The long non-coding RNA PARTICLE is associated with WWOX and the absence of FRA16D breakage in osteosarcoma patients.

Valerie Bríd O'Leary,Saak Victor Ovsepian,Daniel Baumhoer,Michael John Atkinson,Doris Maugg,Michaela Nathrath,Jan Smida

doi:10.18632/oncotarget.21086

Abstract

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.

Highlights

Unstable regions of the human genome frequently harbor tumor-suppressor genes [1, 2]
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 metastasisfree survival
WWOX and PARTICLE reveal contrasting expression patterns in osteosarcoma tumor samples Differential WWOX and PARTICLE expression was determined in OS tumor samples and normal tissue controls [19] obtained from individuals of ~ 15 yr median age (n = 40, Table 1)

Summary

Introduction

Unstable regions of the human genome frequently harbor tumor-suppressor genes [1, 2]. The second most frequently affected site of human chromosomal fragility is FRA16D located at 16q23 within the WWOX (tryptophan domain containing oxidoreductase) locus [3]. The sequences of both orthologous chromosomal fragile site regions for human FRA16D/WWOX and mouse Fra8E1/Wwox exhibit remarkable conservation [4, 5]. The fact that WWOX deletion does not occur frequently but that loss of its expression is common suggests that factors influencing the epigenetic alterations of this gene might be involved in the pathogenesis of osteosarcoma [7]

Methods

Results

Conclusion