ZIP4 is a Novel Molecular Marker for Glioma

Overview

Journal Neuro Oncol

Publisher Oxford University Press

Specialties Neurology
Oncology

Date 2013 Apr 19

PMID 23595627

Citations 40

Authors

Yi Lin

Yong Chen

Yongzhi Wang

Jingxuan Yang

Vivian F Zhu

Yulun Liu

Xiaobo Cui

Leon Chen

Wei Yan

Tao Jiang

Georgene W Hergenroeder

Stephen A Fletcher

Jonathan M Levine

Dong H Kim

Nitin Tandon

Jay-Jiguang Zhu

Min Li

Affiliations

Soon will be listed here.

Abstract

Background: Dysregulated zinc transport has been observed in many cancers. However, the status of zinc homeostasis and the expression profile of zinc transporters in brain and brain tumors have not been reported.

Methods: The gene profiles of 14 zinc importers (ZIPs) and 10 zinc exporters (ZnTs) in patients with glioma were studied by investigating the association between the zinc transporters and brain tumor characteristics (tumor grade and overall survival time). Three independent cohorts were analyzed to cross-validate the findings: the Chinese Glioma Genome Atlas (CGCA) cohort (n = 186), the US National Cancer Institute Repository for Molecular Brain Neoplasia Data (REMBRANDT) cohort (n = 335), and The University of Texas (UT) cohort (n = 34).

Results: The expression of ZIP3, 4, 8, 14, ZnT5, 6, and 7 were increased, and the expression of ZnT10 was decreased in grade IV gliomas, compared with grade II gliomas. Among all 24 zinc transporters, ZIP4 is most significantly associated with tumor grade and overall survival; this finding is consistent across 2 independent cohorts (CGCA and REMBRANDT) and is partially validated by the third cohort (UT). High ZIP4 expression was significantly associated with higher grade of gliomas and shorter overall survival (hazard ratio = 1.61, 95% confidence interval = 1.02-2.53, P = .040 in CGCA cohort; hazard ratio = 1.32, 95% confidence interval = 1.08-1.61, P = .007 in REMBRANDT cohort).

Conclusions: Dysregulated expression of zinc transporters is involved in the progression of gliomas. Our results suggest that ZIP4 may serve as a potential diagnostic and prognostic marker for gliomas.

Citing Articles

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References

Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M, Kamoun R . Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet. 2002; 31(3):239-40. DOI: 10.1038/ng913. View

Wang H, Lathia J, Wu Q, Wang J, Li Z, Heddleston J . Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells. 2009; 27(10):2393-404. PMC: 2825688. DOI: 10.1002/stem.188. View

Michalczyk A, Allen J, Blomeley R, Ackland M . Constitutive expression of hZnT4 zinc transporter in human breast epithelial cells. Biochem J. 2002; 364(Pt 1):105-13. PMC: 1222551. DOI: 10.1042/bj3640105. View

Higgins R, Dickinson P, LeCouteur R, Bollen A, Wang H, Wang H . Spontaneous canine gliomas: overexpression of EGFR, PDGFRalpha and IGFBP2 demonstrated by tissue microarray immunophenotyping. J Neurooncol. 2009; 98(1):49-55. DOI: 10.1007/s11060-009-0072-5. View

Lonnerdal B . Trace element transport in the mammary gland. Annu Rev Nutr. 2007; 27:165-77. DOI: 10.1146/annurev.nutr.27.061406.093809. View

Springgate C, Mildvan A, Abramson R, Engle J, Loeb L . Escherichia coli deoxyribonucleic acid polymerase I, a zinc metalloenzyme. Nuclear quadrupolar relaxation studies of the role of bound zinc. J Biol Chem. 1973; 248(17):5987-93. View

Li M, Zhang Y, Liu Z, Bharadwaj U, Wang H, Wang X . Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression. Proc Natl Acad Sci U S A. 2007; 104(47):18636-41. PMC: 2141829. DOI: 10.1073/pnas.0709307104. View

Gaasch J, Lockman P, Geldenhuys W, Allen D, Van der Schyf C . Brain iron toxicity: differential responses of astrocytes, neurons, and endothelial cells. Neurochem Res. 2007; 32(7):1196-208. DOI: 10.1007/s11064-007-9290-4. View

Lovell M . A potential role for alterations of zinc and zinc transport proteins in the progression of Alzheimer's disease. J Alzheimers Dis. 2009; 16(3):471-83. PMC: 2881701. DOI: 10.3233/JAD-2009-0992. View

10.

Carlsson A, Persson O, Ingvarsson J, Widegren B, Salford L, Borrebaeck C . Plasma proteome profiling reveals biomarker patterns associated with prognosis and therapy selection in glioblastoma multiforme patients. Proteomics Clin Appl. 2010; 4(6-7):591-602. DOI: 10.1002/prca.200900173. View

11.

Ni H, Jiang Y, Xiao Z, Tao L, Jin M, Wu X . Dynamic pattern of gene expression of ZnT-1, ZnT-3 and PRG-1 in rat brain following flurothyl-induced recurrent neonatal seizures. Toxicol Lett. 2010; 194(3):86-93. DOI: 10.1016/j.toxlet.2010.02.008. View

12.

Vallee B, Falchuk K . The biochemical basis of zinc physiology. Physiol Rev. 1993; 73(1):79-118. DOI: 10.1152/physrev.1993.73.1.79. View

13.

Zhang Y, Bharadwaj U, Logsdon C, Chen C, Yao Q, Li M . ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB. Clin Cancer Res. 2010; 16(5):1423-30. PMC: 2841320. DOI: 10.1158/1078-0432.CCR-09-2405. View

14.

Stupp R, Mason W, van den Bent M, Weller M, Fisher B, Taphoorn M . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-96. DOI: 10.1056/NEJMoa043330. View

15.

Morris L, Veeriah S, Chan T . Genetic determinants at the interface of cancer and neurodegenerative disease. Oncogene. 2010; 29(24):3453-64. PMC: 3005561. DOI: 10.1038/onc.2010.127. View

16.

Sandstead H, Frederickson C, Penland J . History of zinc as related to brain function. J Nutr. 2000; 130(2S Suppl):496S-502S. DOI: 10.1093/jn/130.2.496S. View

17.

Pullen R, Franklin P, Hall G . 65Zn uptake from blood into brain in the rat. J Neurochem. 1991; 56(2):485-9. DOI: 10.1111/j.1471-4159.1991.tb08176.x. View

18.

Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S . Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer. Cancer Lett. 2003; 201(1):107-16. DOI: 10.1016/s0304-3835(03)00482-8. View

19.

Snyder J, Shofer F, Van Winkle T, Massicotte C . Canine intracranial primary neoplasia: 173 cases (1986-2003). J Vet Intern Med. 2006; 20(3):669-75. DOI: 10.1892/0891-6640(2006)20[669:cipnc]2.0.co;2. View

20.

Taylor K, Vichova P, Jordan N, Hiscox S, Hendley R, Nicholson R . ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer Cells. Endocrinology. 2008; 149(10):4912-20. DOI: 10.1210/en.2008-0351. View