Functional role of a Ewing-sarcoma-specific vlncRNA in tumor growth and progression.

摘要

The Ewing sarcoma family of tumors (ESFTs) are the second most common bone and soft tissue tumor in children, most commonly in adolescence. A chromosomal translocation t(11:22) generating the EWSR1-FLI1 fusion gene is well known as a molecular pathologic marker of Ewing sarcoma. Current advance showed that several specific gene targets of this chimeric protein EWS-FLI1 have been identified, all possessing multiple GGAA repeats in their promoter region, but until now, no non-coding RNA targets have been found.;Nowadays, over 60% of all known human genes are documented to be non-coding RNA transcripts, and many of these have been shown to be functional that were not previously appreciated. In the past, studies of non-coding RNA focused mainly on non-coding RNAs in small size; however, recent studies have revealed that long non-coding RNAs (lncRNAs, over 200 nucleotides) perform a wide range of functions in cellular development, proliferation, and survival. Moreover, current research in lncRNAs have uncovered a new category of ncRNAs that span more than 50 kb in size and named very long non-coding RNA (vlncRNA) in this study. This new category is unusually difficult to study due to its large size and lack of conventional promoter. Thus, even though this class of ncRNA has been known for several years, few publications have characterized their functions. In this study, one such vlncRNA is shown to be expressed exclusively in the Ewing sarcoma family of tumors, and a function for this vlncRNA is identified.;Unlike the fusion gene EWSR1-FLI1 which drives Ewing sarcoma aggression, sEWVLNC, a 2 kb spliced variant of this Ewing-sarcoma-specific vlncRNA, delays tumor progression dramatically in vitro and in vivo. Moreover, survival analysis and relapse analysis of 52 Ewing sarcoma patients from a COG database indicates that sEWVLNC enhances patient survival rate. Based on signaling pathway analysis, gene cluster selection, and down-stream gene prediction in this study, the results indicate that sEWVLNC might regulate tumor growth and progression by decreasing proto-oncogene MET expression, thereby suppressing the HGF/MET signaling pathway. Corresponding mechanistic investigations suggest a potential interaction between sEWVLNC and the transcription factor c-Jun, a binding partner of c-Fos which together with c-Jun forms the heterodimer AP-1 complex that serves as a major promoter of the MET gene. These findings are the first to document that a tumor specific vlncRNA is spliced into a functional variant that suppresses proto-oncogene MET expression. In conclusion, these results suggest that sEWVLNC plays an important role in Ewing sarcoma suppression and prognosis.