MiR-148a suppressed cell invasion and migration via targeting WNT10b and modulating β-catenin signaling in cisplatin-resistant colorectal cancer cells

Abstract

Cancer stem cells (CSCs) are suggested to be responsible for high recurrence rate and metastasis of colorectal cancer (CRC). Identifying novel targets that can suppress CSCs proliferation and metastasis may provide novel approach to combat against CRC. In the present study, we examined the role of miR-148a in cisplatin-resistant CRC cells with enhanced stem cell marker expression and explored the underlying mechanisms. In this study, we used cisplatin to selectively enrich cisplatin-resistant CRC cells from SW480 cell line, and these selected cisplatin-resistant SW480 cells were with significantly enhanced expression of stem cell markers and increased chemoresistance. MicroRNA (miRNA) array and qRT-PCR assay identified the down-regulation of miR-148a in cisplatin-resistant SW480 cells. Overexpression of miR-148a suppressed expression of stem cell markers, inhibited sphere formation, invasion and migration, induced apoptosis, and reduced chemo-resistance in cisplatin-resistant SW480 cells. Bioinformatics prediction and luciferase reporter assay revealed that WNT10b was a downstream target of miR-148a, and overexpression of miR-148a suppressed WNT10b expression and β-catenin signaling activities. Enforced expression WNT10b attenuated the effects of miR-148a on cisplatin-resistant SW480 cells sphere formation, invasion and migration. Further study showed that overexpression of miR-148a also suppressed in vivo tumor growth, and WNT10b expression and β-catenin signaling activities in tumor tissues were suppressed by miR-148a overexpression. In the clinical samples, miR-184a was found to be down-regulated in CRC tissues, down-regulation of miR-148a predicted poor prognosis in CRC patients. In conclusion, our study for the first time enriched the cisplatin-resistant CRC cells with enhanced stem cell marker expression from sphere-forming and chemo-resistant SW480-derived tumor xenografts in immune-deficient mice, and miR-148a suppressed the expression of stem cell markers, increased chemo-sensitivity, cell invasion and migration at least partly via regulating WNT10b and β-catenin signaling pathway.