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    Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

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    Publication date
    2016-10-03
    Author
    Yuen, H-F.
    Chan, K.K.
    Platt-Higgins, A.
    Dakir, El-Habib
    Matchett, K.B.
    Haggag, Y.A.
    Jithesh, P.V.
    Habib, T.
    Faheem, A.
    Dean, F.A.
    Morgan, Richard
    Rudland, P.S.
    El-Tanani, Mohamed
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    Keyword
    Ran GTP; C-Met; Breast cancer; Lung cancer; Gefitinib
    Rights
    © 2016 Yuen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    Peer-Reviewed
    Yes
    
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    Abstract
    It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reductionmediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a prerequisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator.
    URI
    http://hdl.handle.net/10454/9914
    Version
    published version paper
    Citation
    Yuen H-F, Chan K-K, Platt-Higgins A et al. (2016) Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling. Oncotarget. 7(46): 75854-75864.
    Link to publisher’s version
    http://dx.doi.org/10.18632/oncotarget.12420
    Type
    Article
    Collections
    Life Sciences Publications

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