MiR-452 promotes an aggressive colorectal cancer phenotype by regulating a Wnt/?-catenin positive feedback loop.

ABSTRACT: BACKGROUNDAberrant activation of Wnt/?-catenin signaling pathway is considered to be an important issue in progression and metastasis of various human cancers, especially in colorectal cancer (CRC). MiR-452 could activate of Wnt/?-catenin signaling. But the mechanism remains unclear.METHODSThe expression of miR-452 in CRC and normal tissues was detected by real-time quantitative PCR. The effect of miR-452 on CRC growth and invasion was conducted by functional experiments in vitro and in vivo. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-452 on the 3'-UTR of the GSK3?, which leads to the activation of Wnt/?-catenin signaling.RESULTSMiR-452 was upregulated in CRC compared with normal tissues and was correlated with clinical significance. The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3'-UTR of the GSK3?, which activate the Wnt/?-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3? and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3? and attenuated Wnt/?-catenin-mediated cell metastasis and proliferation. More important, T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which are crucial downstream molecules of the Wnt/?-catenin signaling pathway was verified as a valid transcription factor of miR-452's promoter.CONCLUSIONSOur findings first demonstrate that miR-452-GSK3?-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.

SUBMITTER: Li T 

PROVIDER: S-EPMC6156870 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other