title: Upregulation of the miR-17-92 cluster and its two paraloga in osteosarcoma - reasons and consequences.
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.
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors: Leila
authors: L
authors: Arabi
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Joël R
authors: JR
authors: Gsponer
authors: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Jan
authors: J
authors: Smida
authors: Clinical Cooperation Group Osteosarcoma, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Michaela
authors: M
authors: Nathrath
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Valeria
authors: V
authors: Perrina
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Gernot
authors: G
authors: Jundt
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Christian
authors: C
authors: Ruiz
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Shared senior authorship.
authors: Luca
authors: L
authors: Quagliata
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Bone Tumor Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland.|Shared senior authorship.
authors: Daniel
authors: D
authors: Baumhoer
keywords: BIM; FAS; miR-106a-363; miR-106b-25; miR-17-92; osteosarcoma