The secretory leukocyte protease inhibitor gene is a target of epidermal growth factor receptor action in endometrial epithelial cells.
The over-expression of epidermal growth factor receptor (EGFR) and its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha, is a common feature of epithelial carcinomas and correlates with neoplastic progression. Secretory leukocyte protease inhibitor (SLPI), a member of the Kazal superfamily of serine anti-proteases, induces proliferation and promotes malignancy of epithelial cells and is expressed at high levels in multiple tumor types. In the present study, we have demonstrated that EGF increases SLPI expression in the human endometrial epithelial cell line Ishikawa in a dose- and time-dependent manner. We have shown that this effect of EGF occurs, in part, at the level of the SLPI promoter and involves the MAP kinase signaling pathway. We have further shown that EGF promotion of cell proliferation, but not induction of cyclin D1 gene expression, involves SLPI. Our results suggest that the regulation of SLPI expression by EGFR ligand(s) may represent a 'feed-forward' mechanism by which the enhanced proliferative and migratory properties of EGFR over-expressing cancer cells are sustained. Increased SLPI expression is likely an important component of altered EGFR signaling in human tumors and may have significant therapeutic implications in cancer progression.
Velarde
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MC
Arkansas Children's Nutrition Center and Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, 1120 Marshall St, Little Rock, Arkansas 72202, USA.
Parisek
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SI
Eason
R R
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Simmen
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FA
Simmen
R C M
RC
D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics*; D053481:Secretory Leukocyte Peptidase Inhibitor; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors