Iron and liver cancer: an inseparable connection. (14th October 2021)

• Record Type: Journal Article
• Authors: Hino, Keisuke; Yanatori, Izumi; Hara, Yuichi; Nishina, Sohji
• Is Part Of: FEBS journal. Volume 289:Number 24(2022)
• Page Start: 7810
• Page End: 7829
• Publication Date: 2021-10-14
• Subjects: ferroptosis -- hepatocellular carcinoma -- hepcidin -- mitochondria -- Nrf2 -- p53; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.16208
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Iron is an essential element for all organisms. Iron‐containing proteins play critical roles in cellular functions. The biological importance of iron is largely attributable to its chemical properties as a transitional metal. However, an excess of 'free' reactive iron damages the macromolecular components of cells and cellular DNA through the production of harmful free radicals. On the contrary, most of the body's excess iron is stored in the liver. Not only hereditary haemochromatosis but also some liver diseases with mild‐to‐moderate hepatic iron accumulation, such as chronic hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis, are associated with a high risk for liver cancer development. These findings have attracted attention to the causative and promotive roles of iron in the development of liver cancer. In the last decade, accumulating evidence regarding molecules regulating iron metabolism or iron‐related cell death programmes such as ferroptosis has shed light on the relationship between hepatic iron accumulation and hepatocarcinogenesis. In this review, we briefly present the current molecular understanding of iron regulation in the liver. Next, we describe the mechanisms underlying dysregulated iron metabolism depending on the aetiology of liver diseases. Finally, we discuss the causative and promotive roles of iron in cancer development. Abstract : Dysregulated iron homeostasis induced by various factors such as mutations in haemochromatosis genes, reactive oxygen species and hypoxia causes mild‐to‐severe iron accumulation in the liver, which in turn triggers hepatocarcinogenesis through activation of cell proliferation, ferroptosis, dysregulation of p53 and mitochondrial iron accumulation. Once hepatocellular carcinoma has been developed, cancer cells adapt to the iron‐associated cellular responses mainly through activation of nuclear factor erythroid 2‐related factor 2.