Distinctive role of dysregulated miRNAs in chordoma cancer stem-like cell maintenance

Abstract

Chordoma is a rare, slow-growing tumor thought to arise from remnants of embryonic notochord associated with an aggressive outcome. Cancer stem-like cells (CSCs) are related to tumorigenesis, recurrence, and resistance in cancers. Therefore, chordoma CSCs are possible targets for chordoma treatment. In this study, dysregulated miRNAs were determined in chordoma CSCs and identified their role in chordoma. Dysregulated miRNAs were determined via miRNA microarray and validated through qPCR. miRNAs were transiently transfected to the chordoma cell lines and their roles in proliferation, apoptosis, migration and invasion capacities and stem-like properties were identified. Finally, a relationship between clinicopathological features and dysregulated miRNAs has been evaluated among 21 chordoma patients. CD133+CD15+ cells exhibited CSC phenotype with increased CSC- and Epithelial-Mesenchymal Transition (EMT)-related gene expression, invasion, migration, tumorosphere- and colony-forming abilities. In addition, WNT5A, TGF-α, BTG2 and MYCBP genes involved in CSC-related pathways, were targets of miR-140-3p, miR-148a-3p, miR-210-5p and miR-574-5p, respectively. Transfection of CSC-related miRNAs also increased migration and invasion along with stem cell phenotype. Finally, we determined that miR-140-3p and miR-148a-3p expressions correlated with Ki67 while miR-140-3p and TGF-α expressions were correlated with p53. Moreover, MYCBP expression was positively correlated with tumor volume, and metastasis was associated with the expression of miR-210-5p and TGF-α in our patient cohort. Through these findings, we conclude that chordoma CSCs have distinctive miRNA profile, which can regulate stem-like properties of chordoma CSCs.