title: Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling.
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 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.
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Ka-Kui
authors.initials: KK
authors.lastname: Chan
authors.affiliation: Cancer and Polio Research Fund Laboratories, School of Biological Sciences, University of Liverpool, Liverpool, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Platt-Higgins
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.|Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK.
authors.forename: el-Habib
authors.initials: el-H
authors.lastname: Dakir
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Matchett
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.|Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt.
authors.forename: Yusuf Ahmed
authors.initials: YA
authors.lastname: Haggag
authors.affiliation: Biomedical Informatics Research, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Puthen V
authors.initials: PV
authors.lastname: Jithesh
authors.affiliation: Biomedical Informatics Research, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Tanwir
authors.initials: T
authors.lastname: Habib
authors.affiliation: University of Sunderland, Department of Pharmacy, Health and Well-Being, Sunderland Pharmacy School, Sunderland, UK.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Faheem
authors.affiliation: Translational Clinical Research, University of Leicester, Leicester, UK.
authors.forename: Fennell A
authors.initials: FA
authors.lastname: Dean
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Morgan
authors.affiliation: Cancer and Polio Research Fund Laboratories, School of Biological Sciences, University of Liverpool, Liverpool, UK.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rudland
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Tanani
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D020931:ran GTP-Binding Protein
keywords: C-Met; Ran GTP; breast cancer; gefitinib; lung cancer