The epithelial-mesenchymal transition of colon carcinoma involves expression of IL-8 and CXCR-1-mediated chemotaxis.
The epithelial-mesenchymal transition (EMT) is an essential component of embryonic development, tissue remodeling, and wound repair. In addition, many epithelial tumors, including colorectal carcinomas, appear to undergo this transition that may facilitate their invasion. Using a novel model of EMT in colon carcinoma in which the inflammatory cytokine TNF-alpha accelerates this TGF-beta directed process, we report that TNF-alpha stimulation upregulates expression of the chemokine IL-8, and that this upregulation is dependent on the transcription factor NF-kappaB. Significantly, this effect is not merely an inflammatory response by these colon carcinoma cells because IL-8 expression is induced in cells undergoing a TGF-beta-driven EMT in the absence of exogenous TNF-alpha. During the EMT, a concomitant increase in the chemokine receptor CXCR-1, but not CXCR-2, also occurs. Moreover, both IL-8 and CXCR-1 function in the chemokinetic and chemotactic migration of colon carcinoma cells as assessed by antibody inhibition studies. These studies establish that the regulated expression of a specific chemokine and its receptor are linked to the EMT and they provide a biochemical framework for understanding the mechanisms by which the EMT promotes migration.
Bates
Richard C
RC
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA 02215, USA. rbates@caregroup.harvard.edu
DeLeo
Michael J
MJ
Mercurio
Arthur M
AM
D002465:Cell Movement; D002633:Chemotaxis; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016209:Interleukin-8; D016328:NF-kappa B; D023062:Receptors, Interleukin-8A; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases