BRAF mutations are associated with increased iron regulatory protein-2 expression in colorectal tumorigenesis
| Autor: | Robert Hollingworth, Matthew Bedford, Andrew D Beggs, Tariq Iqbal, Richard D. Horniblow, Chris Tselepis, Neeraj Lal, Emily Sutton, Sarah Evans |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Proto-Oncogene Proteins B-raf
0301 basic medicine Cancer Research Carcinogenesis Colorectal cancer Iron colorectal cancer Biology medicine.disease_cause BRAF 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Receptors Transferrin medicine Humans RNA Small Interfering iron regulatory protein‐2 Iron Regulatory Protein 2 chemistry.chemical_classification Regulation of gene expression Trametinib trametinib MEK inhibitor Original Articles General Medicine HCT116 Cells medicine.disease Ferritin 030104 developmental biology Oncology chemistry Transferrin Caco-2 030220 oncology & carcinogenesis Ferritins Mutation Immunology Cancer research biology.protein Original Article Caco-2 Cells Colorectal Neoplasms HT29 Cells |
| Zdroj: | Cancer Science |
| ISSN: | 1347-9032 |
| DOI: | 10.1111/cas.13234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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