The role of miRNA regulation in response to hypoxia in gliomas
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 ver...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
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2023
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| Online Access: | https://eprints.nottingham.ac.uk/72896/ |
| _version_ | 1848800748593217536 |
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| author | Smith, Louise |
| author_facet | Smith, Louise |
| author_sort | Smith, Louise |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:56:30Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-72896 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:56:30Z |
| publishDate | 2023 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-728962023-07-31T04:40:38Z https://eprints.nottingham.ac.uk/72896/ The role of miRNA regulation in response to hypoxia in gliomas Smith, Louise 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. 2023-07-31 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en cc_by https://eprints.nottingham.ac.uk/72896/1/FINAL%20CORRECTED%20Thesis%20Louise%20Smith%20The%20response%20of%20miRNA%20to%20hypoxia%20in%20gliomas%20November%202022.pdf Smith, Louise (2023) The role of miRNA regulation in response to hypoxia in gliomas. PhD thesis, University of Nottingham. Glioma glioblastoma hypoxia miRNA |
| spellingShingle | Glioma glioblastoma hypoxia miRNA Smith, Louise The role of miRNA regulation in response to hypoxia in gliomas |
| title | The role of miRNA regulation in response to hypoxia in
gliomas |
| title_full | The role of miRNA regulation in response to hypoxia in
gliomas |
| title_fullStr | The role of miRNA regulation in response to hypoxia in
gliomas |
| title_full_unstemmed | The role of miRNA regulation in response to hypoxia in
gliomas |
| title_short | The role of miRNA regulation in response to hypoxia in
gliomas |
| title_sort | role of mirna regulation in response to hypoxia in
gliomas |
| topic | Glioma glioblastoma hypoxia miRNA |
| url | https://eprints.nottingham.ac.uk/72896/ |