Abstract
An increasing number of studies have shown that circRNAs are closely related to the carcinogenesis and development of prostate cancer (PCa). However, little is known about the effect of the biological functions of circRNAs on the enzalutamide resistance of PCa. Through bioinformatic analysis and experiments, we investigated the expression pattern of circRNAs in enzalutamide-resistant PCa cells. Quantitative real-time PCR was used to detect the expression of circRAB3IP, and plasmids that knock down or overexpress circRAB3IP were used to evaluate its effect on the enzalutamide sensitivity of PCa cells. Mechanistically, we explored the potential regulatory effects of eIF4A3 and LEF1 on the biogenesis of circRAB3IP. Our in vivo and in vitro data indicated that increased expression of circRAB3IP was found in enzalutamide-resistant PCa, and knockdown of circRAB3IP significantly enhanced enzalutamide sensitivity in PCa cells. However, upregulation of circRAB3IP resulted in the opposite effects. Further mechanistic research demonstrated that circRAB3IP could regulate the expression of serum and glucocorticoid-regulated kinase 1 (SGK1) by serving as a sponge that directly targets miR-133a-3p/miR-133b. Then, we showed that circRAB3IP partially exerted its biological functions via SGK1 signaling. Furthermore, we discovered that eIF4A3 and LEF1 might increase circRAB3IP expression in PCa.
Highlights
In 2018, prostate cancer (PCa) was the second most frequently diagnosed cancer and the fifth leading cause of cancer deaths in men worldwide [1]
The results showed that hsa_circ_0008518 and hsa_circ_0000419 were both highly enriched in PCa tissues and EnzR PCa cells (Figure 1A)
To provide confirmation that circRAB3IP is differentially expressed in human PCa, prostatectomy specimens of patients with benign prostatic hyperplasia (BPH), low grade PCa (l-PCa, Gleason8) and EnzR PCa samples were examined by qRT-PCR using divergent primers
Summary
In 2018, prostate cancer (PCa) was the second most frequently diagnosed cancer and the fifth leading cause of cancer deaths in men worldwide [1]. Enzalutamide (Enz, named MDV3100) is the first second-generation AR antagonist with an 8-fold higher affinity for AR than bicalutamide and has shown significant efficacies in the clinic when used as first-line therapy for patients with metastatic prostate cancer in combination with androgen deprivation therapy (ADT) [3,4,5]. It has been approved by the US Food and Drug Administration (FDA) for the treatment of metastatic and nonmetastatic castration-sensitive prostate cancer (CRPC), as well as metastatic castration-sensitive prostate cancer (mCSPC).
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