|miR-34a a micromanager of cancer stemness and resistance in NSCLC
|L MacDonagh S Toland S Gray M Gallagher B Ffrench C Gasch M Reidy S Finn S Cuffe K O'Byrne M Barr
|Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, School of Clinical Medicine, St. James's Hospital, Dublin 8
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|Disruption of Dicer-1, a crucial component of microRNA biogenesis depletes the stem cell pool, indicating a role for microRNAs in the maintenance of stem cells. MicroRNAs play a role in cancer stem cell (CSC) self-renewal, differentiation, resistance and metastasis. MicroRNAs associated with cisplatin resistance and CSC maintenance may be key in targeting the CSC root of resistance.
miRNAs associated with resistance were validated by qPCR. An ALDH1-positive CSC subpopulation was isolated using FACS. Expression of the miRNA panel was investigated within CSC populations. Altered miRNAs were inhibited using antagomiRs and stemness reassessed. Expression of the miRNA panel was investigated in FFPE tumour tissue of a xenograft model of CSCs.
A 5-miR signature associated with cisplatin resistance was identified across NSCLC histologies. The ALDH1-positive subpopulation was confirmed as CSCs, within this population miR-34a-5p was shown to be up-regulated. This result was mirrored within FFPE tissue. Inhibition of miR-34a-5p with antagomiRs did not deplete the CSC population however it significantly reduced the clonogenic capacity of cell lines.
These data suggest that miR-34a-5p, while significantly up-regulated within the CSC population, may not play a regulatory role in expression of CSC markers, however it may play a functional role in the survivability of CSCs.