Targeting androgen receptor (AR) with antiandrogen Enzalutamide increases prostate cancer cell invasion yet decreases bladder cancer cell invasion via differentially altering the AR/circRNA-ARC1/miR-125b-2-3p or miR-4736/PPARγ/MMP-9 signals.
Targeting androgen receptor (AR) with antiandrogen Enzalutamide increases prostate cancer cell invasion yet decreases bladder cancer cell invasion via differentially altering the AR/circRNA-ARC1/miR-125b-2-3p or miR-4736/PPARγ/MMP-9 signals.
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使用抗雄激素 Enzalutamide 靶向雄激素受体 (AR)，通过差异改变 AR/circRNA-ARC1/miR-125b-2-3p 或 miR-4736/PPAR·§/MMP-9 信号，增加前列腺癌细胞侵袭，同时减少膀胱癌细胞侵袭
DOI：
10.1038/s41418-021-00743-w
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发表时间：
2021-07
影响因子：
12.4
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Deng G;Wang R;Sun Y;Huang CP;Yeh S;You B;Feng C;Li G;Ma S;Chang C
通过靶向雄激素/雄激素受体（AR）信号的雄激素剥夺疗法（ADT）可以抑制前列腺癌（PCa）和膀胱癌（BCa）中的细胞增殖，但其对这两种泌尿系统癌症的细胞侵袭的影响尚不清楚。在这里，我们发现用最近开发的抗雄激素Enzalutamide（Enzalutamide）或AR-shRNA靶向雄激素/AR导致增加PCa细胞侵袭，但降低BCa细胞侵袭。机械解剖揭示，抑制雄激素/AR信号可能导致作为差异内源性AR转录的结果的选择性环状RNA（circRNA）的差异改变。由于AR与不同雄激素反应元件（战神）的差异结合和区别性组蛋白H3 K4甲基化，PCa中的负性自动调节，而BCa中的正性自动调节可能有助于这两种泌尿系统肿瘤之间的结果。进一步的机制研究表明，AR编码的circRNA-ARC 1可能海绵/改变miRNA miR-125 b-2- 3 p和/或miR-4736的可用性，以影响转移相关的PPARγ/MMP-9信号，从而改变PCa与BCa细胞的侵袭。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，这可以在用sh-circRNA-ARC 1抑制circRNA-ARC 1后得到抑制。总之，这些体外/体内结果表明，通过靶向AR使用Enz的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-ARC 1/miR-125 b-2- 3 p和/或miR-4736/PPARγ/MMP-9信号可能有助于开发新的疗法，以更好地抑制Enz-altered PCa vs. BCa转移。
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.
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