Roberts, John Keith (2010)
Ph.D. thesis, University of Birmingham.
In Western populations the incidence of oesophageal adenocarcinoma (OAC) is increasing greater than any other malignant disease. Increasing epidemiological and experimental evidence associates iron with OAC. Our understanding of iron physiology has increased enormously in recent years due to the elucidation of transport proteins and regulatory pathways. Haem scavenging and metabolism remains to be clearly characterised although candidate import proteins have been identified. This project aimed to characterise the iron transport machinery in the progression of OAC and the effects of iron exposure in-vitro. Overexpression of iron and haem import proteins, with a repression of iron export, was identified in the progression of Barrett’s metaplasia to OAC suggesting a role for iron in disease progression. Interestingly expression of hepcidin, the hepatic peptide responsible for systemic control of iron, was identified in samples of OAC. Culturing OAC cells with iron or haem increased cell proliferation, migration and anchorage independent growth. These effects were inhibited by the addition of alginate, a naturally occurring chelator. Knockdown of LRP-1, the prime haem import candidate, confirmed the role of this transporter. Understanding the differential expression of these proteins between benign and malignant tissue may permit novel therapeutic strategies in the future.
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