Poster Presentation 27th Lorne Cancer Conference 2015

Identification of dysregulated microRNAs in soft-tissue sarcomas through integrative expression analysis (#255)

Regina Ryan 1 , David Goldstein 1 , Phil Crowe 1 , Jia-Lin Yang 1 , Jason Wong 1
  1. Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia

Background: Soft-tissue sarcomas (STSs) are malignant tumours of mesenchymal origin, which occur as a result of aberrant differentiation of mesenchymal stem cells (MSCs) (1). Differentiation is tightly controlled by gene regulatory elements, such as microRNA (miRNA) (2). These microRNAs are small (18-22 nucleotides) non-coding RNAs that bind to gene transcripts thereby regulating translation. Current theories suggest the loss of post-transcriptional control in gene expression leads to the development of sarcomas (3). However, the genetic mechanisms initiating STSs are poorly understood. The aim of this investigation was to identify key miRNAs related to development and progression of STSs as well as patient outcomes.

Methods: High-throughput sequencing was used to characterise miRNA expression profiles of MSCs undergoing adipogenesis (4). Differential expression (fold change >2, p-value <0.05) was used to determine miRNAs of interest. Kaplan-Meier survival analysis was performed on 87 candidate miRNAs of 90 STS patients from The Cancer Genome Atlas (TCGA).
Results: Upregulation of six miRNAs (miR-148b, miR-186, miR-192, miR-335, miR-424, and miR-503) correlated with high patient fatality, and two miRNAs (miR-424 and miR-503) were also highly expressed in MSCs compared to adipocytes. Gene targets were predicted for the six miRNAs and mapped to pathways to investigate their functional activity. Eleven differentially expressed genes (DIXC1, FRY, SLC24A3, NEURL1B, RAB9B, ZDHHC23, MYLK, MYBL1, LPP, PARM1 and SYT10) were predicted to be a target of at least three miRNAs and are involved in 145 pathways, several of which are associated with tumorigenesis.
Conclusion: The analysis identified key miRNAs in sarcoma based on poor patient prognosis. Further validation using a larger dataset and in vitro techniques may provide evidence to suggest miRNA involvement in STS pathogenesis and demonstrate that STSs originate from MSCs. Thus, the identification of key microRNAs has the potential to identify novel biomarkers, prognostic tools and targeted therapies for sarcoma patients.

  1. Hanahan, D. & Weinberg, R.A. (2011) Cell. 144, 646-674.
  2. Schoolmeesters, A., Eklund, T., Leake, D., Vermeulen, A., Smith, Q., Aldred, S.F., Fedorov, Y. (2009) PLoS ONE. 4(5), e5605
  3. Subramanian, S., Lui, W.O., Lee, C.H., Espinosa, I., Nielsen, T.O., Heinrich, M.C., Corless, C.L., Fire, A.Z. & Van De Rijn, M. (2008) Oncogene. 27(14), 2015-2026.
  4. Mikkelsen, T.S., Xu, Z., Zhang, X., Wang, L., Gimble, J.M., Lander, E.S. & Rosen, E.D. (2010) Cell 143, 156-169.