Seattle Children's Hospital Research Institute Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: Editorial BoardLink: AboutLink: SubscribeLink: AdvertiseLink: ContactLink: Sitemap Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Published online on November 14, 2007, 10.1073/pnas.0709307104
PNAS | November 20, 2007 | vol. 104 | no. 47 | 18636-18641


This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a colleague
Right arrow Related articles in PNAS
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Google Scholar
Right arrow Articles by Li, M.
Right arrow Articles by Yao, Q.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, M.
Right arrow Articles by Yao, Q.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg  
What's this?

 Previous Article  | Table of Contents |  Next Article 

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

Min Li*,{dagger}, Yuqing Zhang*, Zijuan Liu{ddagger}, Uddalak Bharadwaj*, Hao Wang*, Xinwen Wang*, Sheng Zhang*, Juan P. Liuzzi§, Shou-Mei Chang§, Robert J. Cousins{dagger}, William E. Fisher*, F. Charles Brunicardi*, Craig D. Logsdon, Changyi Chen*, and Qizhi Yao*

*Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030; {ddagger}Department of Biological Sciences, Oakland University, Rochester Hills, MI 48309; §Food Science and Human Nutrition Department, University of Florida Shands Cancer Center, University of Florida, Gainesville, FL 32611; and Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

Contributed by Robert J. Cousins, October 2, 2007 (received for review September 19, 2007)

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

Author contributions: M.L., C.D.L., C.C., and Q.Y. designed research; M.L., Y.Z., Z.L., U.B., H.W., X.W., S.Z., and W.E.F. performed research; M.L., J.P.L., S.-M.C., R.J.C., W.E.F., and F.C.B. contributed new reagents/analytic tools; M.L., Y.Z., Z.L., U.B., X.W., R.J.C., C.D.L., C.C., and Q.Y. analyzed data; and M.L., R.J.C., C.D.L., C.C., and Q.Y. wrote the paper.

The authors declare no conflict of interest.

{dagger}To whom correspondence may be addressed E-mail: minli{at}bcm.edu or cousins{at}ufl.edu

© 2007 by The National Academy of Sciences of the USA


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg    What's this?

Related articles in PNAS:

In This Issue

PNAS 2007 104: 18345-18346. [Full Text]  



This article has been cited by other articles in HighWire Press-hosted journals:


Home page
 Molecular Cancer TherapeuticsHome page
M. Li, U. Bharadwaj, R. Zhang, S. Zhang, H. Mu, W. E. Fisher, F. C. Brunicardi, C. Chen, and Q. Yao
Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer
Mol. Cancer Ther., February 1, 2008; 7(2): 286 - 296.
[Abstract] [Full Text] [PDF]