Androgen receptor-regulated circFNTA activates KRAS signaling to promote bladder cancer invasion

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.雄激素受体（androgen receptor, AR）已被证实与膀胱癌（bladder cancer, BCa）的进展密切相关，但其调控过程是否涉及环状RNA（circular RNAs, circRNAs）目前尚未明确。本研究发现，AR可通过调控环状RNA-FNTA（circFNTA）的表达水平，增强膀胱癌细胞的侵袭能力与化疗耐药性。从分子机制层面而言，AR可直接结合RNA编辑基因ADAR2的5'启动子区域，抑制其转录，进而升高circFNTA的表达水平；随后circFNTA通过海绵吸附微小RNA miR-370-3p，上调其宿主基因FNTA的表达。上述AR介导的ADAR2/circFNTA/miR-370-3p/FNTA通路可进一步激活KRAS信号通路，最终调控膀胱癌细胞的侵袭特性以及对顺铂的化疗敏感性。临床膀胱癌样本分析结果显示，circFNTA在膀胱癌组织中呈高表达；而膀胱癌小鼠模型实验证实，敲低circFNTA可抑制膀胱癌转移，并增强肿瘤细胞对顺铂的化疗敏感性。综上，结合多株膀胱癌细胞系与体内小鼠模型的实验数据，本研究提出靶向这一新发现的AR/ADAR2/circFNTA/miR-370-3p/FNTA/KRAS信号轴，有望开发出抑制膀胱癌转移、增强其化疗敏感性的新型治疗策略。