miR-574-5p negatively regulates Qki6/7 to impact ß-catenin/Wnt signalling and the development of colorectal cancer.

ABSTRACT

OBJECTIVE: Deficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain. DESIGN: Expression of miR-574-5p, Qki5/6/7/7b splicing variants, ß-catenin and p27(Kip1) was determined in mouse and human CRC cells and tissues to investigate the post-transcriptional regulation of Qki isoforms by miR-574-5p and its impact on ß-catenin/p27(Kip1) signalling, cell cycle progression, proliferation, migration, invasion and tumour growth. RESULTS: In the CRC tissues of C57BL/6-Apc(min/+) mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of ß-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in ß-catenin and p27(Kip1) , increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice. CONCLUSIONS: Together, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic.