期刊
ONCOTARGET
卷 7, 期 17, 页码 24719-24733出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8348
关键词
netrin-1; pancreatic ductal adenocarcinoma; PP2A; MEK/ERK; integrin-beta4
资金
- National Natural Science Foundation of China [31030026]
- '973' Program [2011CB965203, 2011CB964803]
- PUMC Youth funds [3332013138]
- Fondation Franco-Chinoise pour la Science et ses Applications (FFCSA)
- China Scholarship Council (CSC)
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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