The androgen receptor (AR) has been linked to bladder cancer (BCa) progression, but if this involves circular RNAs (circRNAs) remains unclear. Here, we find that AR alters the levels of circRNA-FNTA (circFNTA) to increase BCa cell invasion and chemo-resistance. Mechanistically, AR represses the RNA editing gene ADAR2 via direct binding to its 5' promoter region to increase circFNTA levels, which then sponges the microRNA miR-370-3p to increase the expression of its host gene FNTA. This AR-mediated ADAR2/circFNTA/miR-370-3p/FNTA pathway then activates KRAS signaling to alter BCa cell invasion and chemo-sensitivity to cisplatin. A clinical BCa sample survey shows that circFNTA expression is elevated in BCa tissues, and results from a BCa mouse model indicate that depletion of circFNTA leads to the suppression of BCa metastases and increased cisplatin chemo-sensitivity. Together, based on our results using multiple BCa cell lines and an in vivo mouse model we suggest that targeting this newly identified AR/ADAR2/circFNTA/miR-370-3p/FNTA/KRAS axis may lead to the development of therapies to suppress BCa metastasis and to increase its chemo-sensitivity.

中文翻译：

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雄激素受体调节的 circFNTA 激活 KRAS 信号以促进膀胱癌侵袭。

雄激素受体 (AR) 与膀胱癌 (BCa) 进展有关，但是否涉及环状 RNA (circRNA) 仍不清楚。在这里，我们发现 AR 改变了 circRNA-FNTA (circFNTA) 的水平，以增加 BCa 细胞的侵袭和化学抗性。从机制上讲，AR 通过直接结合其 5' 启动子区域来抑制 RNA 编辑基因 ADAR2 以增加 circFNTA 水平，然后吸收 microRNA miR-370-3p 以增加其宿主基因 FNTA 的表达。这种 AR 介导的 ADAR2/circFNTA/miR-370-3p/FNTA 通路随后激活 KRAS 信号传导以改变 BCa 细胞侵袭和对顺铂的化学敏感性。一项临床 BCa 样本调查显示，circFNTA 在 BCa 组织中的表达升高，BCa 小鼠模型的结果表明，circFNTA 的消耗导致 BCa 转移的抑制和顺铂化学敏感性的增加。总之，基于我们使用多个 BCa 细胞系和体内小鼠模型的结果，我们建议针对这个新发现的 AR/ADAR2/circFNTA/miR-370-3p/FNTA/KRAS 轴可能会导致开发抑制 BCa 的疗法转移并增加其化学敏感性。