Abstract
Androgen-deprivation therapy (ADT) with newly developed antiandrogen enzalutamide (Enz) may increase the castration-resistant prostate cancer (CRPC) patients survival an extra 4.8 months. Yet eventually most patients may fail with development of Enz resistance. While recent clinical studies indicated that the increased expression of the androgen receptor (AR) splicing variant ARv7 might have key roles for the development of Enz resistance in CRPC, its detailed mechanism, especially its linkage to the circular RNAs (circRNAs), a form of non-coding RNA, however, remains unclear. Here we found from human clinical sample survey that circRNA17 (hsa_circ_0001427) has a lower expression in higher Gleason score PCa, and results from in vitro cell lines studies also revealed the lower expression in CRPC C4–2 Enz-resistant (EnzR-C4–2) cells compared to their parental Enz-sensitive (EnzS-C4–2) cells. Mechanism dissection indicated that suppressing circRNA17 in EnzS-C4–2 cells increased ARv7 expression that might then lead to increase the Enz resistance and cell invasion. Mechanism dissection demonstrated that Enz could suppress the circRNA17 expression at the transcriptional level via suppressing transcription of its host gene PDLIM5, and circRNA17 could regulate ARv7 expression via altering the expression of miR-181c-5p that involved the direct binding of miR-181c-5p to the 3′UTR of ARv7. Preclinical study using in vivo mouse model with xenografted EnzR-CWR22Rv1 cells revealed that adding circRNA17 or miRNA-181c-5p could suppress the EnzR-CWR22Rv1 cells growth. Together, results from these preclinical studies suggest that circRNA17 may function as suppressor to alter the Enz sensitivity and cell invasion in CRPC cells via altering the miR-181c-5p/ARv7 signaling and targeting this newly identified signaling may help in the development of a better therapy to further suppress the EnzR cell growth.
Highlights
Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous cancer in men, and is the second leading cause for men of cancer-death in western countries and the sixth most common cause in the world[1,2]
We first confirmed the potential linkage of ARv7 expression to the Enz resistance in vitro by showing its increased expression in Enz-resistant C4–2 (EnzR-C4–2) cells that were developed using a prolonged treatment with 10 μM Enz (Fig. 1a), which is continued throughout all experiments
We identified miRNAs that can target ARv7 through their unique 3′untranslated region (UTR) as well as those that were in a lower expression in recurrent PCa18 while bioinformatically predicted to bind to 21 circRNAs (Fig. 1b)
Summary
Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous cancer in men, and is the second leading cause for men of cancer-death in western countries and the sixth most common cause in the world[1,2]. PCa can be defined as a local or advanced form clinically, and the treatments include surveillance, radical local treatment, and androgen-deprivation therapy (ADT). PCa patients with a higher ARv7 expression have a shorter survival than other CRPC patients[9]. ARv7 expression in circulating tumor cells of CRPC patients is associated with resistance to both abiraterone and enzalutamide (Enz, known as MDV3100)[8]. These findings indicate an association between ARv7 expression and a more lethal form of PCa, and highlight the significance of ARv7 in limiting the efficacy of ADT
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