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.

Intravenous Iron Therapy Replenishes Iron Stores without Enhancing Tumour Responses in Anaemic Patients with Colorectal Cancer: Comparison with Oral Iron Supplementation.

“…In fact, TfR1 expression increased and FTH1 mRNA expression decreased with no correlation with IRP2 mRNA expression. This is contrary to ndings by Horniblow (2017) in which IRP2 and TfR1 expression both increased in CRC and correlated with each other [30].…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…In prostate cancer cells IRP2 was consistently overexpressed and knockdown inhibited growth in vitro and in vivo, while IRP1 was detected in some cell lines and knockdown only modestly reduced proliferation in vitro (77). IRP2 was overexpressed in colon cancer tissues compared to normal and interestingly, correlated with BRAF mutations and it was confirmed in vitro that IRP2 overexpression was driven by hyperactivation of the MAPK pathway (79). Therefore, the expression and roles of IRPs in cancer differ by tumor type.…”

“…correlated with histologic grade and molecular subtype of human breast cancer(76). IRP2 was elevated in colorectal cancers compared to normal colon mucosa(79).…”

Alterations in Cellular Iron Metabolism Provide More Therapeutic Opportunities for Cancer

“…Hypoxia induces the expression of TFR1 and DMT1 in HepG2 cells; however, overexpression of IRP1 could reduce the stability of TfR1 and DMT1 mRNAs under hypoxia condition [ 130 ]. IRP2 is overexpressed in colorectal cancer compared to normal colonic mucosa which is associated with mutations in BRAF, and its expression is positively correlated with TFR1 expression [ 94 ]. IRP2-positive is also a marker of poor prognosis in lung cancer [ 95 ].…”