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

Research output: Contribution to journalArticle

7 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 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.
LanguageEnglish
Pages75854–75864
Number of pages11
JournalOncotarget
Volume7
Issue number46
DOIs
Publication statusPublished - 15 Nov 2016

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GTP Phosphohydrolases
Breast Neoplasms
Cell Line
Matrix Metalloproteinases
Cell Adhesion
Cell Movement
Lung Neoplasms
Neoplasms
Phosphorylation
Cell Proliferation
Survival
Growth
gefitinib

Cite this

Yuen, H-F., Chan, K-K., Platt-Higgins, A., Dakir, E-H., Matchett, K. B., Haggag, Y. A., ... 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
Yuen, Hiu-Fung ; Chan, Ka-Kui ; Platt-Higgins, Angela ; Dakir, El-Habib ; Matchett, Kyle B ; Haggag, Yusuf Ahmed ; Jithesh, Puthen V ; Habib, Tanwir ; Faheem, Ahmed ; Fennell, Dean A ; Morgan, Richard ; Rudland, Philip S ; El-Tanani, Mohamed. / Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling. In: Oncotarget. 2016 ; Vol. 7, No. 46. pp. 75854–75864.
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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.",
author = "Hiu-Fung Yuen and Ka-Kui Chan and Angela Platt-Higgins and El-Habib Dakir and Matchett, {Kyle B} and Haggag, {Yusuf Ahmed} and Jithesh, {Puthen V} and Tanwir Habib and Ahmed Faheem and Fennell, {Dean A} and Richard Morgan and Rudland, {Philip S} and Mohamed El-Tanani",
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Yuen, H-F, Chan, K-K, Platt-Higgins, A, Dakir, E-H, Matchett, KB, Haggag, YA, Jithesh, PV, Habib, T, Faheem, A, Fennell, DA, Morgan, R, Rudland, PS & El-Tanani, M 2016, 'Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling', Oncotarget, vol. 7, no. 46, pp. 75854–75864. https://doi.org/10.18632/oncotarget.12420

Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling. / Yuen, Hiu-Fung; Chan, Ka-Kui; Platt-Higgins, Angela; Dakir, El-Habib; Matchett, Kyle B; Haggag, Yusuf Ahmed; Jithesh, Puthen V; Habib, Tanwir; Faheem, Ahmed; Fennell, Dean A; Morgan, Richard; Rudland, Philip S; El-Tanani, Mohamed.

In: Oncotarget, Vol. 7, No. 46, 15.11.2016, p. 75854–75864.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

AU - Yuen, Hiu-Fung

AU - Chan, Ka-Kui

AU - Platt-Higgins, Angela

AU - Dakir, El-Habib

AU - Matchett, Kyle B

AU - Haggag, Yusuf Ahmed

AU - Jithesh, Puthen V

AU - Habib, Tanwir

AU - Faheem, Ahmed

AU - Fennell, Dean A

AU - Morgan, Richard

AU - Rudland, Philip S

AU - El-Tanani, Mohamed

PY - 2016/11/15

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N2 - 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.

AB - 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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M3 - Article

VL - 7

SP - 75854

EP - 75864

JO - Oncotarget

T2 - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 46

ER -

Yuen H-F, Chan K-K, Platt-Higgins A, Dakir E-H, Matchett KB, Haggag YA et al. Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling. Oncotarget. 2016 Nov 15;7(46):75854–75864. https://doi.org/10.18632/oncotarget.12420