Androgen-deprivation therapy (ADT) via targeting androgens/androgen receptor (AR) signals may suppress cell proliferation in both prostate cancer (PCa) and bladder cancer (BCa), yet its impact on the cell invasion of these two urological cancers remains unclear. Here we found targeting androgens/AR with either the recently developed antiandrogen Enzalutamide (Enz) or AR-shRNAs led to increase PCa cell invasion, yet decrease BCa cell invasion. Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation, likely contributes to this outcome between these two urological tumors. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge/alter the availability of the miRNAs miR-125b-2-3p and/or miR-4736, to impact the metastasis-related PPARγ/MMP-9 signals to alter the PCa vs. BCa cell invasion. The preclinical study using the in vivo mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after suppressing circRNA-ARC1 with sh-circRNA-ARC1. Together, these in vitro/in vivo results demonstrate that antiandrogen therapy with Enz via targeting AR may lead to either increase PCa cell invasion or decrease BCa cell invasion. Targeting these newly identified AR/circRNA-ARC1/miR-125b-2-3p and/or miR-4736/PPARγ/MMP-9 signals may help in the development of new therapies to better suppress the Enz-altered PCa vs. BCa metastasis.

通过靶向雄激素/雄激素受体（AR）信号的雄激素剥夺疗法（ADT）可能会抑制前列腺癌（PCa）和膀胱癌（BCa）的细胞增殖，但其对这两种泌尿系统癌症细胞侵袭的影响仍不清楚。在这里，我们发现用最近开发的抗雄激素恩杂鲁胺 (Enz) 或 AR-shRNA 靶向雄激素/AR 会增加 PCa 细胞侵袭，但会减少 BCa 细胞侵袭。机制剖析表明，抑制雄激素/AR信号可能会由于内源性AR转录的差异而导致选择性环状RNA（circRNA）发生差异性改变。由于 AR 与不同雄激素反应元件 (ARE) 的差异结合以及有区别的组蛋白 H3K4 甲基化，PCa 中出现负向自动调节，而 BCa 中出现正向自动调节，可能导致这两种泌尿肿瘤之间出现这种结果。进一步的机制研究表明，AR 编码的 circRNA-ARC1 可能会吸收/改变 miRNA miR-125b-2-3p 和/或 miR-4736 的可用性，从而影响转移相关的 PPARγ/MMP-9 信号，从而改变 PCa与 BCa 细胞侵袭相比。使用体内小鼠模型的临床前研究证实了体外细胞系数据，表明Enz治疗可以增加PCa转移，而用sh-circRNA-ARC1抑制circRNA-ARC1后可以抑制PCa转移。总之，这些体外/体内结果表明，通过靶向 AR 的 Enz 抗雄激素治疗可能导致增加 PCa 细胞侵袭或减少 BCa 细胞侵袭。靶向这些新发现的 AR/circRNA-ARC1/miR-125b-2-3p 和/或 miR-4736/PPARγ/MMP-9 信号可能有助于开发新疗法，以更好地抑制 Enz 改变的 PCa 与 BCa 转移。