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Integrin-linked kinase regulates cell proliferation and tumor growth in murine colitis-associated carcinogenesis
  1. Kiran Assi (kassi17{at}hotmail.com)
  1. University of British Columbia, Canada
    1. Julia Mills (jmills{at}interchange.ubc.ca)
    1. University of British Columbia, Canada
      1. David Owen (dowen{at}vanhosp.bc.ca)
      1. University of British Columbia, Canada
        1. Christopher Ong (chriso{at}interchange.ubc.ca)
        1. University of British Columbia, Canada
          1. Rene St Arnaud (rst-arnaud{at}shriners.mcgill.ca)
          1. McGill University, Canada
            1. Shoukat Dedhar (sdedhar{at}interchange.ubc.ca)
            1. University of British Columbia, Canada
              1. Baljinder Salh (bsalh{at}interchange.ubc.ca)
              1. University of British Columbia, Canada

                Abstract

                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 tumorigenesis. However, in vivo evidence for the latter is currently lacking. Aim. We tested the hypothesis that epithelial cell- specific deletion of ILK would impact on murine tumorigenesis, using a colitis-associated cancer model.

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

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

                Conclusions. From these findings, we conclude 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 matrix metalloproteinase 9.

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