Alpha2beta1 integrin signalling enhances cyclooxygenase-2 expression in intestinal epithelial cells.
Inflammatory bowel diseases (IBD) are linked to an increased risk of developing colon cancer, by inflammatory mediators and alterations to the extracellular matrix (ECM). The events induced by inflammatory mediators lead to dysregulated activation and induction of inflammatory genes such as cyclooxygenase-2 (COX-2). COX-2 is involved in the conversion of arachidonic acid to biologically active prostanoids and is highly upregulated in colon cancer. Since inflammation-induced changes to the extracellular matrix could affect integrin activities, we here investigated the effect of integrin signalling on the level of COX-2 expression in the non-transformed intestinal epithelial cell lines, Int 407 and IEC-6. Adhesion of these cells to a collagen I- or IV-coated surface, increased surface expression of alpha2beta1 integrin. Activation of integrins with collagen caused an increased cox-2 promoter activity, with a subsequent increase in COX-2 expression. The signalling cascade leading to this increased expression and promoter activity of cox-2, involves PKCalpha, the small GTPase Ras and NFkappaB but not Erk1/2 or Src activity. The integrin-induced increase in cellular COX-2 activity is responsible for an elevated generation of reactive oxygen species (ROS) and increased cell migration. This signalling pathway suggests a mechanism whereby inflammation-induced modulations of the ECM, can promote cancer transformation in the intestinal epithelial cells.
Broom
Oliver Jay
OJ
Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
Massoumi
Ramin
R
Sjölander
Anita
A
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000378:metabolism
D038982:Integrin alpha2beta1; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D003094:Collagen; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D018631:ras Proteins