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Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling
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.
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.
Publication Date
2016-10-03
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© 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.
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openAccess
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2016-09-21
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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.
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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.
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