A modulation of iron transport proteins in human colorectal
carcinogenesis.
Brookes MJ, Hughes S, Turner FE, Reynolds G, Sharma N, Ismail T, Berx
G, McKie AT, Hotchin N, Anderson GJ, Iqbal T, Tselepis C
Gut. 2006 Apr 26;
BACKGROUND AND AIMS: Total body iron and high dietary iron intake are
risk factors for colorectal cancer. To date there is no comprehensive
characterisation of iron transport proteins in progression to
colorectal carcinoma. In this study, we examined the expression of iron
import (DCYTB, DMT1 and TfR1) and export (HEPH and FPN) proteins in
colorectal carcinoma. METHODS: Perl's staining was used to examine
colonocyte iron content. Real-Time PCR and Western blotting were
utilised to examine mRNA and protein levels of the molecules of
interest in 11 human colorectal cancers. Semi-quantitative
immunohistochemistry was used to verify protein levels and information
on cellular localisation. The effect of iron loading on E-cadherin
expression in SW480 and Caco-2 cell lines was examined by promoter
assays, Real-Time PCR and Western blotting. RESULTS: Perl's staining
showed increased iron in colorectal cancers, and there was a
corresponding overexpression of components of the intracellular iron
import machinery (DCYTB, DMT1 and TfR1). The iron exporter FPN was also
overexpressed, but its intracellular location, combined with reduced
HEPH levels, suggests reduced iron efflux in the majority of colorectal
cancers examined. Loss of HEPH and FPN expression was associated with
more advanced disease. Iron loading Caco-2 and SW480 cells caused
cellular proliferation and E-cadherin repression. CONCLUSIONS:
Progression to colorectal cancer is associated with increased
expression in iron import proteins and a block in iron export due to
decreased expression and aberrant localisation of HEPH and FPN
respectively. This results in increased intracellular iron which may
induce proliferation and repress cell adhesion.
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