HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling

Abstract

Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.

Fig. 1. Schematic representation of liver Hepcidin regulation.

When transferrin saturation by circulating iron and/or high intracellular iron in the liver occurs, BMP6 are secreted from liver sinusoidal endothelial cells. These proteins, by binding its receptors and co-receptors (i.e., Hemojuvelin and Neogenin) on hepatocytes' surface, promote SMAD complex activation. Once activated, SMAD complex translocates to the nucleus for the synthesis of Hepcidin, encoded by the gene HAMP. HIF2α, synthesised under hypoxic conditions, is able to suppress Hepcidin synthesis directly or by means of renal EPO and erythroid ERFE. Inflammation-derived IL-6 is able to trigger the BMP-SMAD pathway, further increasing Hepcidin levels. Once released, Hepcidin inhibits iron export through ferroportin from macrophages, enterocytes and hepatocytes. BMP bone morphogenetic protein, HAMP hepcidin antimicrobial peptide gene, hep Hepcidin, HJV hemojuvelin, N Neogenin, HIF2α hypoxia-inducible factor-2-alpha, IL-6 interleukin-6, SMAD small mothers against decapentaplegic, CV cardiovascular, EPO erythropoietin, ERFE erythroferrone, IL-6R IL-6 receptor, JAK Janus kinase, STAT signal transducer and activator of transcription.

Fig. 2. Interaction between HIF2α and hepcidin in physiological (low and high iron levels) and pathological (cancer) conditions in the intestine.

Effects on enterocytes are displayed. In physiological conditions, Hepcidin regulates negatively HIF2α with increase of HIF2α when iron and Hepcidin are low (left panel) and decrease when iron and Hepcidin are high (middle panel). In cancer, an opposite regulation exists with HIF2α, which is increased because of the hypoxic tumour microenvironment, inducing an upregulation of cancer-derived Hepcidin that eventually leads to high intracellular iron concentrations essential for nucleotide synthesis. DMT1 divalent metal transporter 1.