Ewing Sarcoma Associated Long Non-Coding Rna Determines Neural Cell Fate Of The Tumors

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LABACKGROUND: Ewing sarcoma is a highly invasive pediatric bone and soft tissue malignancy with a 20% 5-year survival rate for patients with metastatic disease. 85% of Ewing sarcomas express a chimeric oncogene, mainly EWS-FLI1, which drives the gene expression signature in these tumors. The exact cell of origin for these primitive small round cell tumors is unknown. These undifferentiated tumors express some neuroectodermal, mesenchymal, and epithelial markers. Recently published work suggests that these tumors may have risen either from neural crest or mesenchymal stem cells. These genomic and phenotypic features may be responsible for the aggressive nature of this disease and understanding the tumor biology may help better treatment options for this metastatic cancer.RESULTS: Our study on expression analysis of primary Ewing tumors using Affymetrixu0027s Human Exon arrays identified a highly expressed novel long intergenic non-coding RNA (lincRNA), FEZF1-AS1 in these tumors. Its DNA sequence has no homology in most vertebrates. RNA-mediated knockdown of the lincRNA in Ewing cell lines decreased expression of some of the neural lineage genes as well as genes associated with cell adhesion and migration. In vitro matrigel assays detected a decrease in cell invasion capability of the lincRNA-knockdown cells. In the in vivo studies, the lincRNA-overexpressed cells had better engraftment and tumor growth in the liver than the normal controls. On attempt to differentiate the lincRNA-knockdown Ewing cell lines, we noted that a decrease in the lincRNA expression led to a decrease in the expression of neuroectodermal markers after a week of differentiation when compared to the control cells. We further detected temporal expression of this lincRNA during neuronal differentiation from embryonic stem cells.CONCLUSIONS: Our study identified a unique lincRNA in Ewing sarcoma that may be partly responsible for inducing expression of the neural lineage genes in these tumors as its reduced expression impaired differentiation in the Ewing cell lines. Its prometastatic behavior helps the aggressive nature of these tumors. Its expression during neural differentiation along with its involvement in cell migration suggests that FEZF1-AS1 may be responsible for imparting neural stem cell like-characteristics to Ewing sarcoma.Citation Format: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, Timothy J. Triche. Ewing sarcoma associated long non-coding RNA determines neural cell fate of the tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2517.