Hepcidin in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common reasons for cancer-related deaths. Excess iron increases HCC risk. Inevitably, hepcidin, the iron hormone that maintains systemic iron homoeostasis is involved in HCC pathology. Distinct from other cancers that show high hepcidin expression, HCC patients can show low hepcidin levels. Thus, it is of immense clinical benefit to address the regulation and action of hepcidin in HCC as this may help in identifying molecular targets for diagnosis, prognosis, and therapeutics. Accordingly, this review explores hepcidin in HCC. It presents the levels of tissue and serum hepcidin and explains the mechanisms that contribute to hepcidin reduction in HCC. These include downregulation of HAMP, TfR2, HJV, ALK2 and circular RNA circ_0004913, upregulation of matriptase-2 and GDF15, inactivation of RUNX3 and mutation in TP53. The enigmas around mir-122 and the functionalities of two major hepcidin inducers BMP6 and IL6 in relation to hepcidin in HCC are discussed. Effects of hepcidin downregulation are explained, specifically, increased cancer proliferation via activation of CDK1/STAT3 pathway and increased HCC risk due to reduction in a hepcidin-mediated protective effect against hepatic stellate cell activation. Hepcidin-ferroportin axis in HCC is addressed. Finally, the role of hepcidin in the diagnosis, prognosis and therapeutics of HCC is highlighted.

Fig. 1. Hepcidin–ferroportin axis maintains systemic iron homoeostasis.

The figure shows the three main cell types involved in maintaining systemic iron homoeostasis, namely, hepatocytes, macrophages, and enterocytes. Under iron-deficit conditions, hepcidin secretion by hepatocytes is reduced. This prevents ferroportin degradation and allows iron egress into the circulation. Under iron-excess conditions, hepcidin secretion by the hepatocytes increases. Hepcidin binds to ferroportin, and both hepcidin and ferroportin are degraded intracellularly. This prevents iron entry into the circulation and thereby systemic iron homoeostasis is restored.

Fig. 2. Plausible cellular mechanisms mediating hepcidin downregulation in hepatocellular carcinoma (HCC).

The figure shows alterations in the hepcidin gene (HAMP) and changes in some hepcidin-modulatory proteins in HCC that may be fully or partly responsible for hepcidin downregulation in HCC. Note that BMP6 upregulation in HCC has been observed and this needs to be investigated.

Fig. 3. Summary of events underlying hepcidin suppression in hepatocellular carcinoma.

The figure indicates plausible events in hepatocellular carcinoma (HCC) that may fully or partly, collectively or independently and to a greater or lesser extent be responsible for reduced hepcidin expression in HCC. The question mark indicates uncertainty around the expression of BMP6 in HCC as BMP6 is found to be raised in HCC, but BMP6 hypermethylation and thereby its downregulation has also been observed.