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This Article Full Text Full Text (PDF) All Versions of this Article: gut.2007.142778v1 57/7/931    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this link to a friend Similar articles in this journal Similar articles in PubMed Add article to my folders Download to citation manager Request Permissions Google Scholar Articles by Assi, K Articles by Salh, B PubMed PubMed Citation Articles by Assi, K Articles by Salh, B

Integrin-linked kinase regulates cell proliferation and tumour growth in murine colitis-associated carcinogenesis

¹ Jack Bell Research Center, Vancouver, British Columbia, Canada
² BC Cancer Agency, Vancouver, British Columbia, Canada
³ Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada
⁴ Shriners Hospital and McGill University, Montreal, Quebec, Canada

Correspondence to:
Dr B Salh, Division of Gastroenterology, 5153-2775 Laurel Street, Vancouver, British Columbia, Canada V5Z 1M9; bsalh{at}interchange.ubc.ca

Background: Integrins are transmembrane cell surface receptors that mediate cell–cell and cell–matrix contacts. Integrin-linked kinase (ILK) is the binding partner of β1 and β3 integrins, and has been ascribed essential roles in development, angiogenesis and tumourigenesis. However, in vivo evidence for the latter is currently lacking.

Aim: The hypothesis that epithelial cell-specific deletion of ILK would impact on murine tumourigenesis was tested using a colitis-associated cancer model.

Methods: To create intestinal epithelial cell ILK knockout animals, Fabp/Cre mice (Cre recombinase expressed under the control of a modified Fabp promoter) were used, and they were mated with mice carrying a loxP-flanked (floxed) ILK gene (ILK^flox/flox).

Results: ILK intestinal knockout mice exhibited a reduction in the size of the caecum, and reduced crypt height in the colon. Immunohistochemical analysis confirmed that there was diminished ILK expression, and bromodeoxyuridine (BrdU) staining was significantly reduced in the knockout animals as compared with the wild-type animals in both the caecum and colon (p<0.001 for both). Following azoxymethane and dextran sodium sulfate (DSS) treatment, fewer total tumours were observed in the ILK knockout animals, which were mosaic with respect to ILK expression. Cyclin D1, Snail, fibronectin and matrix metalloproteinase 9 (MMP9) were all reduced, and active caspase 3 increased, in tumours from ILK knockout mice, as compared with wild-type mice, on immunohistochemical analysis. Using small interfering RNA (siRNA) to knock down ILK in colonic cancer cell lines, it was confirmed that it is capable of regulating cyclin D1, Snail, MMP9 and fibronectin transcription.

Conclusions: From these findings, it is concluded that ILK plays an important role in intestinal epithelial cell proliferation, and that it influences the development of colitis-associated cancer, through modulation of cyclin D1, the extracellular matrix and MMP9.