Poster Presentation Advances in Neuroblastoma Research Congress 2016

Stathmin expression regulates miR-382/PTPN14 expression in neuroblastoma cells (#256)

Sela T Po'uha 1 2 , Miriam Brandl 1 2 , Maria Kavallaris 1 2
  1. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Australia, Randwick, NSW, Australia
  2. ARC Centre of Convergent Bio-Nano Science and Technology, Australian Centre for Nanomedicine, University of New South Wales, Sydney, Australia

Advanced stage neuroblastoma is highly aggressive and drug refractory metastasic disease is a major cause of treatment failure. We have recently shown that the phosphoprotein stathmin, which is overexpressed in neuroblastoma, mediates cell migration and invasion in vitro and neuroblastoma metastasis in vivo1. Several miRNAs have been identified to play an important role in neuroblastoma cell proliferation, migration, invasion and metastasis. To investigate whether stathmin regulates miRNA expression and metastasis, miRNA and gene arrays were performed on control versus stathmin depleted neuroblastoma cells. A number of miRNA were found to be significantly altered in stathmin depleted neuroblastoma cells compared to control cells, with analysis of their target genes identifying key signalling pathways involved in cell migration, metastasis and cell survival. Expression of three of these miRNAs was validated by qPCR and found to be consistently altered in stathmin depleted neuroblastoma cells. The protein tyrosine phosphatase, non-receptor type-14 (PTPN14) is a predicted target for three of the differentially expressed miRNAs, and miR-382, was prioritised for further studies. Consistent with gene array data, qPCR analysis showed that PTPN14 expression was downregulated in stathmin depleted neuroblastoma cells. In breast cancer, PTPN14 has been shown to prevent metastasis by restricting protein trafficking2 and mutations in PTPN14 were identified in relapsed neuroblastoma samples3. Analysis of RNAseq data (Tumor SEQC data - 498 primary samples) showed that high expression of PTPN14 gave better overall survival in the neuroblastoma cohort compared to low expression. The same trend was also found when analysing the MYCN amplified subset separately. Collectively, we have identified miR-382 and its predicted target gene, PTPN14 to be modulated by stathmin and these are being investigated to understand their role in stathmin mediated metastasis and to explore their potential as therapeutic targets for treating neuroblastoma.

  1. Byrne FL, Yang L, Phillips PA, Hansford LM, Fletcher JI, Ormandy CJ, McCarroll JA, Kavallaris M. RNAi-mediated stathmin suppression reduces lung metastasis in an orthotopic neuroblastoma mouse model. Oncogene. 2014;33(7):882-90.
  2. Belle L, Ali N, Lonic A et al. The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking. Science Signaling. 2015;8(364):ra18.
  3. Schramm A, Koster J, Assenov Y et al Mutational dynamics between primary and relapse neuroblastomas. Nature Genetics. 2015;47(8):872-7.