Modulation of iron transport proteins in human colorectal carcinogenesis
Modulation of iron transport proteins in human colorectal carcinogenesis
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DOI：
10.1136/gut.2006.094060
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发表时间：
2006-10-01
期刊：
影响因子：
24.5
通讯作者：
Tselepis, C.
中科院分区：
文献类型：
--
作者：
Brookes, M. J.;Hughes, S.;Tselepis, C.
背景与目的：体内总铁和高铁摄入量是结直肠癌的危险因素。到目前为止，还没有全面的表征铁转运蛋白在进展到结直肠癌。在这项研究中，我们检测了铁输入（十二指肠细胞色素b （DCYTB）、二价金属转运蛋白1 （DMT1）和转铁蛋白受体1 （TfR1)）和输出（HEPH）和铁转运蛋白（FPN））蛋白在结直肠癌中的表达。方法：采用Perl染色法检测结肠菌铁含量。采用实时聚合酶链反应（PCR）和western blotting检测11种人类结直肠癌中感兴趣分子的mRNA和蛋白水平。半定量免疫组织化学用于验证蛋白质水平和细胞定位信息。通过启动子实验、实时PCR和western blotting检测铁负载对SW480和Caco-2细胞株E-cadherin表达的影响。结果：Perl染色显示结直肠癌中铁含量增加，细胞内铁输入机制成分（DCYTB、DMT1、TfR1）相应过表达。铁输出蛋白FPN也过表达，但其在细胞内的位置，结合HEPH水平的降低，表明在大多数结肠直肠癌中铁外排减少。HEPH和FPN表达的缺失与更晚期的疾病相关。铁负载Caco-2和SW480细胞引起细胞增殖和E-cadherin抑制。结论：由于HEPH和FPN的表达减少和异常定位，结直肠癌的进展与铁输入蛋白表达增加和铁输出受阻有关。这导致细胞内铁增加，可能诱导增殖和抑制细胞粘附。
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 expression of iron import (duodenal cytochrome b (DCYTB), divalent metal transporter 1 (DMT1), and transferrin receptor 1 (TfR1)) and export (hephaestin (HEPH) and ferroportin (FPN)) proteins in colorectal carcinoma.Methods: Perl's staining was used to examine colonocyte iron content. Real time polymerase chain reaction (PCR) and western blotting were used to examine mRNA and protein levels of the molecules of interest in 11 human colorectal cancers. Semiquantitative 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.