Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3 beta

Background MicroRNAs (miRNAs), the key regulator of gene expression, and N6-methyladenosine (m6A) RNA modification play a significant role in tumour progression. However, regulation of m6A-modified mRNAs by miRNAs in colorectal cancer (CRC), and its effect on progression of CRC, remains to be investigated. Methods Expression of miR-6125 and YTH Domain-Containing Family Protein 2 (YTHDF2) was detected by western blotting and immunohistochemistry. The effects of miR-6125 and YTHDF2 on proliferative capacity of CRC cells were analysed using soft agar, ATP, CCK8 and EdU assays, and in animal experiments. Results MiR-6125 expression was downregulated markedly in CRC, and expression correlated negatively with tumour size and prognosis. MiR-6125 targeted the 3 '-UTR of YTHDF2 and downregulated the YTHDF2 protein, thereby increasing the stability of m6A-modified glycogen synthase kinase 3 beta (GSK3 beta) mRNA. Increased GSK3 beta protein levels inhibited the expression of Wnt/beta-catenin/Cyclin D1 pathway-related proteins, leading to G0-G1 phase arrest and ultimately inhibiting the proliferation of CRC cells. Conclusions MiR-6125 regulates YTHDF2 and thus plays a critical role in regulating the Wnt/beta-catenin pathway, thereby affecting the growth of CRC. Collectively, these results suggest that miR-6125 and YTHDF2 are potential targets for treatment of CRC.