A Circ-0007022/miR-338-3p/Neuropilin-1 Axis Reduces the Radiosensitivity of Esophageal Squamous Cell Carcinoma by Activating Epithelial-To-Mesenchymal Transition and PI3K/AKT Pathway

• Published in: Frontiers in genetics Vol. 13; p. 854097
• Main Authors: Zhang, Junpeng, Yu, Yanyan, Yin, Xiaoyang, Feng, Lei, Li, Zhe, Liu, Xiaomeng, Yu, Xinshuang, Li, Baosheng
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 29.04.2022
• Subjects: circ-0007022; ESCC; Genetics; miR-338-3p; neuropilin-1; radiosensitivity; circ-0007022; miR-338-3p; ESCC; neuropilin-1; radiosensitivity
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2022.854097

Radiotherapy resistance is an important cause of treatment failure in esophageal squamous cell carcinoma (ESCC). Circular RNAs have attracted a lot of attention in cancer research, but their role in ESCC radiosensitivity has not been elucidated yet. Here, we aimed to evaluated the functional impacts of circ-0007022 on ESCC radiosensitivity. In this study, a stable radiotherapy-resistant cell line was established and verified by a series of functional experiments. Subsequently, high-throughput sequencing revealed that circ-0007022 was significantly overexpressed in the radiotherapy-resistant cell line and this conclusion was verified in ESCC patients' tumor tissues by real-time quantitative PCR. Moreover, loss-of-function and overexpression experiments and revealed that, after irradiation, the abilities of proliferation and migration in circ-0007022-overexpressing stable transgenic strain were significantly higher than that in circ-0007022-knockdown stable transgenic strain. Additionally, RNA Immunoprecipitation, RNA pull-down, luciferase reporter assays, and fluorescence hybridization experiments demonstrated the mechanism of how circ-0007022 could sponge miR-338-3p and upregulate downstream target of miR-338-3p, neuropilin-1 (NRP1). Moreover, NRP1 led to poor prognosis for ESCC patients receiving radiotherapy, and NRP1 knock-down enhanced radiosensitivity of ESCC cells. Furthermore, circ-0007022 overexpression activated Epithelial-to-mesenchymal transition and PI3K/Akt pathway, and NRP1 knock-down could reversed this phenomenon. Finally, Akt Inhibitor reversed circ-0007022s role in radiotherapy in ESCC cells. Taken together, the circ-0007022/miR-338-3p/NRP1 axis enhances the radiation resistance of ESCC cells regulating EMT and PI3K/Akt pathway. The new circRNA circ-0007022 is thus expected to be a therapeutic target for ESCC patients.