Abstract
Circular RNA (circRNA) has been demonstrated to play a pivotal role in tumor development. This study aimed to investigate the regulatory mechanism of circMBOAT2 in non-small cell lung cancer (NSCLC) and its association with tumor growth induced by chronic stress. We constructed stably transfected A549 and H1299 cell lines with circMBOAT2 overexpression and knockdown. Colony formation, scratch healing, Transwell and CCK-8 assays were conducted to evaluate the effects of circMBOAT2 in the presence or absence of norepinephrine (NE) treatment on the proliferation, migration, and invasion of NSCLC cells, respectively. Additionally, A chronic unpredictable mild stress (CUMS)-induced depression with heterotopic transplantation LLC and injection of antisense oligonucleotides (ASOs) targeting circMBOAT2 mouse model was established to evaluate the effect of chronic stress on tumorigenesis via circMBOAT2. Moreover, we investigated the regulatory effect of CCCTC binding factor (CTCF) on circMBOAT2 expression through in vivo and in vitro silencing of CTCF. Our results revealed a significant upregulation of circMBOAT2 in NSCLC cell lines and tumor tissues. circMBOAT2 knockdown inhibited the proliferation, migration, and invasion of NSCLC cells, while NE treatment reversed the cell suppression effect caused by circMBOAT2 knockdown. Notably, CUMS promoted tumor growth, while silencing circMBOAT2 inhibited tumor growth in vivo. Furthermore, we identified CTCF as the upstream regulator of circMBOAT2, which exhibited upregulation in NSCLC cells and tissues. Knockdown of CTCF reversed the promotional effect of CUMS on circMBOAT2 expression and tumor growth. Our findings 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 the treatment of comorbid depression in NSCLC patients.
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