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

• Published in: Journal of experimental & clinical cancer research Vol. 37; no. 1; p. 238
• Main Authors: Li, Tingting, Jian, Xiangyu, He, Han, Lai, Qiuhua, Li, Xianzheng, Deng, Danling, Liu, Tengfei, Zhu, Jiehong, Jiao, Hongli, Ye, Yaping, Wang, Shuyang, Yang, Minhui, Zheng, Lin, Zhou, Weijie, Ding, Yanqing
• Format: Journal Article
• Language: English
• Published: England BioMed Central 25.09.2018; BMC
• Subjects: Bioinformatics; Biomarkers; Colorectal cancer; Colorectal caner; Feedback; Gastroenterology; Genotype & phenotype; GSK3β; Kinases; Liver cancer; Metastasis; MicroRNAs; miR-452; Mutation; TCF4/LEF1; Transcription factors; Tumorigenesis; Wnt/β-catenin pathway; GSK3β; TCF4/LEF1; Wnt/β-catenin pathway; Colorectal caner; miR-452
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-018-0879-z

Aberrant activation of Wnt/β-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/β-catenin signaling. But the mechanism remains unclear. 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 GSK3β, which leads to the activation of Wnt/β-catenin signaling. 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 GSK3β, which activate the Wnt/β-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3β and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3β and attenuated Wnt/β-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/β-catenin signaling pathway was verified as a valid transcription factor of miR-452's promoter. Our findings first demonstrate that miR-452-GSK3β-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.