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LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance

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Abstract

Cofilin phospho-regulation is important for actin filament turnover and is implicated in cancer. Phosphorylation of cofilin is mediated by LIM kinases (LIMKs) and dephosphorylation by Slingshot phosphatases (SSH). LIMKs and SSH promote cancer cell invasion and metastasis and represent novel anti-cancer targets. However, little is known regarding LIMK/cofilin and SSH in human colorectal cancer (CRC). In this study, we aimed to address their expression and significance in human CRC. We evaluated expression of non-phosphorylated (active) and phosphorylated cofilin, LIMK1, LIMK2, and SSH1 by immunohistochemistry in 143 human CRC samples in relation to clinicopathologic parameters, response of metastatic disease to chemotherapy, and epithelial-mesenchymal transition (EMT) markers β-catenin, E-cadherin, and ZEB. We show that active cofilin, LIMK1, LIMK2, and SSH1 are overexpressed in human CRC and are associated with tumor progression parameters. SSH1 is an independent predictor of lymph node metastasis by multivariate analysis. LIMK1 and SSH1 expression is also higher in non-responders to chemotherapy, and SSH1 is shown by multivariate analysis to independently predict response of metastatic disease to chemotherapy. Active cofilin, LIMK1, LIMK2, and SSH1 also correlated with the EMT markers examined. In addition, immunofluorescence analysis showed increased expression of active cofilin, LIMK1, LIMK2, and SSH1 in HT29 colon cancer cells resistant to 5-fluorouracil compared to parental HT29 cells. Our results suggest that F-actin regulators LIMK/cofilin pathway and SSH1 are associated with CRC progression and chemoresistance representing promising tumor biomarkers and therapeutic targets in CRC.

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Authors and Affiliations

  1. Department of Anatomy-Histology-Embryology, Medical School, University of Patras, 26500, Patras, Greece

    Helen Aggelou, Panagiota Chadla, Sofia Nikou, Sofia Karteri, Helen Papadaki & Vasiliki Bravou

  2. Department of Surgery, University of Patras Medical School, Patras, Greece

    Ioannis Maroulis

  3. Division of Oncology, University of Patras Medical School, Patras, Greece

    Haralabos P. Kalofonos

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  1. Helen Aggelou
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  2. Panagiota Chadla
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Correspondence to Vasiliki Bravou.

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Human tissue samples anonymously used in the study were paraffin blocks (redundant tissue) for the archives of the Department of Pathology. The study was performed in compliance with the Declaration of Helsinki and was approved by the Committee on Research and Ethics and the Scientific Committee of the University Hospital of Patras, Greece.

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Aggelou, H., Chadla, P., Nikou, S. et al. LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance. Virchows Arch 472, 727–737 (2018). https://doi.org/10.1007/s00428-018-2298-0

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