Department of Urology, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Cell Death Dis. 2019 Jan 15;10(2):37. doi: 10.1038/s41419-018-1048-1.
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.
新开发的抗雄激素药物恩杂鲁胺（Enz）的雄激素剥夺治疗（ADT）可能使去势抵抗性前列腺癌（CRPC）患者的生存额外延长 4.8 个月。然而，最终大多数患者可能会因恩杂鲁胺耐药而失败。虽然最近的临床研究表明，雄激素受体（AR）剪接变体 ARv7 的表达增加可能在 CRPC 中恩杂鲁胺耐药的发展中起关键作用，但它的详细机制，特别是它与环状 RNA（circRNA）的联系，一种非编码 RNA，然而，目前尚不清楚。在这里，我们从人类临床样本调查中发现，circRNA17（hsa_circ_0001427）在较高的 Gleason 评分 PCa 中表达较低，体外细胞系研究的结果也显示，CRPC C4-2 恩杂鲁胺耐药（EnzR-C4-2）细胞中的表达低于其亲本恩杂鲁胺敏感（EnzS-C4-2）细胞。机制分析表明，在 EnzS-C4-2 细胞中抑制 circRNA17 会增加 ARv7 的表达，从而导致恩杂鲁胺耐药和细胞侵袭的增加。机制分析表明，恩杂鲁胺可以通过抑制其宿主基因 PDLIM5 的转录来抑制 circRNA17 的表达，circRNA17 可以通过改变 miR-181c-5p 的表达来调节 ARv7 的表达，涉及 miR-181c-5p 与 ARv7 的 3'UTR 的直接结合。使用异种移植恩杂鲁胺耐药 CWR22Rv1 细胞的体内小鼠模型进行的临床前研究表明，添加 circRNA17 或 miR-181c-5p 可以抑制 EnzR-CWR22Rv1 细胞的生长。总之，这些临床前研究的结果表明，circRNA17 可能通过改变 miR-181c-5p/ARv7 信号来作为抑制剂发挥作用，改变 CRPC 细胞中的恩杂鲁胺敏感性和细胞侵袭，针对这个新发现的信号可能有助于开发更好的治疗方法，进一步抑制恩杂鲁胺耐药细胞的生长。
