Abstract
circNOL10 is a circular RNA expressed at low levels in lung cancer, though its functions in lung cancer remain unknown. Here, the function and molecular mechanism of circNOL10 in lung cancer development are investigated using in vitro and in vivo studies, and it is shown that circNOL10 significantly inhibits the development of lung cancer and that circNOL10 expression is co‐regulated by methylation of its parental gene Pre‐NOL10 and by splicing factor epithelial splicing regulatory protein 1 (ESRP1). circNOL10 promotes the expression of transcription factor sex comb on midleg‐like 1 (SCML1) by inhibiting transcription factor ubiquitination and thus also affects regulation of the humanin (HN) polypeptide family by SCML1. circNOL10 also affects mitochondrial function through regulating the humanin polypeptide family and affecting multiple signaling pathways, ultimately inhibiting cell proliferation and cell cycle progression, and promoting the apoptosis of lung cancer cells, thereby inhibiting lung cancer development. This study investigates the functions and molecular mechanisms of circNOL10 in the development of lung cancer and reveals its involvement in the transcriptional regulation of the HN polypeptide family by SCML1. The results also demonstrate the inhibitory effect of HN on lung cancer cells growth. These findings may identify novel targets for the molecular therapy of lung cancer.
Highlights
Lung cancer is the main cause of cancermechanism of circNOL10 in lung cancer development are investigated using in vitro and in vivo studies, and it is shown that circNOL10 significantly inhibits the development of lung cancer and that circNOL10 expression is co-regulated by methylation of its parental gene Pre-NOL10 and by splicing factor epithelial splicing regulatory protein 1 (ESRP1). circNOL10 promotes the expression of related deaths worldwide, and has been a focus of cancer research.[1]
Compared with overexpressing HN2 and HN8 alone, the combined treatment had the opposite effects to those observed with silencing circNOL10 alone. These results indicated that HN2 and HN8 could inhibit lung cancer cell viability, promote apoptosis, shorten S and G2/M phases, and inhibit cell proliferation, while the inhibitory effect of circNOL10 on lung cancer cell growth may be achieved through regulating the HN polypeptide family
Increasing numbers of circRNAs are being identified and their functions and molecular mechanisms elucidated. circRNAs have been shown to play important roles in various cancers. circRNA MYLK can act as an endogenous competitive RNA to promote the development of bladder cancer through regulating the vascular endothelial growth factor (VEGF)A/VEGF receptor 2 signaling pathway.[35] circRNACCDC66 was shown to accelerate the proliferation and metastasis of colon cancer,[36] circLARP4 regulated LARP4 expression by competitively binding to miR424-5p in gastric cancer,[37] and circLMO7 was involved in the regulation of myogenic differentiation in cattle.[38] circRNAs have been shown to regulate the lung cancer phenotype by acting as endogenous competitive RNAs during carcinogenesis and tumor development[39,40]; studies on the function and mechanism of circRNAs in lung cancer are still limited
Summary
2.1. circNOL10 Inhibited Lung Cancer Development circNOL10 was shown to be a circRNA formed by cyclization of exons 6–12 of Pre-NOL10. Silencing circNOL10 combined with overexpressing HN2 and HN8 induced a more significant increase in ROS and decreases in MMP and total ATP level compared with overexpressing HN2 and HN8 alone These results suggest that the HN family (HN2 and HN8) and circNOL10 can both modulate mitochondrial function in lung cancer cells, and circNOL10 may affect mitochondrial function by regulating the HN polypeptide family. Ten markers (POLE, MLH3, MSH2, p53, P-p53, CKEK2, P-CHEK2, P-CDC25A, Rb, and P-E2F1) were increased and six (LIG4, CDC25A, CCND1, CDK2, P-Rb, and E2F1) were decreased in the circNOL10 OE-ST group compared with the vec-ST group Detection of these 16 key molecules with western blot and immunohistochemistry confirmed that circNOL10 inhibited the development of lung cancer by regulating the HN polypeptide family, involving alterations in multiple signaling pathways.
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