Bountali, Aikaterini (2021) Investigation into the role of long non-coding RNAs in neuroblastoma and glioma. Doctoral thesis, Keele University.

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Abstract

Long non-coding RNAs (lncRNAs) play key roles in several processes in healthy and cancer settings and the underpinning mechanisms of their action are thoroughly investigated. In line with this, this study investigates the role of the lncRNA myocardial infarction associated transcript (MIAT) and other novel lncRNAs in neuroblastoma and glioblastoma.
Silencing of MIAT, both siRNA- and GapmeR-mediated, led to decreased long-term survival, promoted apoptosis and attenuated migration in neuroblastoma and glioblastoma cells. RNA sequencing showed that reduced MIAT expression levels were associated with perturbed expression of genes involved in cancer-related processes, such as cell growth and survival, migration, reactive oxygen species (ROS) production and apoptosis. Further analysis confirmed that MIAT knockdown induces an increase in ROS levels in neuroblastoma cells and was associated with perturbed expression of genes involved in apoptosis, on mRNA and protein level. Notably, RNA sequencing also revealed that MIAT acts as cis and trans gene expression regulator and contributes to regulating alternative splicing.
Given the complex signalling networks of metformin action, short- and long-term exposure of neuroblastoma cells to metformin was used as a platform for an RNA sequencing approach, which revealed that hundreds of novel lncRNAs display aberrant expression and could, therefore, be potentially involved in the regulation of cell fate determination. Of these, the knockdown of LINC00176 and LOC648987 led to increased apoptosis and decreased migration. Furthermore, multiple novel pathways, in which the novel lncRNAs could be integrated, were discovered to be deregulated, including DNA replication and DNA damage response-related pathways.
Taken together, this study suggests that MIAT exerts a key role in neuroblastoma and glioblastoma cells, confirming its oncogenic role, while multiple novel lncRNAs could also be drivers of cell fate decisions in metformin response of neuroblastoma cells. Further research is essential to establish MIAT and other novel lncRNAs, such as LINC00176 and LOC648987, as biomarkers and therapeutic targets.

Item Type: Thesis (Doctoral)
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Natural Sciences > School of Life Sciences
Contributors: Maarabouni, MM (Thesis advisor)
Williams, Gwyn (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 17 Mar 2021 12:58
Last Modified: 17 Mar 2021 12:58
URI: https://eprints.keele.ac.uk/id/eprint/9263

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