Shen Chong, Wu Zhouliang, Wang Yujie, Gao Shen, Da La, Xie Linguo, Qie Yunkai, Tian Dawei, Hu Hailong
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Cancer Med. 2020 Jun;9(11):3885-3903. doi: 10.1002/cam4.3006. Epub 2020 Apr 6.
Growing evidence has indicated that circular RNAs (circRNAs) play crucial roles in multiple biological processes. However, alterations in circRNA profiles during bladder cancer progression and the clinical significance thereof remain unclear. Therefore, high-throughput RNA sequencing was conducted to identify circRNA and mRNA profiles in five pairs of bladder cancer tissues and adjacent noncancerous tissues. A total of 87 differentially expressed circRNAs and 2756 mRNAs were detected in above bladder cancer samples compared with paired noncancerous samples. Functional enrichment analyses, circRNA-microRNA-mRNA, and protein-protein interaction networks revealed that these dysregulated circRNAs were potentially involved in carcinogenesis and evolution of bladder cancer. Subsequently, the differential expression of eight circRNAs was detected by real-time qPCR. Hsa_circ_0003141 and hsa_circ_0008039 were significantly upregulated as well as hsa_circ_0026782, hsa_circ_0077837, hsa_circ_0004826, and hsa_circ_0001946 were significantly downregulated among validation of 70 matched bladder cancer tissues (≥75%). Moreover, hsa_circ_0077837 and hsa_circ_0004826 were also verified as markedly downregulated in four bladder cancer cells (100%). Naturally, hsa_circ_0077837 and hsa_circ_0004826 were also demonstrated using RNase-R+ resistance experiments. In addition, Fisher's exact test, Kaplan-Meier plots, Cox regression analyses, and receiver operating characteristic curve was performed to assess their clinical value. Downregulation of hsa_circ_0077837 and hsa_circ_0004826 all was significantly correlated with worse clinicopathological features and poor prognosis of bladder cancer patients. The area under the receiver operating characteristic curve of them was 0.775 (P < .0001) and 0.790 (P < .0001), respectively. Not surprisingly, in vitro functional experiments also demonstrated that the overexpression of hsa_circ_0077837 and hsa_circ_0004826 significantly weakened the proliferation, migration, and invasion of bladder cancer cells. Overall, hsa_circ_0077837 and hsa_circ_0004826 might act as tumor suppressors in the bladder cancer progression and serve as a potential biomarker for the diagnosis, prognosis, and therapy of bladder cancer.
越来越多的证据表明，环状RNA（circRNA）在多种生物学过程中发挥着关键作用。然而，膀胱癌进展过程中circRNA谱的变化及其临床意义仍不清楚。因此，进行了高通量RNA测序，以鉴定五对膀胱癌组织和相邻非癌组织中的circRNA和mRNA谱。与配对的非癌样本相比，在上述膀胱癌样本中总共检测到87种差异表达的circRNA和2756种mRNA。功能富集分析、circRNA-微RNA-mRNA和蛋白质-蛋白质相互作用网络显示，这些失调的circRNA可能参与了膀胱癌的发生和发展。随后，通过实时定量PCR检测了8种circRNA的差异表达。在70对匹配的膀胱癌组织（≥75%）的验证中，hsa_circ_0003141和hsa_circ_0008039显著上调，hsa_circ_0026782、hsa_circ_0077837、hsa_circ_0004826和hsa_circ_0001946显著下调。此外，hsa_circ_0077837和hsa_circ_0004826在四种膀胱癌细胞中也被证实显著下调（100%）。自然地，hsa_circ_0077837和hsa_circ_0004826也通过RNase-R+抗性实验得到了证实。此外，进行了Fisher精确检验、Kaplan-Meier曲线分析、Cox回归分析和受试者工作特征曲线分析，以评估它们的临床价值。hsa_circ_0077837和hsa_circ_0004826的下调均与膀胱癌患者较差的临床病理特征和不良预后显著相关。它们的受试者工作特征曲线下面积分别为0.775（P <.0001）和0.790（P <.0001）。不出所料，体外功能实验也表明，hsa_circ_0077837和hsa_circ_0004826的过表达显著减弱了膀胱癌细胞的增殖、迁移和侵袭。总体而言，hsa_circ_0077837和hsa_circ_0004826可能在膀胱癌进展中作为肿瘤抑制因子，并作为膀胱癌诊断、预后和治疗的潜在生物标志物。
