Departments of Urology, Xiangya Hospital, Central South University, 410008, Changsha, China.
Cell Death Dis. 2019 Aug 27;10(9):635. doi: 10.1038/s41419-019-1827-3.
Epidemiological studies show obvious gender differences in the incidence and the prognosis of bladder cancer (BCa). Estrogen receptor alpha (ERα) was recently shown to play a protective role in BCa. However, the mechanisms by which ERα mediates BCa progression need to be further elucidated. In the present study, we explored the mechanisms by which ERα inhibits BCa invasion by modulating circRNA levels. ERα suppressed BCa invasion by decreasing circ_0023642 expression. Chromatin immunoprecipitation (ChIP) and luciferase assays revealed that ERα reduced circ_0023642 expression by regulating the expression of its host gene, UVRAG, at the transcriptional level. ERα decreased circ_0023642 levels and subsequently increased miR-490-5p expression, resulting in decreased EGFR expression to suppress BCa cell invasion. Circ_0023642 was demonstrated to directly bind to miR-490-5p. Notably, miR-490-5p regulated EGFR expression by binding to the miR-490-5p-binding site located in the 3'-untranslated region (UTR) of the EGFR mRNA. Preclinical studies using an in vivo mouse model also confirmed that this ERα/circ_0023642/miR-490-5p/EGFR signaling pathway suppressed BCa progression. Altogether, this newly identified pathway may serve as the basis for developing novel therapeutic strategies to treat BCa.
流行病学研究表明，膀胱癌（BCa）的发病率和预后存在明显的性别差异。最近的研究表明，雌激素受体α（ERα）在 BCa 中发挥保护作用。然而，ERα介导 BCa 进展的机制仍需进一步阐明。在本研究中，我们通过调节环状 RNA 水平来探索 ERα 抑制 BCa 侵袭的机制。ERα 通过降低 circ_0023642 的表达来抑制 BCa 的侵袭。染色质免疫沉淀（ChIP）和荧光素酶报告基因实验表明，ERα 通过在转录水平上调节其宿主基因 UVRAG 的表达来降低 circ_0023642 的表达。ERα 降低 circ_0023642 的水平，进而增加 miR-490-5p 的表达，从而降低 EGFR 的表达，抑制 BCa 细胞的侵袭。circ_0023642 被证明可以直接结合 miR-490-5p。值得注意的是，miR-490-5p 通过结合 EGFR mRNA 3'非翻译区（UTR）中的 miR-490-5p 结合位点来调节 EGFR 的表达。体内小鼠模型的临床前研究也证实，这种 ERα/circ_0023642/miR-490-5p/EGFR 信号通路抑制了 BCa 的进展。总之，这条新发现的通路可能为开发治疗 BCa 的新治疗策略提供基础。
