TY - JOUR
T1 - ZIP4 promotes pancreatic cancer progression by repressing ZO-1 and claudin-1 through a ZEB1-dependent transcriptional mechanism
AU - Liu, Mingyang
AU - Yang, Jingxuan
AU - Zhang, Yuqing
AU - Zhou, Zhijun
AU - Cui, Xiaobo
AU - Zhang, Liyang
AU - Fung, Kar Ming
AU - Zheng, Wei
AU - Allard, Felicia D.
AU - Yee, Eric U.
AU - Ding, Kai
AU - Wu, Huanwen
AU - Liang, Zhiyong
AU - Zheng, Lei
AU - Fernandez-Zapico, Martin E.
AU - Li, Yi Ping
AU - Bronze, Michael S.
AU - Morris, Katherine T.
AU - Postier, Russell G.
AU - Houchen, Courtney W.
AU - Yang, Jing
AU - Li, Min
N1 - Funding Information:
This work was supported in part by the NIH grants R01 CA138701, R01 CA186338-01A1, R01 CA203108-01 (M. Li), the William and Ella Owens Medical Research Foundation (M. Li), Mayo Clinic Pancreatic SPORE P50 CA102701 and Mayo Clinic Center for Cell Signaling in Gastroenterology P30 DK84567 (M.E. Fernandez-Zapico). We thank the Peggy and Charles Stephenson Cancer Center (SCC) at the University of Oklahoma, Oklahoma City, OK, and an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH under grant number P20 GM103639 for the use of Histology and Immunohistochemistry Core, which provided immunohistochemistry and image analysis services.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease.
AB - Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease.
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U2 - 10.1158/1078-0432.CCR-18-0263
DO - 10.1158/1078-0432.CCR-18-0263
M3 - Article
C2 - 29615456
AN - SCOPUS:85049363321
SN - 1078-0432
VL - 24
SP - 3186
EP - 3196
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -