Open AccessBRAF mutations are associated with increased iron regulatory protein‐2 expression in colorectal tumorigenesis
Author(s) -
Horniblow Richard D.,
Bedford Matthew,
Hollingworth Robert,
Evans Sarah,
Sutton Emily,
Lal Neeraj,
Beggs Andrew,
Iqbal Tariq H.,
Tselepis Chris
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13234
Subject(s) - colorectal cancer , carcinogenesis , transferrin receptor , cancer research , biology , ferritin , trametinib , transferrin , immunohistochemistry , cancer , gene expression , gene , endocrinology , immunology , microbiology and biotechnology , signal transduction , genetics , biochemistry , mapk/erk pathway
A role for iron in carcinogenesis is supported by evidence that iron metabolism proteins are modulated in cancer progression. To date, however, the expression of iron regulatory protein‐2 ( IRP 2), which is known to regulate several iron metabolism proteins, has not been assessed in colorectal cancer. Expression of IRP 2 was assessed by quantitative RT ‐ PCR and immunohistochemistry in human colorectal cancer tissue. By interrogating The Cancer Genome Atlas ( TCGA ) database, expression of IRP 2 and transferrin receptor‐1 (TfR1) was assessed relative to common mutations that are known to occur in cancer. The impact of suppressing IRP 2 on cellular iron metabolism was also determined by using si RNA and by using the MEK inhibitor trametinib. IRP 2 was overexpressed in colorectal cancer compared to normal colonic mucosa and its expression was positively correlated with TfR1 expression. In addition, IRP 2 expression was associated with mutations in BRAF . The MEK inhibitor trametinib suppressed IRP 2 and this was associated with a suppression in TfR1 and the labile iron pool ( LIP ). Moreover, epidermal growth factor stimulation resulted in decreased ferritin expression and an increase in the LIP which were independent of IRP 2. Results presented here suggest that ablating IRP 2 provides a therapeutic platform for intervening in colorectal tumorigenesis.