title: BRAF mutations are associated with increased iron regulatory protein-2 expression in colorectal tumorigenesis.
abstract: 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 (IRP2), which is known to regulate several iron metabolism proteins, has not been assessed in colorectal cancer. Expression of IRP2 was assessed by quantitative RT-PCR and immunohistochemistry in human colorectal cancer tissue. By interrogating The Cancer Genome Atlas (TCGA) database, expression of IRP2 and transferrin receptor-1 (TfR1) was assessed relative to common mutations that are known to occur in cancer. The impact of suppressing IRP2 on cellular iron metabolism was also determined by using siRNA and by using the MEK inhibitor trametinib. IRP2 was overexpressed in colorectal cancer compared to normal colonic mucosa and its expression was positively correlated with TfR1 expression. In addition, IRP2 expression was associated with mutations in BRAF. The MEK inhibitor trametinib suppressed IRP2 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 IRP2. Results presented here suggest that ablating IRP2 provides a therapeutic platform for intervening in colorectal tumorigenesis.
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Horniblow
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bedford
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Hollingworth
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Evans
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Sutton
authors.affiliation: Immunity and Immunotherapy, University of Birmingham, Birmingham, UK.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Lal
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Beggs
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Tariq H
authors.initials: TH
authors.lastname: Iqbal
authors.affiliation: Institutes of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tselepis
mesh_terms: D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005293:Ferritins / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D011990:Receptors, Transferrin / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D005293:Ferritins; D007501:Iron; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C546174:IREB2 protein, human; D035942:Iron Regulatory Protein 2
keywords: 
  BRAF
  ; colorectal cancer; iron; iron regulatory protein-2; trametinib