Expression of zinc transporters ZIP4, ZIP14 and ZnT9 in hepatic carcinogenesis-An immunohistochemical study

Introduction: Dysregulation of both, systemic zinc levels and tissue-specific zinc transporters, is reported in chronic inflammatory and malignant liver disease (hepatocellular carcinoma, HCC). Aim of this study is to assess the expression level of three zinc transporters in liver tissue and HCC: ZIP4, ZIP14 and ZnT9. Methods: The study is based on tissue samples obtained from 138 patients with histologically proven HCC. Tissue specimens from tumor (n = 138) and extra-lesional specimens (n = 72) were assessed immunohistochemically for the expression of the three zinc transporters. Expression levels were semi-quantitatively scored and statistically analyzed with respect to the etiology of HCC (alcohol, AFLD; non-alcoholic fatty liver disease, NAFLD; virus-hepatitis, VH) and survival. Results: Overall, expression levels of ZIP4, ZIP14 and ZnT9 were significantly higher in HCC tissue than in adjacent extra-lesional liver tissue. Expression levels in tumor tissue and survival time revealed a negative correlation for ZIP4 and ZIP14, and in part for ZnT9 (nuclear staining) (p < 0.05), whereas cytoplasmic staining of ZnT9 did not correlate with survival. Furthermore, the expression level of ZIP4 in extra-lesional tissue showed inverse correlation with survival time. Conclusion: The upregulation of zinc transporters in hepatic carcinogenesis and its negative correlation with survival time implies a regulatory/functional link between zinc-homeostasis and development/progression of HCC that deserves to be further explored.