Chronic stress promotes NSCLC progression through circMBOAT2 upregulation mediated by CTCF

Abstract Circular RNA (circRNA) has been shown to play an important role in tumor development. This study aimed to investigate the regulatory mechanism of circMBOAT2 in NSCLC and its involvement in chronic stress induced tumor growth. Stably transfected A549 and H1299 cell lines with circMBOAT2 overexpression and knockdown were constructed. Colony formation, scratch healing, Transwell and CCK-8 assays were conducted to evaluate the effects of circMBOAT2 with or without norepinephrine treatment on the proliferation, migration, and invasion of NSCLC cells, respectively. A chronic unpredictable mild stress (CUMS)-induced depression with xenografted LLC plus ASO targeting circMBOAT2 injection mouse model was established to determine the effect of chronic stress on tumorigenesis via circMBOAT2. Additionally, silencing CTCF in vivo and in vitro to investigate the regulatory effect of CTCF on circMBOAT2 expression. The results showed that circMBOAT2 was significantly upregulated in NSCLC cell lines and tumor tissues. CUMS promoted tumor growth, while silencing circMBOAT2 inhibited tumor growth in vivo. circMBOAT2 knockdown inhibited the proliferation, migration, and invasion of NSCLC cells. CTCF was identified as the upstream regulator of circMBOAT2 and was upregulated in NSCLC tissues. Knockdown of CTCF expression reversed the promotional effect of CUMS on circMBOAT2 expression and tumor growth. Our data thus provide evidence that CTCF mediates chronic stress in promoting of NSCLC progression through circMBOAT2. circMBOAT2 may serve as a potential biomarker and therapeutic target for NSCLC as well as depression NSCLC comorbidity treatment.