Abstract
BackgroundOsteosarcoma is the most common primary malignant tumour of bone occurring in children and young adolescents and is characterised by complex genetic and epigenetic changes. The miRNA miR-486-5p has been shown to be downregulated in osteosarcoma and in cancer in general.ResultsTo investigate if the mir-486 locus is epigenetically regulated, we integrated DNA methylation and miR-486-5p expression data using cohorts of osteosarcoma cell lines and patient samples. A CpG island in the promoter of the ANK1 host gene of mir-486 was shown to be highly methylated in osteosarcoma cell lines as determined by methylation-specific PCR and direct bisulfite sequencing. High methylation levels were seen for osteosarcoma patient samples, xenografts and cell lines based on quantitative methylation-specific PCR. 5-Aza-2′-deoxycytidine treatment of osteosarcoma cell lines caused induction of miR-486-5p and ANK1, indicating common epigenetic regulation in osteosarcoma cell lines. When overexpressed, miR-486-5p affected cell morphology.ConclusionsmiR-486-5p represents a highly cancer relevant, epigenetically regulated miRNA in osteosarcoma, and this knowledge contributes to the understanding of osteosarcoma biology.
Highlights
High-grade osteosarcoma is the most prevalent primary malignant tumour of bone, affecting both children, adolescents and, more rarely, elderly people
In an effort to advance the understanding of osteosarcoma biology, we aimed to investigate if the expression of miR-486-5p was epigenetically regulated through methylation of promoter regions
Low expression of miR‐486‐5p in osteosarcoma To follow up on our earlier observations of miR-486-5p in osteosarcoma [24], miR-486-5p expression level was examined in a panel of osteosarcoma patient samples (n = 9), osteosarcoma cell lines (n = 17) and normal bone samples (n = 6) by quantitative real-time reversetranscription PCR
Summary
High-grade osteosarcoma is the most prevalent primary malignant tumour of bone, affecting both children, adolescents and, more rarely, elderly people. Osteosarcoma is characterized by considerable phenotypic and genomic heterogeneity, and few recurrent targetable genetic changes have been reported. Osteosarcoma exhibits a complex karyotype with high genetic and chromosomal instability seen as multiple rearrangements across the genome, kataegis and chromothripsis [3,4,5,6]. The limited extent of recurrent profiles identified indicates that a substantial regulation of the transcriptional programs in osteosarcoma may rather be caused by epigenetic programs [9,10,11,12,13], providing novel avenues for cancer therapy [14]. Osteosarcoma is the most common primary malignant tumour of bone occurring in children and young adolescents and is characterised by complex genetic and epigenetic changes. The miRNA miR-486-5p has been shown to be downregulated in osteosarcoma and in cancer in general
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