Regulation of iron metabolism-related genes in diethylnitrosamine-induced mouse liver tumors

Abstract

Background: It has been suggested that the altered iron metabolism in liver tumors, characterized by the iron-deficient phenotype, is of importance for tumor growth. Aim: This study was performed to elucidate the mechanisms underlying iron deficiency in liver tumors by examining how the liver tumor development affects the expression of iron metabolism-related genes. Methods: Iron metabolism reference values were analyzed in the sera of diethylnitrosamine-induced hepatocellular adenoma-bearing mice. Expression of iron metabolism-related genes was analyzed in adenomas and surrounding non-tumor tissues, and a subgroup of adenoma-bearing mice loaded with iron 72 h before sacrifice. Results: Iron content of the adenoma tissues was 2.0–2.5-fold lower compared to surrounding and agematched control tissues. There was no significant difference in serum iron levels between the adenomabearing and control mice, while the adenoma-bearing mice exhibited a 2.4-fold lower level of serum transferrin saturation. Expression of iron metabolism-related genes was dysregulated in the adenomas. Iron loading affected protein expression similarly in the adenomas and surrounding tissues suggesting that iron-responsive regulation of the proteins was not impaired. However, the mRNA expression for ceruloplasmin and divalentmetal transporter 1 (DMT1) IRE(+) in the adenomaswas alteredindependently of iron status, and the dysregulation may contribute to diminished iron content. Conclusion: These findings suggest that diethylnitrosamine-induced liver adenoma-bearing mice have abnormal iron metabolism and that dysregulation of iron metabolism-related genes contributes to iron deficiency in the adenomas.