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

Hiu-Fung Yuen, Ka-Kui Chan, Angela Platt-Higgins, El-Habib Dakir, Kyle B Matchett, Yusuf Ahmed Haggag, Puthen V Jithesh, Tanwir Habib, Ahmed Faheem, Dean A Fennell, Richard Morgan, Philip S Rudland, Mohamed El-Tanani

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28 Citations (Scopus)
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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 reduction-mediated 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 pre-requisite 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.
Original languageEnglish
Pages (from-to)75854–75864
Number of pages11
Issue number46
Publication statusPublished (in print/issue) - 3 Oct 2016


  • Ran GTP
  • C-Met
  • breast cancer
  • lung cancer
  • gefitinib


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