Accumulating evidence has demonstrated that circular RNAs (circRNAs) play important roles in regulating gene expression involved in tumor development. However, the role of circRNAs in modulating the radiosensitivity of oral squamous cell carcinoma (OSCC) and its potential mechanisms have not been documented. We performed high-throughput RNA sequencing (RNA-seq) to investigate the circRNA expression profile in OSCC patients and discovered that the circATRNL1 expression was significantly downregulated and closely related to tumor progression. The circATRNL1 was structurally validated via Sanger sequencing, RNase R treatment, and specific convergent and divergent primer amplification. Importantly, the expression levels of circATRNL1 decreased after irradiation treatment, and upregulation of circATRNL1 enhanced the radiosensitivity of OSCC through suppressing proliferation and the colony survival fraction, inducing apoptosis and cell-cycle arrest. Moreover, we observed that circATRNL1 could directly bind to microRNA-23a-3p (miR-23a-3p) and relieve inhibition for the target gene PTEN. In addition, the tumor radiosensitivity-promoting effect of circATRNL1 overexpression was blocked by miR-23a-3p in OSCC. Further experiments also showed that PTEN can reverse the inhibitory effect of OSCC radiosensitivity triggered by miR-23a-3p. We concluded that circANTRL1 may function as the sponge of miR-23a-3p to promote PTEN expression and eventually contributes to OSCC radiosensitivity enhancement. This study indicates that circANTRL1 may be a novel therapeutic target to improve the efficiency of radiotherapy in OSCC.

中文翻译：

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环状RNA circATRNL1的上调使口腔鳞状细胞癌对辐射敏感


越来越多的证据表明，环状RNA（circRNA）在调节肿瘤发展相关基因表达方面发挥着重要作用。然而，circRNA在调节口腔鳞状细胞癌（OSCC）放射敏感性中的作用及其潜在机制尚未被记录。我们进行了高通量RNA测序（RNA-seq）来研究OSCC患者的circRNA表达谱，发现circATRNL1表达显着下调且与肿瘤进展密切相关。通过 Sanger 测序、RNase R 处理以及特异性收敛和发散引物扩增对 circATRNL1 进行了结构验证。重要的是，circATRNL1的表达水平在放射治疗后下降，并且circATRNL1的上调通过抑制增殖和集落存活分数、诱导细胞凋亡和细胞周期停滞来增强OSCC的放射敏感性。此外，我们观察到circATRNL1可以直接结合microRNA-23a-3p（miR-23a-3p）并减轻对靶基因PTEN的抑制。此外，在 OSCC 中，circATRNL1 过表达的肿瘤放射敏感性促进作用被 miR-23a-3p 阻断。进一步的实验还表明，PTEN可以逆转miR-23a-3p引发的OSCC放射敏感性的抑制作用。我们得出结论，circANTRL1可能作为miR-23a-3p的海绵发挥作用，促进PTEN表达，并最终有助于OSCC放射敏感性增强。本研究表明circANTRL1可能成为提高OSCC放疗效率的新治疗靶点。