NDLI: Netrin-4 Promotes Glioblastoma Cell Proliferation through Integrin β4 Signaling1 2

Content Provider	PubMed Central
Author	Hu, Yizhou Irene, Ylivinkka Chen, Ping Li, Li Hautaniemi, Sampsa Nyman, Tuula A. Keski-oja, Jorma Marko, Hyytiäinen
Copyright Year	2012
Abstract	Netrin-4 is a laminin-related secreted molecule originally found to have roles in neuronal axon migration. Recent studies have indicated that netrin-4 also participates in the development of nonneural tissues and modulates tumor cell proliferation and tumor metastasis. Here we have explored the functions and molecular mechanisms of netrin-4 in glioblastoma multiforme. The suppression of netrin-4 expression in glioblastoma cell lines significantly reduced cell proliferation and motility and increased serum deprivation-induced apoptosis. Using tandem affinity purification combined with protein identification by mass spectrometry, we found that integrin β4 interacts with netrin-4 and that it mediates mitogenic effects as well as AKT and mammalian target of rapamycin phosphorylation induced by netrin-4. Interestingly, netrin-4 acted as an inhibitor of cell proliferation in integrin β4-silenced glioblastoma cells, and high concentrations of netrin-4 reduced cell proliferation. The negative effects of netrin-4 on proliferation were mediated by UNC5B. Analysis of more than 400 primary tumors from The Cancer Genome Atlas repository revealed that the expression of netrin-4 is significantly downregulated in glioblastoma and that the reduced expression is linked to poor patient survival time. The expression of integrin β4 is increased in glioblastoma, and it predicts poor patient survival time. Current results illustrate a novel mechanism for glioma progression, where glioma cells reduce netrin-4 expression to decrease its inhibitory effects. In parallel, the expression of integrin β4 is upregulated to sensitize the cells to low concentrations of netrin-4 for maintaining cell proliferation.
Starting Page	219
File Format	PDF
ISSN	14765586
e-ISSN	14765586
Journal	Neoplasia (New York, N.Y.)
Issue Number	3
Volume Number	14
Language	English
Publisher	Neoplasia Press Inc.
Publisher Date	2012-03-01
Access Restriction	Open
Rights Holder	Neoplasia Press Inc.
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cancer Research

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