E-Thesis 374 views 105 downloads
The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression / CARMEN TSE
Swansea University Author: CARMEN TSE
DOI (Published version): 10.23889/SUthesis.60060
Abstract
Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers globally. High-grade serous ovarian carcinomas (HGSOC) comprise 75% of EOCs and are characterised by diagnosis at advanced stages due to the late manifestation of non-specific symptoms. The majority of HGSOC...
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Swansea
2022
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Cronin, James G. ; Francis, Lewis ; Johnson, Amy |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa60060 |
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| Abstract: |
Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers globally. High-grade serous ovarian carcinomas (HGSOC) comprise 75% of EOCs and are characterised by diagnosis at advanced stages due to the late manifestation of non-specific symptoms. The majority of HGSOC cells are found to metastasise to the omentum, an adipocyte-rich membrane which can metabolise chemotherapeutic drugs. EOC patients develop malignant ascites, characterised by the high concentration of cytokines and the presence of multicellular aggregates of EOC cells known as spheroids. Both characteristics can facilitate EOC metastasis. EOC patients initially respond well to platinum-based chemotherapy, but the vast majority will relapse and eventually develop chemotherapy-resistant disease. Long-term survival for OC has shown no recent improvement which highlights the needs for new strategies that improve EOC prognosis. The dysregulation of the epigenetic landscape is a hallmark of EOC leading to the activation of oncogenes and suppression of anti-tumour genes. Ten-eleven translocation (TET) 2 is involved in DNA demethylation, playing a role in transcriptional regulation and gene expression. Oncometabolites present in EOC can inhibit TET2 which leads to aberrant gene regulation, contributing to malignant transformation and progression. Additionally, TET2 can be stabilised by metformin through activation of AMPK, a key regulator of cellular energy homeostasis. Metformin, a biguanide drug widely prescribed as first line treatment for diabetes, has shown promise as an anti-cancer drug. In EOC, metformin has been linked with an increased survival rate in addition to being able to decrease cytokine production and tumour formation in ovarian tumour cells. However, here metformin was found to increase cytokine (IL-6 and IL-8) production in chemosensitive EOC cells, under conditions of a physiological EOC tumour microenvironment (i.e., restricted glucose conditions), but not in chemoresistant EOC cells. This may be unfavourable if metformin was to be repurposed as treatment for EOC and may account for its inconsistent efficacy as a potential therapeutic drug in other cancers. Pathways including AMPK/TET2, and JAK/STAT were explored using techniques such as western Blot, Chromatin immunoprecipitation (ChIP) and methylated DNA immunoprecipitation (MeDIP) as possible mechanisms for this response. Cell viability and proliferation assays were used to explore the effect of oncometabolites on EOC cells. The results will provide insights into how metabolites affect EOC progression in addition to identifying potential therapeutic targets. |
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| Keywords: |
Ovarian Cancer, Immunometabolism, Oncometabolites, Metformin, Epigenetics |
| College: |
Faculty of Medicine, Health and Life Sciences |