Zhang Yinbin, Shan Changyou, Chen Yinxi, Sun Shiyu, Liu Di, Zhang Xin, Zhang Shuqun
Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Front Genet. 2020 Sep 1;11:987. doi: 10.3389/fgene.2020.00987. eCollection 2020.
The mechanism regulating non-small cell lung cancers (NSCLCs) is unclear. In this study, we aimed to determine the roles of DENN domain containing 2A (circDENND2A) in the progression of NSCLC. Circular RNAs (circRNAs) are composited by "head to tail" splicing of coding or non-coding RNAs (ncRNAs), whose crucial roles in human cancers had been revealed. CircDENND2A, a new circRNA, was revealed to induce cell proliferation and migration. Our data indicated that circDENND2A was a probable oncogene in human cancers. However, the roles of circDENND2A in NSCLC remained unknown. Here, we demonstrated that circDENND2A was down-regulated in NSCLC samples. Loss-of-function assays showed circDENND2A knockdown suppressed cell growth via inducing cell cycle arrest and apoptosis and inhibited cell migration and invasion. Bioinformatics analysis and competing endogenous RNA (ceRNA) network analysis revealed that circDENND2A was involved in regulating cell cycle and tumor protein p53 (TP53) signaling via miR-34a/CCNE1 (cyclin E1). Further validation showed that circDENND2A could directly bind to miR-34a, promoting CCNE1 expression in NSCLC. In addition, rescue assays demonstrated that restoration of CCNE1 significantly impaired the suppressive effects of circDENND2A silencing in terms of NSCLC growth, migration, and invasion. We thought this study indicated that circDENND2A/miR-34a/CCNE1 may be a potential therapeutic target for NSCLC.
调节非小细胞肺癌（NSCLC）的机制尚不清楚。在本研究中，我们旨在确定含DENN结构域蛋白2A（circDENND2A）在NSCLC进展中的作用。环状RNA（circRNAs）由编码或非编码RNA（ncRNAs）的“头对尾”剪接组成，其在人类癌症中的关键作用已被揭示。CircDENND2A是一种新的环状RNA，被发现可诱导细胞增殖和迁移。我们的数据表明，circDENND2A可能是人类癌症中的一种癌基因。然而，circDENND2A在NSCLC中的作用仍不清楚。在此，我们证明circDENND2A在NSCLC样本中表达下调。功能丧失实验表明，敲低circDENND2A可通过诱导细胞周期停滞和凋亡抑制细胞生长，并抑制细胞迁移和侵袭。生物信息学分析和竞争性内源RNA（ceRNA）网络分析显示，circDENND2A通过miR-34a/细胞周期蛋白E1（CCNE1）参与调节细胞周期和肿瘤蛋白p53（TP53）信号通路。进一步验证表明，circDENND2A可直接与miR-34a结合，促进NSCLC中CCNE1的表达。此外，挽救实验表明，恢复CCNE1的表达可显著削弱circDENND2A沉默对NSCLC生长、迁移和侵袭的抑制作用。我们认为本研究表明circDENND2A/miR-34a/CCNE1可能是NSCLC的一个潜在治疗靶点。
