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, Fennell A. Dean, Richard Morgan, Philip S. Rudland, Mohamed El-Tanani

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9 Citations (Scopus)

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 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 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.

Original languageEnglish
Pages (from-to)75854-75864
Number of pages11
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - 2016

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Keywords

  • Breast cancer
  • C-Met
  • Gefitinib
  • Lung cancer
  • Ran GTP

ASJC Scopus subject areas

  • Oncology

Cite this

Yuen, H. F., Chan, K. K., Platt-Higgins, A., Dakir, E. H., Matchett, K. B., Haggag, Y. A., Jithesh, P. V., Habib, T., Faheem, A., Dean, F. A., Morgan, R., Rudland, P. S., & El-Tanani, M. (2016). Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling. Oncotarget, 7(46), 75854-75864. https://doi.org/10.18632/oncotarget.12420