Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression

Abstract

Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth.cell proliferation ͉ tumor progression ͉ zinc uptake

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

“…Instead, they relied on their identification of an increase in ZIP4 in ductal adenocarcinoma, and on experimental studies with cell lines, genetically manipulated cells, and with an animal model. 6,16 However, the increase in ZIP4 in situ in the ductal adenocarcinoma tissue section does not exhibit transporter association with the basilar membrane, which should be expected for a functional cellular zinc uptake transporter. No information regarding the stages of malignancy is provided in their study.…”

“…In the only other report relating to zinc and zinc transporter in normal exocrine pancreas and adenocarcinoma, Li et al 6 suggested that zinc is increased in human ductal adenocarcinoma and promotes the development of malignancy. However, they provided no data and/or information of zinc levels or measurements in human normal pancreas and in adenocarcinoma in structures, which is the focus of the normal and adenocarcinoma studies presented in this report.…”

“…One exception is a preliminary study with only one tissue sample, 5 which suggested that a decrease in zinc level might be associated with pancreatic adenocarcinoma. Li et al 6 suggested that increased zinc accumulation is associated with ductal adenocarcinoma; however no measurements of zinc levels in human normal and adenocarcinoma pancreatic tissues were presented; and their supposition was not supported by any measurements of zinc in human pancreatic tissues. The absence of essential information concerning the zinc levels in normal pancreatic tissue and in adenocarcinoma prompted us to conduct in situ zinc measurements in pancreatic tissues in order to establish the zinc relationship in human pancreatic adenocarcinoma.…”

Developing a Novel Embryo–Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics

“…Research in breast and prostate cancer cells with overexpression of zinc ion importers demonstrates that exposure to small amounts of ionic zinc can enhance cancer cell proliferation and invasion. 41,42 Lin et al identified several zinc ion importers with increased expression in malignant glioma samples and waterborne exposure of embryonic zebrafish to zinc can result in distribution to the brain. 43,44 Furthermore, invasion of glioblastoma cells is partly controlled by matrix metalloproteinases (MMPs), which require zinc as cofactor.…”

New applications of old metal-binding drugs in the treatment of human cancer

“…Multiple zinc transporters, including ZIP4, ZIP6, ZIP10, and ZIP1, have been identified as factors in the progression of various types of cancer. ZIP4 has been reported to increase cell proliferation through zinc transport, resulting in tumor growth, most specifically in pancreatic cancer (44,55). Both ZIP6 and ZIP10 have roles in the progression and metastasis of breast cancer (46,(57)(58) and ZIP1 has been suggested as a tumor suppressor of prostate cancer (56).…”