Investigation of Oncogenic Long Non-coding RNAs in Ewing sarcoma
Long non-coding RNAs (lncRNAs) are RNA sequences that do not encode proteins. In the past, they were regarded as having no biological functions. However, recent studies have shown that lncRNAs regulate a number of cellular activities. More importantly, lncRNAs are beginning to be recognized as key players in oncogenesis in various cancers.
The role of lncRNAs in sarcomas remains poorly understood. Therefore, unraveling how they trigger oncogenesis in sarcoma presents a promising direction to further the understanding of sarcoma biology and improving sarcoma treatment.
We propose to study lncRNAs that may play a role in Ewing's sarcoma, an aggressive malignancy that arises in bone and soft tissues in children and adolescents. Most Ewing's sarcoma tumors are characterized by the chromosomal translocation EWS-FLI1 (the fusion of two genes), which is hypothesized to be the key oncogenic event that drives sarcoma formation. It is postulated that EWS-FLI1 acts as an aberrant transcription factor that activates oncogenic targets. By manipulating the expression of EWS-FLI1 in cells and performing RNA-sequencing analysis, we have identified numerous lncRNAs that are activated by EWS-FLI1. We propose to characterize the function of these lncRNAs using biochemical, functional genomics, and in vitro and in vivo approaches. We anticipate validating one or more of the lncRNAs as novel regulators responsible for EWS-FLI1 driven oncogenesis.
Because EWS is also a translocation partner in other sarcoma subtypes, understanding the functions of EWS-FLI1 regulated lncRNAs in Ewing's sarcoma may be more broadly relevant to other sarcomas.