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

Filipe C Lourenco, June Munro, Jennifer Brown, Julia Cordero, Rhoda Stefanatos, Karen Strathdee, Clare Orange, Stephan M Feller, Owen J Sansom, Marcos Vidal, Graeme I Murray, Michael F Olson

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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.

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.

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.

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.
Original languageEnglish
Pages (from-to)480-493
Number of pages14
JournalGut
Volume63
Issue number3
Early online date12 Apr 2013
DOIs
Publication statusPublished - Mar 2014

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Lim Kinases
Colorectal Neoplasms
Stem Cells
Cell Proliferation
Drosophila
Neoplasms
Neoplastic Stem Cells
Intestinal Neoplasms
Colitis
Tumor Cell Line
Colon
Homeostasis
Epithelial Cells
Phosphorylation

Cite this

Lourenco, F. C., Munro, J., Brown, J., Cordero, J., Stefanatos, R., Strathdee, K., ... Olson, M. F. (2014). Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut, 63(3), 480-493. https://doi.org/10.1136/gutjnl-2012-303883

Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. / Lourenco, Filipe C; Munro, June; Brown, Jennifer; Cordero, Julia; Stefanatos, Rhoda; Strathdee, Karen; Orange, Clare; Feller, Stephan M; Sansom, Owen J; Vidal, Marcos; Murray, Graeme I; Olson, Michael F.

In: Gut, Vol. 63, No. 3, 03.2014, p. 480-493.

Research output: Contribution to journalArticle

Lourenco, FC, Munro, J, Brown, J, Cordero, J, Stefanatos, R, Strathdee, K, Orange, C, Feller, SM, Sansom, OJ, Vidal, M, Murray, GI & Olson, MF 2014, 'Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation', Gut, vol. 63, no. 3, pp. 480-493. https://doi.org/10.1136/gutjnl-2012-303883
Lourenco FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K et al. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut. 2014 Mar;63(3):480-493. https://doi.org/10.1136/gutjnl-2012-303883
Lourenco, Filipe C ; Munro, June ; Brown, Jennifer ; Cordero, Julia ; Stefanatos, Rhoda ; Strathdee, Karen ; Orange, Clare ; Feller, Stephan M ; Sansom, Owen J ; Vidal, Marcos ; Murray, Graeme I ; Olson, Michael F. / Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. In: Gut. 2014 ; Vol. 63, No. 3. pp. 480-493.
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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.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.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.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.",
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