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

Background: Aberrant activation of Wnt/beta-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/beta-catenin signaling. But the mechanism remains unclear. Methods: The 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 beta, which leads to the activation of Wnt/beta-catenin signaling. Results: MiR-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 beta, which activate the Wnt/beta-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3 beta and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3 beta and attenuated Wnt/beta-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/beta-catenin signaling pathway was verified as a valid transcription factor of miR-452's promoter. Conclusions: Our findings first demonstrate that miR-452-GSK3 beta-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.