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Title: Regulation of stem cell marker LGR5 by hypoxia in colorectal cancer
Author: Emery, Elizabeth Dorothy
ISNI:       0000 0004 5914 6688
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Leucine rich repeat containing G-protein coupled receptor 5 (LGR5) is a well-established stem cell marker in the normal intestine. Recent evidence suggests LGR5 is also a marker of cancer stem cells in colorectal tumours. Cancer stem cells propagate and maintain tumours and are hypothesized to be refractory to therapy. Solid tumours frequently experience hypoxia and an unresolved question remains as to how the cancer stem cell population survives this environmental stress. Several regulatory links are known to exist between hypoxic and stem cell signalling pathways. However, the role of hypoxia in regulating LGR5 is yet to be elucidated. Here it is reported that hypoxia down-regulates LGR5 expression. Both protein and mRNA expression is reduced in hypoxia. LGR5 down regulation was observed in cells derived from adenoma, primary carcinoma and metastases, suggesting this process occurs throughout tumourigenesis. LGR5 was found to be re-expressed following re-oxygenation, demonstrating tumour cells ability to switch between expressing LGR5 in normoxic conditions and reducing expression in hypoxia. LGR5 is an established target gene of the WNT signalling pathway and hypoxia has been reported previously to regulate the WNT pathway. Results presented here suggest hypoxic down-regulation of the WNT pathway mediates the hypoxic regulation of LGR5. Topflash WNT reporter activity and expression of a selection of additional WNT target genes decreased in hypoxia in the cell lines tested here. Preliminary ChiP experiments suggest WNT signalling effectors Beta-catenin and TCF4 are lost from the LGR5 promoter in hypoxia. It has been reported previously that HIF-1 interacts with the WNT pathway in hypoxia to down-regulate WNT target gene expression. However HIF-1 does not regulate LGR5 in the cell lines tested here. Highly related HIF-2, though, is critical in the hypoxic regulation of LGR5 in the LoVo cell line and not in other cell lines tested here. The reversible down regulation of stem cell markers during hypoxia may have important implications for targeting cancer stem cells in vivo where tumours are heterogeneous with fluctuating areas of hypoxia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available