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. 2014 Apr;5(1-2):56-63.
doi: 10.18632/genesandcancer.6.

Upregulation of the miR-17-92 cluster and its two paraloga in osteosarcoma - reasons and consequences

Leila Arabi #  1   2 , Joël R Gsponer #  1 , Jan Smida  3 , Michaela Nathrath  3 , Valeria Perrina  1 , Gernot Jundt  1   4 , Christian Ruiz  1 , Luca Quagliata  1   5 , Daniel Baumhoer  1   4   5
Affiliations

Upregulation of the miR-17-92 cluster and its two paraloga in osteosarcoma - reasons and consequences

Leila Arabi et al. Genes Cancer. 2014 Apr.

Abstract

Osteosarcomas (OS) are aggressive bone tumors characterized by complex karyotypes with highly variable structural and numerical chromosomal aberrations. Although several genes and pathways commonly altered in malignant tumors have also been identified in OS, the molecular pathogenesis and driving genetic events eventually leading to tumor development are still poorly understood. The microRNA (miRNA) cluster 17-92 and its two paraloga 106a-363 and 106b-25 are known to have diverse oncogenic properties and have been shown to be constantly upregulated in several established OS cell lines. In this study we analyzed a series of 75 well characterized pretherapeutic OS samples for their expression of cluster-related miRNAs and correlated our findings with clinico-pathological parameters including prognosis, metastases and response to neoadjuvant therapy. Interestingly, higher expression levels of specific miRNAs were significantly associated with an adverse outcome of patients and were also higher in patients with systemic spread. We could furthermore show a direct correlation between the expression of cluster activators (MYC, E2F1-3), inhibitors (TP53), individual miRNAs, and pro-apoptotic targets (FAS, BIM). Our findings therefore underline a critical role of the miR-17-92 cluster and its two paraloga in OS biology with pathogenetic and prognostic impact.

Keywords: BIM; FAS; miR-106a-363; miR-106b-25; miR-17-92; osteosarcoma.

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Figures

Figure 1
Figure 1
The miR-17-92 cluster and its two paraloga miR-106a-363 and miR-106b-25 are centered in a complex network of regulators (upper half) and targets (lower half) of which this scheme only shows a selection for a better overview [8, 9].
Figure 2
Figure 2
The miRNA clusters are transcribed in polycistronic transcripts and organized in four families with high sequence homology (* = not included in the analysis).
Figure 3
Figure 3
Relative miRNA expression of all analyzed tumors compared to the corresponding expression in L87/4 cells (a). Kaplan-Meier plots showing an adverse outcome for OS patients with higher expression levels miRNAs miR-92a (b) and miR-20a (c). Statistical significance was assessed by means of the logrank test. Relative miRNA expression of all analyzed tumor stratified by metastatic spread (d).
Figure 4
Figure 4
Comparison between regulator / target gene and miRNA expression levels. Higher expression levels of MYC showed a trend towards concomitant higher expression levels of the depicted miRNAs (a1) which is presented exemplarily for miR-25 in a separate box-plot (a2). Representing a cluster inhibitor, lower expression levels of TP53 correlated with higher expression levels of the presented miRNAs (b1). Again, miR-106a is shown exemplarily in a separate box plot (b2). Higher expression levels of the miRNA depicted revealed a trend towards concomitant lower expression levels of the pro-apoptotic targets FAS and BIM (c1). Exemplarily, the association between FAS and miR-18a expression is shown in a separate box plot (c2).
See this image and copyright information in PMC

References

    1. Rosenberg AE, Cleton-Jansen A-M, de Pinieux G, Deyrup AT, Hauben E, Squire J. Conventional osteosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors. WHO Classification of Tumours of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2013. pp. 282–288.
    1. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20(3):776–790. - PubMed
    1. Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P, Alvegard TA, Picci P, Capanna R, Bernini G, Muller C, Tienghi A, Wiebe T, Comandone A, Bohling T, Del Prever AB, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol. 2005;23(34):8845–8852. - PubMed
    1. Kong C, Hansen MF. Biomarkers in osteosarcoma. Expert Opin Med Diagn. 2009;3(1):13–23. - PMC - PubMed
    1. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM. A microRNA polycistron as a potential human oncogene. Nature. 2005;435(7043):828–833. - PMC - PubMed