CircCDK1 blocking IGF2BP2-mediated m6A modification of CPPED1 promotes laryngeal squamous cell carcinoma metastasis via the PI3K/AKT signal pathway
Jinling Li, Huan Cao, Jianwang Yang, Baoshan Wang
Abstract
BACKGROUND: Circular RNA (circRNA) is a novel noncoding RNA (ncRNA) that plays a critical role in various cancers. However, the clinical significance, biological function, and molecular mechanisms of circRNAs in laryngeal squamous cell carcinoma (LSCC) remain unclear. METHODS: A circRNA array was performed to identify the differentially expressed circRNAs. In vitro and in vivo assays were proceeded to verify the biological function of circCDK1 in LSCC. RNA pulldown assays and RNA immunoprecipitation (RIP) were used to confirm the binding between circCDK1 and insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2). The MeRIP assay was then used to identified the N6-methyladenisine (m6A) methylation of calcineurin like phosphatase domain containing1 (CPPED1). RESULTS: Hsa_circ_0005774 (circCDK1) was found upregulated in LSCC tissues compared to adjacent normal tissues. The level of circCDK1 was positively correlated with poor prognosisof LSCC patients. In vitro and in vivo, circCDK1 promoted migration and invasion of LSCC cells. Mechanistically, eukaryotic translation initiation factor4A3(EIF4A3) induced biogenesis of circCDK1 by binding to its flanking. By competitively binding to IGF2BP2, circCDK1 blocked the m6A modification of CPPED1 in IGF2BP2-dependent manner. Moreover, the circCDK1-mediated decrease of CPPED1 activated the PI3K/AKT signal pathway to facilitate progression of LSCC. CONCLUSIONS: Our findings demonstrated that EIF4A3-induced upregulation of circCDK1 promoted LSCC metastasis via EIF4A3-circCDK1-IGF2BP2-CPPED1 to activate PI3K-AKT signal pathway. CircCDK1 might serve as a new diagnostic and prognostic marker or potential therapeutic target for LSCC.