Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma.

Dongyao Wang, Huiwen Wu, Jianxin Yang, Min Li, Changquan Ling, Zelong Gao, Hongtao Lu, Hui Shen, Yuxiao Tang

Hepatology communications 2022 Oct

filter terms:

It is interesting that high iron is an independent inducer or cofactor of hepatocellular carcinoma (HCC) while the amount of iron is decreased in the liver tumor tissues. Due to the previous findings that iron deficiency promoted HCC metastasis, it is of significance to identify the underlying mechanism of iron deficiency in HCC. The tumor iron content and expressions of iron-metabolic molecules were observed in the primary liver cancers of rats and mice. The molecules that changed independently of iron were identified by comparing the expression profiles in the human HCC tissues and iron-deprived HCC cells. The downstream effects of these molecules on regulating intracellular iron content were investigated in vitro and further validated in vivo. Both in primary liver cancers of rats and mice, we confirmed the decreased iron content in tumor tissues and the altered expressions of iron-metabolic molecules, including transferrin receptor 1 (TfR1), six-transmembrane epithelial antigen of prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), SLC46A1, ferroportin, hepcidin, and ferritin. Among these, STEAP3, DMT1, and SLC46A1 were altered free of iron deficiency. However, only silence or overexpression of SLC46A1 controlled the intracellular iron content of HCC cells. The interventions of STEAP3 or DMT1 could not change the intracellular iron content. Lentivirus-mediated regain of SLC46A1 expression restored the iron content in orthotopically implanted tumors, with correspondingly changes in the iron-metabolic molecules as iron increasing. Conclusion: Taken together, these results suggest that the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues, which would be an effective target to manage iron homeostasis in HCC. © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Citation

Dongyao Wang, Huiwen Wu, Jianxin Yang, Min Li, Changquan Ling, Zelong Gao, Hongtao Lu, Hui Shen, Yuxiao Tang. Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma. Hepatology communications. 2022 Oct;6(10):2914-2924