The long non-coding RNA PARTICLE is associated with WWOX and the absence of FRA16D breakage in osteosarcoma patients
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Valerie Bríd O'Leary1, Doris Maugg1,2, Jan Smida1, Daniel Baumhoer3, Michaela Nathrath2,4, Saak Victor Ovsepian5,6,7 and Michael John Atkinson1,8
1Institute of Radiation Biology, Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg, Germany
2Department of Pediatrics and Children′s Cancer Research Center, Technical University Munich, Munich, Germany
3Bone Tumour Reference Center, Institute of Pathology, University Hospital Basel, Basel, Switzerland
4Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany
5Institute of Biological and Medical Imaging, Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg, Germany
6Faculty for Electrical Engineering and Information Technology, Technical University Munich, Munich, Germany
7International Centre for Neurotherapeutics, Glasnevin, Dublin, Republic of Ireland
8Chair of Radiation Biology, Technical University Munich, Munich, Germany
Valerie Bríd O'Leary, email: [email protected]
Keywords: WW-domain, PARTICLE, osteosarcoma, FRA16D
Received: June 29, 2017 Accepted: August 31, 2017 Published: September 19, 2017
Breakage of the fragile site FRA16D disrupts the WWOX (WW Domain Containing Oxidoreductase) tumor suppressor gene in osteosarcoma. However, the frequency of breakage is not sufficient to explain the rate of WWOX loss in pathogenesis. The involvement of non-coding RNA transcripts is proposed due to their accumulation at fragile sites, where they are advocated to influence specific chromosomal regions associated with malignancy. The long ncRNA PARTICLE (promoter of MAT2A antisense radiation-induced circulating long non-coding RNA) is transiently elevated in response to irradiation and influences epigenetic silencing modification within WWOX. It now emerges that elevated PARTICLE levels are significantly associated with FRA16D non-breakage in OS patients. Although not associated with overall survival, high PARTICLE levels were found to be significantly linked to metastasis free outcome. The transcription of both PARTICLE and WWOX are transiently responsive to exposure to low doses of radiation in osteosarcoma cell lines. Herein, a relationship between WWOX and PARTICLE transcription is suggested in human osteosarcoma cell lines representing alternative genetic backgrounds. PARTICLE over-expression ameliorated WWOX promoter activity in U2OS harboring FRA16D non-breakage. It can be concluded that the lncRNA PARTICLE influences the WWOX tumor suppressor and in the absence of WWOX FRA16D breakage, it is associated with OS metastasis-free survival.
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