Submitted to: Journal of Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2004
Publication Date: 1/13/2005
Citation: Velarde, M.C., Parisek, S.I., Eason, R.R., Simmen, F.A., Simmen, R.C. 2005. The secretory leukocyte protease inhibitor (SLPI) gene is a target of epidermal growth factor receptor action in endometrial epithelial cells. Journal of Endocrinology. 184(1):141-151. Interpretive Summary: Cancer of the reproductive system is common and represents a major health risk for both men and women. The Epidermal Growth Factor Receptor (EGFR) is a protein that binds other proteins (epidermal growth factor, EGF, and transforming growth factor, TGF). Defects in the interactions of these proteins are common features of epithelial cancers and correlates with progression of cancers. Secretory leukocyte protease inhibitor (SLPI) promotes malignancy of epithelial cells and is present at high levels in multiple tumor types. In the present study, we demonstrate that EGF increases SLPI in the human endometrial epithelial cancer cells. Importantly, we found that this involves a well known cell signaling system (the MAPK signaling pathway). Our results suggest that the regulation of SLPI by EGFR-related proteins may represent a mechanism by which the cancer promoting properties 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. With these new data, we can explore the ways various dietary factors can prevent these cancers in children and adults.
Technical Abstract: The over-expression of Epidermal Growth Factor Receptor (EGFR) and it's ligands epidermal growth factor (EGF) and transforming growth factor (TGF)-' is a common feature of epithelial carcinomas and correlates with neoplastic progression. Secretory luekocyte protease inhibitor (SLPI), a member of the Kazal superfamily of serine antiproteases, induces proliferation and promotes malignancy of epithelial cells and is expressed at high levels in multiple tumor types. In the present study, we demonstrate that EGF increases SLPI expression in the human endometrial epithelial cell line Isikowa in a dose- and time-dependent manner. We show that this effect of EGF occurs in part, at the level of the SLPI promoter and involves the MAPK signaling pathway. We further show that EGF promotion of cell proliferation but not induction of cycline 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 and important component of altered EGFR signaling in human tumors and may have significant therapeutic implications in cancer progression.