Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation

Lourenco, F.C. et al. (2014) Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut, 63(3), pp. 480-493. (doi:10.1136/gutjnl-2012-303883)

Lourenco, F.C. et al. (2014) Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut, 63(3), pp. 480-493. (doi:10.1136/gutjnl-2012-303883)

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Publisher's URL: http://dx.doi.org/10.1136/gutjnl-2012-303883

Abstract

Objective: Colorectal cancer (CRC) is a major contributor to cancer mortality and morbidity. LIM kinase 2 (LIMK2) promotes tumour cell invasion and metastasis. The objectives of this study were to determine how LIMK2 expression is associated with CRC progression and patient outcome, and to use genetically modified Drosophila and mice to determine how LIMK2 deletion affects gastrointestinal stem cell regulation and tumour development.<p></p> Design: LIMK2 expression and activity were measured by immunostaining tumours from CRC-prone mice, human CRC cell lines and 650 human tumours. LIMK knockdown in Drosophila or Limk2 deletion in mice allowed for assessment of their contributions to gastrointestinal stem cell homeostasis and tumour development.<p></p> Results: LIMK2 expression was reduced in intestinal tumours of cancer-prone mice, as well as in human CRC cell lines and tumours. Reduced LIMK2 expression and substrate phosphorylation were associated with shorter patient survival. Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. Limk2 deletion increased colon tumour size in a colitis-associated colorectal mouse cancer model.<p></p> Conclusions: This study revealed that LIMK2 expression and activity progressively decrease with advancing stage, and supports the hypothesis that there is selective pressure for reduced LIMK2 expression in CRC to relieve negative constraints imposed upon gastrointestinal stem cells.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Orange, Miss Clare and Brown, Dr Jennifer and Munro, Dr June and Vidal, Dr Marcos and Strathdee, Mrs Karen and Cordero, Dr Julia and Lourenco, Dr Filipe and Stefanatos, Miss Rhoda and Sansom, Professor Owen and Olson, Professor Michael
Authors: Lourenco, F.C., Munro, J., Brown, J., Cordero, J., Stefanatos, R., Strathdee, K., Orange, C., Feller, S.M., Sansom, O.J., Vidal, M., Murray, G.I., and Olson, M.F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Gut
Publisher:BMJ Publishing Group Ltd & British Society of Gastroenterology
ISSN:0017-5749
ISSN (Online):1468-3288
Published Online:12 April 2013
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Gut 63(3):480-493
Publisher Policy:Reproduced under a Creative Commons License

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