Poster Presentation ANZSCDB National Scientific Meeting 2019

The miR-200 family of microRNAs regulate neuroblastoma plasticity and metastasis (#Poster 33)

Xiaochun Li 1 , Cameron Bracken 1 , Kaitlin Scheer 1 , Kathleen Kimpton 2 , Maria Kavallaris 2 , Gregory Goodall 1 , Yeesim Khew-Goodall 1
  1. SA Pathology and University of South Australia, Adelaide, SA, Australia
  2. Children’s Cancer Institute, University of New South Wales, Sydney, New South Wales, Australia

The miR-200 family of microRNAs are enforcers of the epithelial phenotype and their loss can lead to a dramatic EMT. miR-200s are expressed in neural crest cells and are downregulated when neural crest cells undergo EMT, a process necessary for their delamination and migration away from the neural tube to undergo further differentiation. Cells of the neural crest give rise to the sympathetic neurons but some neural crest cells destined to become sympathetic neurons that do not complete their differentiation program give rise to neuroblastomas, a childhood cancer. Neuroblastomas are highly heterogeneous in nature but, in general, those without myc-N amplification or are more differentiated – possessing more neuronal features – have a better prognosis. All neuroblastoma cell lines that we have examined show barely detectable levels of miR-200 expression. Re-introduction of the miR-200a, but not miR-200b, sub-family to neuroblastoma cell lines results in differentiation of neuroblastoma cell lines – increased neurite outgrowths and upregulation of neuronal markers – retarded their proliferation and inhibited their ability to form colonies in soft agar. Significantly, a metastatic neuroblastoma cell line ectopically expressing miR-200a showed a 10-fold reduction in metastasis from the orthotopic site. We have identified downstream targets of miR-200a that mediate the neuronal differentiation conferred by ectopic expression of miR-200a and identified the signalling pathway leading to differentiation of neuroblastoma cells. In contrast, re-introduction of the miR-200b sub-family leads to a morphological transformation resembling an MET and a reduction in cell growth and invasion, but have no effect on tumour metastasis. we have found that miR-200a is expressed in mature sympathetic neurons but not differentiating, migrating neuron-progenitors during embryonic development.