Tumour hypoxia has been linked to increased resistance to both radiotherapy and chemotherapy, especially in solid metastatic GI tumours. Under hypoxic conditions, genes that promote tumour growth and survival are up-regulated, via the transcription factor hypoxia-inducible factor-1 (HIF-1). The digestive hormone gastrin, which is often over-expressed in GI cancers, has also been shown to act as a pro-survival factor, up-regulating processes such as tumour proliferation, angiogenesis and migration, and down-regulating apoptosis. Due to the high level of similarity between the downstream events mediated by the two proteins, the relationship between gastrin and HIF-1 was investigated. HIF-1α nuclear protein expression was inducible under hypoxic conditions, which led to an expected increase in VEGF gene expression, followed by a 12-50 fold increase in hypoxic gastrin mRNA expression. HIF-1α expression and transcriptional activity were not consistently affected by exogenous gastrin. RNA-interference-mediated knockdown of HIF-1α resulted in a 40-60% down-regulation of gastrin gene expression under hypoxic conditions suggesting that HIF-1α is partially responsible for gastrin up-regulation in hypoxia. Potential hypoxia-response elements (HREs) were identified within the gastrin promoter, but were only partially responsive to hypoxic incubation in GI carcinoma cells in luciferase-reporter assays. Other possible mechanisms that may account for the increased gastrin gene expression induced under hypoxic conditions include interactions of gastrin with other transcriptional regulators, either in synergy with or independent from HIF-1, or the sequestration of gastrin within the cell by ‘P’-bodies or RNA-binding proteins. These findings may indicate that the addition of anti-gastrin agents such as CCK-2 receptor antagonists or gastrin immunogens to the treatment regime of patients with solid GI tumours may be clinically beneficial, especially if combined with agents used to reduce radiotherapy and chemotherapy resistance.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:514799 |
| Date | January 2009 |
| Creators | Royal, E. L. |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/10805/ |
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