 Attenuates the Ferroptosis of Prostate Cancer Cells via miR-18a-5p/SLC7A11/GPX4 Signaling.

Abstract

Background: According to current worldwide cancer data, Prostate Cancer (PC) ranks as the second most common type of cancer and is the fifth leading cause of cancer-related mortality among men worldwide. PC in China has the 10th highest number of new cases and the 13th highest fatality rate, both of which show an ongoing annual increase. One of the significant challenges with prostate cancer is the difficulty in early detection, often resulting in diagnosis at intermediate or late stages, complicating treatment. Although hormonal therapy is initially successful in controlling the progression of prostate cancer, almost all tumors that respond to hormones eventually transform into Castration-resistant Prostate Cancer (CRPC) within 18-24 months of hormonal therapy. This poses clinical difficulties due to an absence of successful therapeutic approaches. Therefore, understanding the fundamental mechanisms of prostate cancer development, identifying effective therapeutic targets, and discovering reliable molecular biomarkers are crucial objectives.

Methods: CircRNA expression in plasma was assessed in 4 samples obtained from patients with Benign Prostatic Hyperplasia (BPH), and PC was detected through microarray probes. Statistical analysis of the expression of circDUSP22 and clinicopathological features was conducted. The investigation of target genes was conducted using luciferase reporter assays and bioinformatics analysis. The expression levels of circDUSP22, miR-18a-5p, and Solute Carrier Family 7 member 11 (SLC7A11) were assessed using a quantitative Real-time Polymerase Chain Reaction (qRT-PCR) assay. Cell invasion, migration, colony formation, and proliferation were evaluated using Transwell, wound healing, colony formation, and CCK-8 assays, respectively. RNA Immunoprecipitation (RIP) and dual-luciferase reporter assays were used to examine the connections among circDUSP22, miR-18a-5p, and SLC7A11. The impact of circDUSP22 on the expression of ferroptosis-related proteins, specifically SLC7A11, as well as its effects on Fe2+ and ROS were also examined.

Results: In both plasma samples and PCa cell lines, there was a substantial elevation of circDUSP22 and SLC7A11 expression and a decline in miR-18a-5p expression. Suppression of circDUSP22 significantly impeded the migration, invasion, and proliferation of PC cells in vitro. The target gene of miR-18a-5p, SLC7A11, was found to be upregulated as an effect of circDUSP22's competitive binding to miR-18a-5p. Cellular experiments demonstrated that interference with circDUSP22 expression in DU145 and PC-3 cells led to increased ferroptosis and decreased SLC7A11 expression. The modulation of prostate cancer cell proliferation was reversed by either overexpressing SLC7A11 or inhibiting miR-18a-5p in response to the silencing of circDUSP22.

Conclusion: The circDUSP22 has been found to have a substantial effect on the development of ferroptosis in PC. It has been observed to influence the formation and evolution of this disorder by affecting the miR-18a-5p/SLC7A11 signaling pathway.