期刊
CLINICAL AND TRANSLATIONAL MEDICINE
卷 11, 期 10, 页码 -出版社
JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.602
关键词
cell cycle; colorectal cancer; GSK3 beta; m6A; miR-6125; Wnt/beta-catenin; YTHDF2
资金
- Key Project of Science and Technology Innovation Team of Zhejiang Province [2013TD10]
- Key Discipline of Zhejiang Province in Medical Technology, Wenzhou Science & Technology Bureau [Y20180857]
- Wenzhou Medical University [89219018]
MiR-6125 is downregulated in CRC, negatively correlated with tumor size and prognosis. MiR-6125 targets YTHDF2, downregulates its protein, stabilizes m6A-modified GSK3 beta mRNA. Increased GSK3 beta protein inhibits Wnt/beta-catenin/Cyclin D1 pathway proteins, leading to G0-G1 phase arrest and inhibiting CRC cell proliferation.
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.
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