Down-regulation of ZIP4 by RNA interference inhibits pancreatic cancer growth and increases the survival of nude mice with pancreatic cancer xenografts.
OBJECTIVE
Zinc levels have been correlated with cancer risk, although the role of zinc and zinc transporters in cancer progression is largely unknown. We recently found that a zinc transporter, ZIP4, is overexpressed in pancreatic cancer. In this study, we further deciphered the role that ZIP4 plays in a pancreatic cancer mouse model by silencing ZIP4.


METHODS
ZIP4 stable silencing was established in pancreatic cancer cell lines ASPC-1 (ASPC-shZIP4) and BxPC-3 (BxPC-shZIP4) by short hairpin RNA using retrovirus vectors. The stable cells were characterized in vitro and in vivo using a nude mouse xenograft model.


RESULTS
Silencing of ZIP4 was associated with decreased cell proliferation, migration, and invasion. Both ASPC-shZIP4 and BxPC-shZIP4 cells showed a significant reduction in tumor volume and weight in the s.c. model, and decreased primary tumor weight in the orthotopic model compared with the vector control cells (ASPC-shV and BxPC-shV). Silencing of ZIP4 also caused reduced incidence of tumor metastasis in the mice and downsized the tumor grade. More importantly, silencing of ZIP4 significantly increased the survival rate of nude mice with orthotopic xenografts (P = 0.005). All ASPC-shZIP4-injected mice (100%) remained alive up to 32 days after tumor implantation, whereas only 30% of the ASPC-shV mice were alive at the same time point. CyclinD1 expression was decreased in the ASPC-shZIP4 xenografts.


CONCLUSIONS
These results identify a previously uncharacterized role of ZIP4 in pancreatic cancer progression, and indicate that knocking down ZIP4 by short hairpin RNA might be a novel treatment strategy for pancreatic cancers with ZIP4 overexpression.
Li
Min
M
Molecular Surgeon Research Center, Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. minli@bcm.edu
Zhang
Yuqing
Y
Bharadwaj
Uddalak
U
Zhai
Qihui Jim
QJ
Ahern
Charlotte H
CH
Fisher
William E
WE
Brunicardi
F Charles
FC
Logsdon
Craig D
CD
Chen
Changyi
C
Yao
Qizhi
Q
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D027682:Cation Transport Proteins; D034741:RNA, Small Interfering; C477530:Slc39a4 protein, mouse