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

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.

The status of zinc in the development of hepatocellular cancer

“…Only one study (Ebara et al 13 ) had reported a zinc increase in HCC, which was subsequently reversed by pursuant studies of the Ebara group 5,6 that showed a consistent significant decrease in zinc in HCC. In addition, our studies 14 with tissue samples from 26 HCC cases identifies the specific zinc decrease in the hepatoma cells in well-differentiated and advancing malignancy, as compared to the higher zinc in the normal hepatocytes (Fig. 2).…”

“…With this brief background, the issue of zinc treatment for HCC can be addressed. The commonly employed HepG2 cell line exhibits ZIP14 expression with evidence of the transporter localization at the plasma membrane, 14 which is in contrast to the HCC in situ silencing of ZIP14 expression and absence of transporter localization at the plasma membrane shown in Figure 3. This is an important relationship that must be recognized and addressed in any experimental studies of the potential efficacy of a zinc treatment approach for HCC.…”

“…This brief background calls attention to the importance of the identification of the zinc transporters that are involved in the maintenance of the normal and malignant cell zinc levels. Thus, it is surprising that, until our report in 2012, 14 there existed no reported studies regarding the identification, role, and mechanism of zinc transporters in association with the maintenance of zinc in the hepatocytes in normal human liver, and the decrease in zinc in the hepatoma cells in HCC.…”

“…14 Lemire et al 50 reported that zinc treatment of HepG2 cells exhibited cytotoxic effects that involved the inhibition of mitochondrial m-aconitase activity; which is a specific direct effect of zinc accumulation in mammalian cells. 51 ZnO nanoparticles reportedly exhibit cytotoxic effects on HepG2 cells; but whether or not the effects are due to the zinc component is questionable.…”

Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma

“…Such a relationship exists for zinc and ZIP1 in prostate cancer. [32][33][34] These are potential biomarkers for the early developing premalignant stages of pancreatic carcinogenesis.…”