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Cancer Genet. 2011 Mar;204(3):138-46. doi: 10.1016/j.cancergen.2010.12.012.

Analysis of miRNA-gene expression-genomic profiles reveals complex mechanisms of microRNA deregulation in osteosarcoma.

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  • 1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.

Abstract

Osteosarcoma is an aggressive sarcoma of the bone characterized by a high level of genetic instability and recurrent DNA deletions and amplifications. This study assesses whether deregulation of microRNA (miRNA) expression is a post-transcriptional mechanism leading to gene expression changes in osteosarcoma. miRNA expression profiling was performed for 723 human miRNAs in 7 osteosarcoma tumors, and 38 miRNAs differentially expressed ≥10-fold (28 under- and 10 overexpressed) were identified. In most cases, observed changes in miRNA expression were DNA copy number-correlated. However, various mechanisms of alteration, including positional and/or epigenetic modifications, may have contributed to the expression change of 23 closely linked miRNAs in cytoband 14q32. To develop a comprehensive molecular genetic map of osteosarcoma, the miRNA profiles were integrated with previously published array comparative genomic hybridization DNA imbalance and mRNA gene expression profiles from a set of partially overlapping osteosarcoma tumor samples. Many of the predicted gene targets of differentially expressed miRNA are involved in intracellular signaling pathways important in osteosarcoma, including Notch, RAS/p21, MAPK, Wnt, and the Jun/FOS pathways. By integrating data on copy number variation with mRNA and miRNA expression profiles, we identified osteosarcoma-associated gene expression changes that are DNA copy number-correlated, DNA copy number-independent, mRNA-driven, and/or modulated by miRNA expression. These data collectively suggest that miRNAs provide a novel post-transcriptional mechanism for fine-tuning the expression of specific genes and pathways relevant to osteosarcoma. Thus, the miRNA identified in this manner may provide a starting point for experimentally modulating therapeutically relevant pathways in this tumor.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21504713
[PubMed - indexed for MEDLINE]
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