MiRNA-124-3p Reduces Cell Viability in Cisplatin Resistant Neuroblastoma Cell Models. John Christopher Nolan 10.25419/rcsi.10801727.v1 https://repository.rcsi.com/articles/thesis/MiRNA-124-3p_Reduces_Cell_Viability_in_Cisplatin_Resistant_Neuroblastoma_Cell_Models_/10801727 <p>Neuroblastoma is a highly heterogeneous disease, responsible for 15 % of paediatric cancer deaths. Acquired drug resistance is a major obstacle in high risk neuroblastoma, making the elucidation of mechanisms in development and modulation of drug resistance essential.</p> <p>Three drug-resistant models, KellyCis83, CHP212Cis100 and SK-N-ASCis24 were developed previously to elucidate mechanisms involved in cisplatin resistance development.</p> <p>Cisplatin resistance induces phenotypic changes in neuroblastoma. The aim of this work was to characterise phenotypic and proteomic changes and validate a miRNA capable of regulating the expression of up-regulated genes from proteomic analysis of cisplatin resistant sub-lines.</p> <p>Proteomic profiling was carried out on the <em>MYCN </em>amplified KellyCis83 and non-<em>MYCN </em>amplified SK-N-ASCis24, which demonstrated cross<em> </em>resistance. Profiling identified an<em> </em>increase in proteins involved with ILK signalling, actin cytoskeletal signalling, epithelial adherens junction signalling and remodelling of epithelial adherens junctions pathways, indicating a mesenchymal phenotype in SK-N-ASCis24.<em></em></p> <p>MiR-124-3p targets overexpressed proteins from our dataset and low expression is associated with poor survival in a cohort of non-<em>MYCN </em>amplified tumours. Microfluidic card and individual Taqman analysis of miR-124-3p did not find decreased expression in SK-N-ASCis24.</p> <p>We conclude; rather than acting as a powerful inducer of apoptosis or cell cycle arrest, miR-124-3p decreased cell viability through a more subtle mechanism, targeting a large proportion of cytoskeletal genes associated with cell cycle checkpoints and proliferation. Gene ontology analysis of miR-124-3p targets provided a better understanding of the extensive cellular processes and mechanisms targeted by this tumour suppressor miRNA, demonstrating the highly context and cancer type dependent role of miR-124-3p.</p> 2019-11-22 17:34:55 Neuroblastoma Drug Therapy Drug Resistance