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MYCN Silencing as Therapeutics for Neuroblastoma using RNA interference

Maeshima, Ruhina; (2018) MYCN Silencing as Therapeutics for Neuroblastoma using RNA interference. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Neuroblastoma (NB) is the most common solid tumour in childhood and accounts for 15% of childhood cancer deaths. It is known that high-risk NB is highly correlated with MYCN amplification. Overexpressed MYCN induces proliferation and cell growth and suppresses apoptosis and differentiation pathways in NB cells. Since RNA interference (RNAi) was first described, many research groups have investigated the application of RNAi with the use of short interfering RNA (siRNA). Our aim is to induce apoptosis and differentiation using RNAi as a novel therapeutic strategy for MYCN-amplified NB. Our hypothesis is that MYCN silencing by anti-MYCN siRNA induces apoptosis and differentiation at the mRNA and protein level. We are encapsulating siRNA with liposome and integrin-receptor targeting peptide to deliver MYCN siRNA into NB cells and optimising cationic and anionic polyethylene glycol (PEG)ylated receptor-targeting nanocomplexes (RTNs). In this project, we also aimed to optimise the methods to store RTNs for a long time in trehalose, which is known as a cryoprotectant. As a result, MYCN was silenced by the siRNA at both the mRNA and protein levels, and the siRNA-mediated MYCN reduction induced downstream effects, such as a neuronal differentiation marker TrkA upregulation and the morphological changes of the cells. The anti-MYCN siRNA delivered using RTNs successfully silenced MYCN mRNA in vivo as well. We used an NB cell line with non-functional p53 and resistance toward p53-pathway dependent anti-cancer drugs, probably induced by multiple sessions of chemotherapy and radiotherapy. Therefore, the results are promising for a novel therapy for relapse NB with MYCN amplification. In addition, we successfully demonstrated that trehalose maintains the biophysical properties and the function of RTNs, consisting of either DNA or siRNA at -80 °C. This allows us to make a large amount of RTN for many experiments, store it for the long term, and transport it to a place far from the laboratory.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: MYCN Silencing as Therapeutics for Neuroblastoma using RNA interference
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10043849
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