Correlation between the expression of divalent metal transporter 1 and the content of hypoxia‐inducible factor‐1 in hypoxic HepG2 cells

Transferrin and transferrin receptor are two key proteins of iron metabolism that have been identified to be hypoxia‐inducible genes. Divalent metal transporter 1 (DMT1) is also a key transporter of iron under physiological conditions. In addition, in the 5′ regulatory region of human DMT1 (between −412 and −570), there are two motifs (CCAAAGTGCTGGG) that are similar to hypoxia‐inducible factor‐1 (HIF‐1) binding sites. It was therefore speculated that DMT1 might also be a hypoxia‐inducible gene. We investigated the effects of hypoxia and hypoxia/re‐oxygenation on the expression of DMT1 and the content of HIF‐1alpha in HepG2 cells. As we expected, a very similar tendency in the responses of the expression of HIF‐1α, DMT1+IRE (iron response element) and DMT1−IRE proteins to chemical (CoCl₂) or physical hypoxia was observed. A highly significant correlation was found between the expression of DMT1 proteins and the contents of HIF‐1 in hypoxic cells. After the cells were exposed to hypoxia and subsequent normoxia, no HIF‐1α could be detected and a significant decrease in DMT1+IRE expression (P<0.05), but not in DMT1−IRE protein (versus the hypoxia group), was observed. The findings implied that the HIF‐1 pathway might have a role in the regulation of DMT1+IRE expression during hypoxia.