Abstract
BackgroundOsteosarcomas are the most common primary malignant tumors of bone and show multiple and complex genomic aberrations. miRNAs are non-coding RNAs capable of regulating gene expression at the post transcriptional level, and miRNAs and their target genes may represent novel therapeutic targets or biomarkers for osteosarcoma. In order to investigate the involvement of miRNAs in osteosarcoma development, global microarray analyses of a panel of 19 human osteosarcoma cell lines was performed.Principal findingsWe identified 177 miRNAs that were differentially expressed in osteosarcoma cell lines relative to normal bone. Among these, miR-126/miR-126*, miR-142-3p, miR-150, miR-223, miR-486-5p and members of the miR-1/miR-133a, miR-144/miR-451, miR-195/miR-497 and miR-206/miR-133b clusters were found to be downregulated in osteosarcoma cell lines. All miRNAs in the paralogous clusters miR-17-92, miR-106b-25 and miR-106a-92 were overexpressed. Furthermore, the upregulated miRNAs included miR-9/miR-9*, miR-21*, miR-31/miR-31*, miR-196a/miR-196b, miR-374a and members of the miR-29 and miR-130/301 families. The most interesting inversely correlated miRNA/mRNA pairs in osteosarcoma cell lines included miR-9/TGFBR2 and miR-29/p85α regulatory subunit of PI3K. PTEN mRNA correlated inversely with miR-92a and members of the miR-17 and miR-130/301 families. Expression profiles of selected miRNAs were confirmed in clinical samples. A set of miRNAs, miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-142-3p, miR-133b, miR-144, miR-195, miR-223, miR-451 and miR-497 was identified with an intermediate expression level in osteosarcoma clinical samples compared to osteoblasts and bone, which may reflect the differentiation level of osteosarcoma relative to the undifferentiated osteoblast and fully differentiated normal bone. Significance: This study provides an integrated analysis of miRNA and mRNA in osteosarcoma, and gives new insight into the complex genetic mechanisms of osteosarcoma development and progression.
Highlights
MicroRNAs are small, non-coding RNA molecules that are highly conserved across species and play key roles as regulators of gene expression. miRNAs have been estimated to regulate as much as 60% of the human protein coding genes [1], and modulate the levels of proteins involved in most biological processes, including development, cell proliferation, apoptosis and differentiation.miRNAs are transcribed as monocistronic or polycistronic stemloop RNA structures
EuroBoNeT human osteosarcoma cell lines and four bone samples, 340 miRNAs were identified as expressed in at least 25% of the cell lines and/or 75% of the normal bone samples. mRNA profiles were obtained, and distinct miRNA or mRNA patterns could be identified that distinguished certain subclasses of the osteosarcoma cell lines, clearly distinct from the pattern of normal bone
MiRNA*s, that were significantly differently expressed between osteosarcoma cell lines and normal bone
Summary
MicroRNAs (miRNAs) are small, non-coding RNA molecules that are highly conserved across species and play key roles as regulators of gene expression. miRNAs have been estimated to regulate as much as 60% of the human protein coding genes [1], and modulate the levels of proteins involved in most biological processes, including development, cell proliferation, apoptosis and differentiation.miRNAs are transcribed as monocistronic or polycistronic stemloop RNA structures. MiRNAs have been estimated to regulate as much as 60% of the human protein coding genes [1], and modulate the levels of proteins involved in most biological processes, including development, cell proliferation, apoptosis and differentiation. MiRNAs are non-coding RNAs capable of regulating gene expression at the post transcriptional level, and miRNAs and their target genes may represent novel therapeutic targets or biomarkers for osteosarcoma. Principal findings: We identified 177 miRNAs that were differentially expressed in osteosarcoma cell lines relative to normal bone. The most interesting inversely correlated miRNA/mRNA pairs in osteosarcoma cell lines included miR-9/TGFBR2 and miR-29/p85a regulatory subunit of PI3K. A set of miRNAs, miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-142-3p, miR-133b, miR-144, miR-195, miR-223, miR-451 and miR-497 was identified with an intermediate expression level in osteosarcoma clinical samples compared to osteoblasts and bone, which may reflect the differentiation level of osteosarcoma relative to the undifferentiated osteoblast and fully differentiated normal bone. Significance: This study provides an integrated analysis of miRNA and mRNA in osteosarcoma, and gives new insight into the complex genetic mechanisms of osteosarcoma development and progression
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