The role of miRNA regulation in response to hypoxia in gliomas

Smith, Louise (2023) The role of miRNA regulation in response to hypoxia in gliomas. PhD thesis, University of Nottingham.

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Glioblastoma multiforme (GBM) is the most aggressive and frequent adult brain tumour. Current therapy consists of debulking surgery followed by radiotherapy and temozolomide chemotherapy. The median survival is only 14 months post-therapy due to the high rates of recurrence. GBMs are known to be very heterogenous both within the tumour and between patients, this is a key contributor to GBM recurrence. Solid tumours, including GBM, often harbour hypoxic regions which are areas of low oxygen, often around 1% or lower. Physiologically, the brain is usually at 7% oxygen and can vary often between 12.5% and 2.5%. Hypoxia is a tumour microenvironment which is known to exacerbate and accelerate tumorigenesis. As tumours proliferate and become denser, a hypoxic gradient occurs with less oxygenated cells at the core and more oxygenated cells towards the periphery. Although hypoxic pockets can be found throughout the tumour. Hypoxia causes hypoxia-induced transcription which consequently up or downregulates genes that are important within different hallmarks of cancer. These processes are regulated by many factors including miRNAs. miRNAs are small non-coding sequences which bind to complimentary sequences which cleaves target mRNA and subsequently causes mRNA degradation, translation inhibition or deadenylation. miRNAs regulate gene expression; however, their expression can be affected by many microenvironmental conditions such as hypoxia.

Different screening techniques were employed to determine significantly changed miRNA expression in response to hypoxia, in order to select hypoxia-sensitive miRNAs. This research aims to identify changed miRNAs in response to hypoxia, to then explore the depths of this response further including functional changes and gene target expression. Two miRNAs, miR-149-5p and miR-92a-3p were identified as significantly up and downregulated respectively, in response to hypoxia in glioblastoma cell lines. These findings were mostly also seen within glioblastoma tissue samples. Using miRNA mimics and inhibitors, the level of apoptosis is affected by hypoxia and changed expression of miRNAs. Further work analysed the gene targets of the selected miRNA and the effects of hypoxia on their expression using the mimics and inhibitors. The final aspect of this work identified that miR-149-5p is potentially a hypoxia-induced miRNA. This work highlights the importance of hypoxia in tumours at the molecular level and provides a basis of which individual miRNAs and their gene targets may be exploited to combat hypoxia in glioblastomas.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Smith, Stuart
McIntyre, Alan
Lourdsamy, Anbarasu
Keywords: Glioma, glioblastoma, hypoxia, miRNA
Subjects: W Medicine and related subjects (NLM Classification) > WL Nervous system
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 72896
Depositing User: Smith, Louise
Date Deposited: 31 Jul 2023 04:40
Last Modified: 31 Jul 2023 04:40

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