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Netrin-4 promotes glioblastoma cell proliferation through integrin ?4 signaling.

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 ?(4) 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 ?(4)-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 ?(4) 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 ?(4) is upregulated to sensitize the cells to low concentrations of netrin-4 for maintaining cell proliferation.

SUBMITTER: Hu Y

PROVIDER: S-EPMC3323899 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Netrin-4 promotes glioblastoma cell proliferation through integrin β4 signaling.

Hu Yizhou Y Ylivinkka Irene I Chen Ping P Li Li L Hautaniemi Sampsa S Nyman Tuula A TA Keski-Oja Jorma J Hyytiäinen Marko M

Neoplasia (New York, N.Y.) 20120301 3

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 incre ...[more]

PMID: 22496621

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Project description:The leucine‑rich repeats and immunoglobulin‑like domains (LRIG) gene family, comprising LRIG1, 2 and 3, encodes integral membrane proteins. It has been well established that LRIG1 negatively regulates multiple growth factor signaling pathways and is considered to be a tumor suppressor; however, the biological functions of LRIG2 remain largely unexplored. It was previously demonstrated that LRIG2 positively regulates epidermal growth factor receptor (EGFR) signaling, the most common aberrant receptor tyrosine kinase (RTK) signaling in glioblastoma multiforme (GBM), which promotes GBM growth. In the present study, the effect of LRIG2 on the proliferation of GBM cells was further addressed, as well as the possible mechanisms underlying the regulatory effect of LRIG2 on platelet‑derived growth factor receptor β (PDGFRβ) signaling, another common oncogenic RTK signaling pathway in GBM. First, the expression levels of endogenous LRIG2 and PDGFRβ were found to vary notably in human GBM, and the LRIG2 expression level was positively correlated with the expression level of PDGFRβ. Furthermore, to the best of our knowledge, this is the first study to demonstrate that LRIG2 promoted the PDGF‑BB‑induced proliferation of GBM cells in vitro and in vivo through regulating the PDGFRβ signaling‑mediated cell cycle progression. Mechanistically, LRIG2 has the ability to physically interact with PDGFRβ, promoting the total expression and the activation of PDGFRβ, and enhancing its downstream signaling pathways of Akt and signal transducer and activator of transcription 3 and the effectors of key regulators of cell cycle progression, resulting in increased GBM cell proliferation. Collectively, these data indicated that LRIG2 may serve as a tumor promoter gene in gliomagenesis by positively regulating PDGFRβ signaling, another important oncogenic RTK signaling pathway, in addition to the previously reported EGFR signaling in GBM modulated by LRIG2, and validated LRIG2 as a promising therapeutic target for the treatment of GBM characterized by multiple aberrant RTK signaling.

Dataset Information

Netrin-4 promotes glioblastoma cell proliferation through integrin ?4 signaling.

Publications

Netrin-4 promotes glioblastoma cell proliferation through integrin β4 signaling.

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