miR-653-3p promotes genomic instability of colorectal cancer cells via targeting SIRT1/TWIST1 signaling pathway

Abstract

Development of colorectal cancer (CRC) accompanied with genomic instability. Genomic instability was promoted by microRNAs (miRNAs) inhibiting key genes in DNA damage repair and spindle assembly processes. Whether miR-653-3p affects genomic instability is unknown. The aim of this study is to explore the effect of miR-653-3p on genomic instability in CRC cells. Based on RT-qPCR analysis, miR-653-3p was highly expressed in CRC cells. Through single-cell electrophoresis assay and chromosome karyotype analysis, we determined ectopic expression of miR-653-3p induced increased DNA damage but inhibited apoptosis by promoting chromosomal instability. Mechanistically, luciferase assay identified the direct interaction of miR-653-3p with the 3' UTR of SIRT1, and western blot analysis indicated miR-653-3p inhibited SIRT1 and then promoted STAT3 phosphorylation and TWIST1 expression. The results of karyotype analysis showed that the upregulation of SIRT1 and the downregulation of TWIST1 caused by the downregulation of miR-653-3p suppressed chromosomal instability. Additionally, our evidence showed that miR-653-3p promoted CRC cell proliferation, migration, and 5-FU resistance, and miR-653-3p induced the development of CRC in the xenograft mice model. Altogether, our evidence suggests that miR-653-3p regulates SIRT1/TWIST1 signaling pathway and plays an important role in promoting genomic instability, proliferation, migration, and chemoresistance of CRC cells, which may serve as a promising therapeutic target for CRC therapy.

Keywords: Colorectal cancer; Genomic instability; SIRT1/TWIST1; miR-653-3p.