A21
The role of LRP1 in oesophageal adenocarcinoma
Keith Roberts1, Lewis Stevens1, Matthew Brookes1, Robert Spychal2, Tariq Iqbal1, Chris Tselepis1
1University of Birmingham, Birmingham, UK, 2Birmingham City Hospital, Birmingham, UK
Background
There is emerging epidemiological, animal and cellular evidence implicating iron in carcinogenesis. In particular in oesophageal adenocarcinoma there is an increase in cellular iron uptake through the process of transferrin receptor-mediated endocytosis. However, to date what has not been addressed is whether cancer cells can also capture a circulating pool of haem in addition to transferrin bound iron. Thus the study aims were to determine if LRP1; the receptor responsible for capturing circulating haem is expressed in the malignant progression of oesophageal adenocarcinoma.
Method
Utilising qRT-PCR and immunohistochemistry the mRNA expression and cellular localisation of LRP1 was determined in matched samples of Barrett’s metaplasia and oesophageal adenocarcinoma. Haem uptake was determined in oesophageal lines (OE33 and FLO) and its effect on cellular proliferation determined by Brdu assay. The importance of the haem receptor LRP1 was further determined by using shRNA to silence expression.
Results
LRP1 mRNA was overexpressed in 65% of adenocarcinoma specimens compared to matched Barrett’s metaplastic controls. Furthermore, LRP1 transcript was 1,000 fold more abundant than transferrin receptor expression in these specimens. Overexpression at the protein level was also evident by semi-quantitative evaluation of the immunohistochemistry studies. Oesophageal cell lines both expressed LRP1 and also mediated an induction in cellular proliferation when cultured with haem. This could be markedly inhibited by silencing LRP1 expression.
Conclusion
We report for the first time that the receptor LRP1 is overexpressed in the progression from Barrett’s metaplasia to adenocarcinoma and that blocking this receptor may provide a platform for therapeutic intervention.
