miRNA profiling identifies deregulated miRNAs associated with osteosarcoma development and time to metastasis in two large cohorts

Publikation: Forskning - peer reviewTidsskriftartikel

DOI

  • Gitte Brinch Andersen
  • Alice Knudsen
  • Henrik Hager
    Henrik HagerDepartment of Pathology, Aarhus University Hospital, Nørrebrogade 45, DK-8000 Aarhus C, Denmark.Department of Pathology, Vejle Hospital, Beriderbakken 4, DK-7100, Vejle, Denmark.
  • Lise Lotte Hansen
  • Jörg Tost
    Jörg TostLaboratory for Epigenetics and Environment, Centre National de la Recherche en Génomique Humaine, CEA - Institut de Biologie Francois Jaçob, 2 rue Gaston Crémieux, 91000, Evry, France.

Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays. The identified miRNA expression changes were correlated with gene expression in the same samples. Furthermore, miRNA expression changes were validated in a second independent cohort consisting of 78 OS samples. Analysis of 752 miRNAs in the discovery cohort led to the identification of 33 deregulated miRNAs in OS. Twenty-nine miRNAs validated with statistical significance in the second cohort comprising 78 OS samples. miRNA-mRNA targets were determined, and 361 genes with an inverse expression of the target miRNA were identified. Both the miRNAs and the identified target genes, associated with multiple pathways related to cancer as well as bone cell biology, thereby correlating the deregulated miRNAs with OS tumorigenesis. An analysis of the prognostic value of the 29 miRNAs identified miR-221/miR-222 to be significantly associated with time to metastasis in both cohorts. This study contributes to a more profound understanding of OS tumorigenesis, by substantiating the importance of miRNA deregulation. We have identified and validated 29 deregulated miRNAs in the - to our knowledge - largest discovery and validation cohorts used so far for miRNA analyses in OS. Two of the miRNAs showed a promising potential as prognostic biomarkers for the aggressiveness of OS.

OriginalsprogEngelsk
TidsskriftMolecular Oncology
ISSN1574-7891
DOI
StatusUdgivet - 2 jan. 2018

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