ABSTRACT

Bladder cancer is one of the most commonly diagnosed and fatal malignancies of the urinary tract. Noncoding RNAs have been reported to be new biomarkers and effective treatment targets for bladder cancer. In the present study, we identified a novel bladder cancer-related circRNA-miRNA-mRNA network, the circ_0004463/miR-380-3p/FOXO1 axis. circ_0004463 is significantly downregulated, whereas miR-380-3p is upregulated in bladder carcinoma tissue samples and cells. circ_0004463 acts as a tumor suppressor by inhibiting bladder cancer cell proliferation. Genes that negatively correlated with miR-380-3p and genes that miR-380-3p might target are enriched in mitochondrial respiration chain-related pathways. miR-380-3p promotes the proliferation of bladder cancer cells and mitochondrial respiration by acting as an oncogenic miRNA. circ_0004463 competes with FOXO1 for miR-380-3p binding to counteract miR-380-3p-mediated repression of FOXO1. Circ_0004463 overexpression inhibits cancer cell proliferation and mitochondrial respiration in bladder cancer cell lines, while miR-380-3p overexpression dramatically reverses the roles of circ_0004463 overexpression. In conclusion, the circ_0004463/miR-380-3p/FOXO1 axis could regulate mitochondrial respiration and bladder cancer cell apoptosis via FOXO1 signaling.

摘要

膀胱癌是泌尿道最常诊断和致命的恶性肿瘤之一。据报道，非编码 RNA 是膀胱癌的新生物标志物和有效治疗靶点。在本研究中，我们鉴定了一个新的膀胱癌相关 circRNA-miRNA-mRNA 网络，circ_0004463/miR-380-3p/FOXO1 轴。circ_0004463 显着下调，而 miR-380-3p 在膀胱癌组织样本和细胞中上调。circ_0004463 通过抑制膀胱癌细胞增殖作为肿瘤抑制因子。与 miR-380-3p 负相关的基因和 miR-380-3p 可能靶向的基因在线粒体呼吸链相关通路中富集。miR-380-3p 作为致癌 miRNA 促进膀胱癌细胞增殖和线粒体呼吸。circ_0004463 与 FOXO1 竞争 miR-380-3p 结合以抵消 miR-380-3p 介导的 FOXO1 抑制。Circ_0004463 过表达抑制膀胱癌细胞系中的癌细胞增殖和线粒体呼吸，而 miR-380-3p 过表达显着逆转了 circ_0004463 过表达的作用。总之，circ_0004463/miR-380-3p/FOXO1轴可以通过FOXO1信号调节线粒体呼吸和膀胱癌细胞凋亡。