Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling
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Hiu-Fung Yuen1, Ka-Kui Chan1, Angela Platt-Higgins2, El-Habib Dakir1,4, Kyle B. Matchett1, Yusuf Ahmed Haggag1,7, Puthen V. Jithesh6, Tanwir Habib6, Ahmed Faheem5, Fennell A. Dean3, Richard Morgan4, Philip S. Rudland2, Mohamed El-Tanani4
1Center for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK
2Cancer and Polio Research Fund Laboratories, School of Biological Sciences, University of Liverpool, Liverpool, UK
3Translational Clinical Research, University of Leicester, Leicester, UK
4Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK
5University of Sunderland, Department of Pharmacy, Health and Well-Being, Sunderland Pharmacy School, Sunderland, UK
6Biomedical Informatics Research, Sidra Medical and Research Center, Doha, Qatar
7Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt
Mohamed El-Tanani, email: [email protected]
Keywords: Ran GTP, C-Met, breast cancer, lung cancer, gefitinib
Received: June 17, 2016 Accepted: September 21, 2016 Published: October 03, 2016
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.
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