Oncotarget

Research Papers:

Netrin-1 suppresses the MEK/ERK pathway and ITGB4 in pancreatic cancer

Xi-Zhou An, Zhi-Guo Zhao, Yu-Xuan Luo, Ran Zhang, Xiao-Qiang Tang, De-Long Hao, Xiang Zhao, Xiang Lv and De-Pei Liu _

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Oncotarget. 2016; 7:24719-24733. https://doi.org/10.18632/oncotarget.8348

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Abstract

Xi-Zhou An1,*, Zhi-Guo Zhao1,*, Yu-Xuan Luo1, Ran Zhang1, Xiao-Qiang Tang1, De-Long Hao1, Xiang Zhao1, Xiang Lv1, De-Pei Liu1

1State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, P.R. China

*These authors contributed equally to this work

Correspondence to:

De-Pei Liu, e-mail: liudp@pumc.edu.cn

Xiang Lv, e-mail: lvxiang@pumc.edu.cn

Keywords: netrin-1, pancreatic ductal adenocarcinoma, PP2A, MEK/ERK, integrin-beta4

Received: September 30, 2015     Accepted: February 05, 2016     Published: March 25, 2016

ABSTRACT

The axon guidance factor netrin-1 promotes tumorigenesis in multiple types of cancers, particularly at their advanced stages. Here, we investigate whether netrin-1 is involved in the in vivo growth of pancreatic adenocarcinoma. We show that netrin-1 is significantly under-expressed in stage-I/II pancreatic ductal adenocarcinoma (PDAC). Netrin-1 over-expression effectively arrests the growth of xenografted PDAC cells without decreasing cell proliferation or increasing apoptosis in two-dimensional cultures in vitro. Integrin-beta4 (ITGB4) expression is significantly reduced, and ITGB4-knockdown mimics the tumor-suppressive effect of netrin-1, implying that ITGB4 is a main target of netrin-1 in constraining PDAC. We further show that netrin-1 signals to UNC5B/FAK to stimulate nitric oxide production, which promotes PP2A-mediated inhibition of the MEK/ERK pathway and decreases phosphorylated-c-Jun recruitment to the ITGB4 promoter. Our findings suggest that netrin-1 can suppress the growth of PDAC and provide a mechanistic insight into this suppression.


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