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Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer

Oncogene volume 30, pages 2997–3002 (2011)Cite this article

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Abstract

CTEN/TNS4 is an oncogene in colorectal cancer (CRC), which can induce cell motility although its mechanistic basis of activity and the clinical implications of Cten expression are unknown. As Cten is in complex with integrins at focal adhesions, we hypothesised that it may interact with integrin-linked kinase (ILK). Through forced expression and knockdown of Cten in HCT116 and SW620 (respectively, showing low and high Cten expression), we showed that Cten could regulate ILK. However, inhibition of ILK after forced expression of Cten abrogated the motility-inducing effects of Cten, thereby demonstrating that the Cten–ILK interaction was functionally relevant. Combined knockdown of Cten and ILK had no additive effects on cell motility compared with knockdown of each individually. In order to investigate the clinical implications of Cten expression, a series of 462 CRCs were evaluated by immunohistochemistry. High expression of Cten was associated with advanced Dukes’ stage (P<0.001), poor prognosis (P<0.001) and distant metastasis (P=0.008). The role of Cten in metastasis was tested by (a) intrasplenic injection of CRC cells stably transfected with a Cten expression vector into nude mice and (b) testing a series of primary human CRCs and their metastases by immunohistochemistry. Compared with controls, mice injected with cells expressing Cten developed larger tumours in the spleen (P<0.05) and liver (P<0.05). In the human cases, compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (P=0.002). We conclude that Cten expression is of prognostic significance in CRC, and we delineate a Cten–ILK pathway controlling cell motility and possibly promoting metastasis.

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Acknowledgements

We thank Professor I Tomlinson for kindly donating cell lines, Miss Carol Dunn for helping with the preparation of the histology sections and Miss Anne Kane for helping with slide scanning. Image analysis was supported by Cost action IC0604.

Funding: The study was funded by the University of Nottingham and Cancer Research Nottingham. KBK is funded by the National Association for Colitis and Crohn’s Disease (NACC).

Author contribution: Study concept and design: MI, SW, LD, KBK. Acquisition of data: AA, SA, WF, MA, YL, DJ, RK. Analysis and interpretation of data: MI, SW, KBK. Drafting of the paper & critical revision of the manuscript: MI, SW, KBK, DNL, SL. Technical/material support: DNL, SL.

Declaration of originality

It is declared that this paper has not been published elsewhere and is not being considered by any other journal.

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Author notes

  1. A Albasri and S Al-Ghamdi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Pathology, Nottingham University, Nottingham, UK

    A Albasri, S Al-Ghamdi, W Fadhil, M Aleskandarany, D Jackson, K B Kindle & M Ilyas

  2. Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, USA

    Y-C Liao & S H Lo

  3. Division of Gastrointestinal Surgery, Nottingham University, Nottingham, UK

    D N Lobo

  4. Nottingham Digestive Diseases Centre, NIHR Biomedical Research Unit, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK

    D N Lobo, S Watson & M Ilyas

  5. Division of Pre-clinical Oncology, Nottingham University, Nottingham, UK

    R Kumari & S Watson

  6. Division of Academic Oncology, Nottingham University, Nottingham, UK

    L Durrant

Authors
  1. A Albasri
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  2. S Al-Ghamdi
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  3. W Fadhil
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  4. M Aleskandarany
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  7. D N Lobo
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  8. S H Lo
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  10. L Durrant
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  11. S Watson
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  13. M Ilyas
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Corresponding author

Correspondence to M Ilyas.

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Supplementary Information accompanies the paper on the Oncogene website

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Albasri, A., Al-Ghamdi, S., Fadhil, W. et al. Cten signals through integrin-linked kinase (ILK) and may promote metastasis in colorectal cancer. Oncogene 30, 2997–3002 (2011). https://doi.org/10.1038/onc.2011.26

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  • DOI: https://doi.org/10.1038/onc.2011.26

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