| Autor: |
Yuen HF; Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK., Chan KK; Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK., Platt-Higgins A; Cancer and Polio Research Fund Laboratories, School of Biological Sciences, University of Liverpool, Liverpool, UK., Dakir el-H; Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.; Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK., Matchett KB; Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK., Haggag YA; 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., Jithesh PV; Biomedical Informatics Research, Sidra Medical and Research Center, Doha, Qatar., Habib T; Biomedical Informatics Research, Sidra Medical and Research Center, Doha, Qatar., Faheem A; University of Sunderland, Department of Pharmacy, Health and Well-Being, Sunderland Pharmacy School, Sunderland, UK., Dean FA; Translational Clinical Research, University of Leicester, Leicester, UK., Morgan R; Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK., Rudland PS; Cancer and Polio Research Fund Laboratories, School of Biological Sciences, University of Liverpool, Liverpool, UK., El-Tanani M; Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire, UK. |
| Abstrakt: |
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. |
