Hepcidin, Inflammation, and Obesity: Iron Regulation in Colorectal Carcinogenesis

Hepcidin, a peptide hormone produced by the liver, constitutes the master regulator of human iron homeostasis, allowing body iron adaptation according to metabolic needs. Hepcidin dysregulation leads to iron-related disorders, such as inflammatory diseases and cancers. Recent studies in normal iron regulation mechanisms have enabled focused investigation in colorectal carcinogenesis (CRC), the second most common cancer diagnosed in developed countries. Hepcidin binds to ferroportin, an iron efflux transporter, causing ferroportin internalization and degradation. Cancer cells are hypothesized to subvert this physiologic pathway, suggesting that cancer cells sequester and accumulate as much iron as possible to stimulate proliferation, thus perpetuating the cancer phenotype. CRC occurs sporadically and environmental factors, such as diet, are risk factors. This study proposes the inflammation that accompanies obesity induces alterations in iron metabolism that stimulate hepatic secretion of hepcidin. A quantitative real time polymerase chain reaction (qPCR) assay was developed to determine expression levels of hepcidin, ferroportin, interleukin-6 (IL-6) and divalent metal transporter-1 (DMT1) to evaluate iron regulation in colorectal cancer and control patients with varying body mass indexes. Enzyme-linked immunoabsorbant assays (ELISAs) were also performed to measure bone morphogenetic protein 2 (BMP2). Among the 6 hepatocyte RNA samples initially studied, ferroportin levels were 1.89 times as high as DMT1. This outcome suggests that iron is captured by ferroportin, which is expressed in abundance on the cancer cell surface. Determination of these molecular markers may provide a less invasive alternative to colonoscopy and guidance toward earlier detection of the roughly 150,000 new cases of CRC per year.