Zip4 (Slc39a4) Expression is Activated in Hepatocellular Carcinomas and Functions to Repress Apoptosis, Enhance Cell Cycle and Increase Migration

Abstract

BackgroundThe zinc transporter ZIP4 (Slc39a4) is important for proper mammalian development and is an essential gene in mice. Recent studies suggest that this gene may also play a role in pancreatic cancer.Methods/Principal FindingsHerein, we present evidence that this essential zinc transporter is expressed in hepatocellular carcinomas. Zip4 mRNA and protein were dramatically elevated in hepatocytes in the majority of human hepatocellular carcinomas relative to noncancerous surrounding tissues, as well as in hepatocytes in hepatocellular carcinomas occurring in farnesoid X receptor-knockout mice. Interestingly, meta-analysis of microarray data in the Geo and Oncomine databases suggests that Zip4 mRNA may also be elevated in many types of cancer. Potential mechanisms of action of ZIP4 were examined in cultured cell lines. RNAi knockdown of Zip4 in mouse Hepa cells significantly increased apoptosis and modestly slowed progression from G0/G1 to S phase when cells were released from hydroxyurea block into zinc-deficient medium. Cell migration assays revealed that RNAi knockdown of Zip4 in Hepa cells depressed in vitro migration whereas forced over-expression in Hepa cells and MCF-7 cells enhanced in vitro migration.ConclusionsZIP4 may play a role in the acquisition of zinc by hepatocellular carcinomas, and potentially many different cancerous cell-types, leading to repressed apoptosis, enhanced growth rate and enhanced invasive behavior.

Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways

“…To the best of our knowledge, this is the first report on subcellular distribution of zinc transporters in the liver regardless of alcohol exposure. Although ZIP4 has been detected in human liver at the tissue level (31,32), information on subcellular distribution of zinc transporters in human liver is not available. Therefore, one limitation of the study is that the data of hepatic zinc transporters lack support by human data.…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…Aberrant expression of ZIP4 is associated with pathogenesis and progression in cancer and carcinomas (238,244,438). In the case of pancreatic cancer, ZIP4 enhances CREB activity by the uptake of zinc, which transcriptionally increases miR-373 expression, leading to silencing of molecules with tumor suppressor activity (459).…”

The Effect of NOP16 Mutation in Chronic Lymphocytic Leukemia

“…With respect to the genes shown in Table 1, SLC39A4 (also named ZIP4) is zinc transporter and it has been shown that ZIP4 expression in Hepatocellular Carcinomas serves to repress apoptosis, enhancing cell cycle and increasing migration [28]. Also, Xu et al have shown in hepatocellular carcinomas that suppression of ZIP4 reduced cell migration and invasiveness, whereas ZIP4 over expression caused increasing of cell migration and invasiveness [29].…”