Background: Circular RNAs (circRNAs) have been increasingly demonstrated to play critical roles in cancer progression. However, the biological functions and underlying mechanism of circRNA SEC24 homolog A, COPII coat complex component (circSEC24A) in cutaneous squamous cell carcinoma (CSCC) have not been well elucidated yet.
Methods: The expression levels of circSEC24A, microRNA-1193 (miR-1193) and mitogen-activated protein kinase kinase kinase 9 (MAP3K9) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay were used to assess cell proliferation ability. Flow cytometry and transwell assay were utilized to detect cell apoptosis and migration and invasion. Glycolytic metabolism was examined via the measurement of lactate production, glucose consumption, extracellular acidification rate (ECAR), hexokinase 2 (HK2) and Lactate dehydrogenase A (LDHA) expression. The interaction between miR-1193 and circSEC24A or MAP3K9 was predicted by starBase v2.0 and verified by dual-luciferase reporter, RNA Immunoprecipitation (RIP) and pull-down assay assays. The mice xenograft model was established to investigate the roles of circSEC24A in vivo.
Results: CircSEC24A and MAP3K9 were upregulated and miR-1193 was downregulated in CSCC tissues and cells. CircSEC24A knockdown inhibited the progression of CSCC cells by inhibiting cell proliferation, migration, invasion, and glycolysis and inducing apoptosis. Moreover, miR-1193 was a direct target of circSEC24A and its downregulation reversed the inhibitory effect of circSEC24A knockdown on the progression of CSCC cells. Furthermore, MAP3K9 was a downstream target of miR-1193 and its upregulation attenuated the anti-cancer role of miR-1193 in CSCC cells. Additionally, circSEC24A acted as a molecular sponge of miR-1193 to regulate MAP3K9 expression. Furthermore, interference of circSEC24A repressed tumor growth via upregulating miR-1193 and downregulating MAP3K9.
Conclusion: CircSEC24A interference suppressed the progression of CSCC by regulating miR-1193/MAP3K9 axis, which might be a promising strategy for CSCC treatment.
Keywords: cutaneous squamous cell carcinoma, circSEC24A, miR-1193, MAP3K9