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Title: The mechanistic link between type 2 diabetes and colorectal cancer
Author: Thompson, Hannah L.
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Compared to non-diabetics, type 2 diabetics (T2D) have a 30% increased risk of colorectal cancer (CRC), which exhibits more serious histopathological features and has an increased risk of recurrence. Cell stress following hyperglycaemia or hypoxia reduces fumarate hydratase (FH) activity promoting increased intracellular fumarate. Fumarate irreversibly modifies cysteine residues by succination to form 2-succino-cysteine (2-SC) which can inactivate proteins. A significant increase in 2-SC staining was found in CRC compared to matched normal tissue and in tumours from T2D individuals compared to non-diabetics. Tumours positive for KRAS or BRAF mutation showed elevated staining, which was higher in T2D patients. Adenomas also showed 2-SC staining. The 2-SC staining was non-uniform across tumours, underlining metabolic heterogeneity of CRC. Paradoxically, tumours showed intense cytoplasmic FH staining. In a mouse model of polyposis and diabetes, overexpression of cytoplasmic FH in the gut led to larger polyps. In CRC cells, fumarate increased and gene expression altered after mitochondrial stress via treatment with 25mM glucose and 0.2% oxygen: FH was active and increased in cells cultured without glucose; its activity inversely correlated with fumarate. Mitochondria function was higher in CRC cells without glucose, but cells retained their ability to utilise glucose metabolism pathways. Separately, oxaliplatin therapy led to DUOX2 transcription mediated by STAT1, whereas cetuximab treatment inhibited STAT1 activation, oxaliplatin-induced DUOX2 upregulation, and ROS generation. This may explain why CRC patients on oxaliplatin alone have a better prognosis than those treated with a combination of oxaliplatin and cetuximab. This work has increased our understanding of CRC and aspects linked indirectly to mitochondria: diabetes mediating altered metabolism and potentially altered protein function. Dysregulated metabolism, as typified by FH dysfunction in CRC developing in the context of T2D, is significant and requires further investigation including identification of succinated proteins, which may give insights into improved therapies.
Supervisor: Not available Sponsor: Constance Travis Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available