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Expression of the Hemochromatosis (HFE) Gene Modulates the Cellular Uptake of ⁶⁷Ga

Division of Neoplastic Diseases, Medical College of Wisconsin, Milwaukee, Wisconsin

ABSTRACT

Recent studies have revealed that the wild-type hemochromatosis protein (HFE) interacts with the transferrin receptor (TfR) and modulates TfR-mediated iron uptake by cells. Because of similarities in the transport of gallium and iron and the use of ⁶⁷Ga scanning in lymphoid malignancies, we examined the effect of HFE expression on ⁶⁷Ga uptake. Methods: ⁶⁷Ga and ⁵⁹Fe uptakes were measured in HeLa cells transfected with a FLAG-tagged wild-type HFE (fHFE) gene under control of a tetracycline-repressible promoter. fHFE and TfR protein levels were measured by Western blotting; cellular transferrin (Tf) binding sites were measured by ¹²⁵I-Tf binding assay. Results: Induction of fHFE expression produced an increase in TfR protein that was accompanied by a decrease, rather than an increase, in cellular ⁶⁷Ga and ⁵⁹Fe uptake. The difference in ⁶⁷Ga uptake between fHFE-expressing and fHFE-nonexpressing cells was markedly increased in the presence of Tf. Although fHFE expression produced an increase in cellular TfR protein, cell surface and intracellular Tf binding sites were actually decreased in these cells. Conclusion: Our studies suggest that expression of wild-type HFE in cells produces a decrease in ⁶⁷Ga uptake due to a reduction in available Tf binding sites for ⁶⁷Ga-Tf on the TfR. These results imply that ⁶⁷Ga uptake by cells with wild-type HFE may differ from cells with the HFE C282Y mutation.

Key Words: gallium • transferrin receptor • hemochromatosis • iron • tumor imaging

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