The Novel CircSLC6A6/miR-1265/C2CD4A Axis Promotes Colorectal Cancer Growth by Suppressing P53 Signaling Pathway

Abstract Background: Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer and is a leading cause of cancer-related deaths. Therefore, further researches were required to identify novel and more effective diagnoses and to identify molecular targets in treatment of CRC.Methods: CRC fresh frozen tissues and cell lines were used to detect C2CD4A expression by qRT-PCR and western blotting. The biological functions of C2CD4A were performed in vitro and in vivo. Western blotting, cDNA array, IP-MS, Co-IP, and Ubiquitination assay were used to analyze the interaction between C2CD4A and p53. Bioinformatics analysis, FISH, RNA sequencing, luciferase reporter assay, RNA immunoprecipitation, RNA pull-down and rescue experiments, were deployed to detect upstream regulation mechanism of C2CD4A.Results: C2CD4A was aberrantly upregulated in CRC tissues compared with adjacent normal colorectal tissues. C2CD4A knockdown significantly promoted cell apoptosis and with inhibited proliferation in vitro, and tumorigenicity in vivo, whereas C2CD4A overexpression had displayed an opposite effect. Moreover, circSLC6A6 was upregulated and positively associated with C2CD4A expression in CRC tissues. C2CD4A was positively regulated by circSLC6A6 via sponging miR-1265. Fundamentally, C2CD4A inhibited P53 signaling pathway through interacting with P53 and increasing its ubiquitination and degradation.Conclusion: Our results identified that circSLC6A6/miR-1265/C2CD4A axis, which was involved in CRC via the P53 signaling pathway, could be as a therapeutic target for CRC.