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ZIP14 Zinc Transporter Downregulation and Zinc Depletion in the Development and Progression of Hepatocellular Cancer

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Abstract

Purpose

Hepatocellular cancer (HCC) is a deadly and most rapidly increasing cancer in the USA and worldwide. The etiology and factors involved in development of HCC remain largely unknown. A marked decrease in zinc occurs in HCC. Its role and involvement in HCC has not been identified. We investigated the relationship of cellular zinc changes to the development of malignancy, and the identification of potential zinc transporters associated with the inability of hepatoma cells to accumulate zinc.

Methods

The detection of relative zinc levels in situ in normal hepatic cells vs. hepatoma was performed on normal and HCC tissue sections. ZIP1, 2, 3, and 14 transporters were identified by immunohistochemistry.

Results

Intracellular zinc levels are markedly decreased in HCC hepatoma cells vs. normal hepatic cells in early stage and advanced stage malignancy. ZIP14 transporter is localized at the plasma membrane in normal hepatocytes, demonstrating its functioning for uptake and accumulation of zinc. The transporter is absent in the hepatoma cells and its gene expression is downregulated. The change in ZIP14 is concurrent with the decrease in zinc. ZIP1, 2, 3 are not associated with normal hepatocyte uptake of zinc, and HCC zinc depletion. HepG2 cells exhibit ZIP14 transporter. Zinc treatment inhibits their growth.

Conclusions

ZIP14 downregulation is likely involved in the depletion of zinc in the hepatoma cells in HCC. These events occur early in the development of malignancy possibly to protect the malignant cells from tumor suppressor effects of zinc. This provides new insight into important factors associated with HCC carcinogenesis.

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Acknowledgements

We are grateful to Dr. Robert Cousins (University of Florida) for kindly providing us with the ZIP14 antibody employed in this study. We are also grateful to Dr. Peter Zalewski (University of Adelaide, Australia) for kindly providing us with the Zinquin ester employed in this study. These studies were supported by NIH grants DK076783 and CA79903.

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Authors and Affiliations

  1. Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, Baltimore, MD, 21201, USA

    Renty B. Franklin, Bernard A. Levy, Jing Zou & Leslie C. Costello

  2. The University of Maryland Greenebaum Cancer Center, Baltimore, MD, 21201, USA

    Renty B. Franklin, Nader Hanna & Leslie C. Costello

  3. Division of Surgical Oncology, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Nader Hanna

  4. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Mohamed Mokhtar Desouki

  5. South Carolina Center for Biotechnology, Orangeburg, SC, 29115, USA

    Omar Bagasra & Leslie A. Johnson

  6. Biology Department, Claflin University, Orangeburg, SC, 29115, USA

    Omar Bagasra & Leslie A. Johnson

Authors
  1. Renty B. Franklin
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  2. Bernard A. Levy
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  3. Jing Zou
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  4. Nader Hanna
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  5. Mohamed Mokhtar Desouki
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  6. Omar Bagasra
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  7. Leslie A. Johnson
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  8. Leslie C. Costello
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Corresponding authors

Correspondence to Renty B. Franklin or Leslie C. Costello.

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Franklin, R.B., Levy, B.A., Zou, J. et al. ZIP14 Zinc Transporter Downregulation and Zinc Depletion in the Development and Progression of Hepatocellular Cancer. J Gastrointest Canc 43, 249–257 (2012). https://doi.org/10.1007/s12029-011-9269-x

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  • DOI: https://doi.org/10.1007/s12029-011-9269-x

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