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J. Biol. Chem., Vol. 278, Issue 3, 1824-1830, January 17, 2003
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From the Epidermal growth factor receptor
(EGFR) overexpression is observed in a number of malignancies,
especially those of esophageal squamous cell origin. However, little is
known about the biological functions of EGFR in primary esophageal
squamous epithelial cells. Using newly established primary human
esophageal squamous epithelial cells as a platform, we overexpressed
EGFR through retroviral transduction and established novel
three-dimensional organotypic cultures. Additionally, EGFR was targeted
in a cell type- and tissue-specific fashion to the esophageal
epithelium in transgenic mice. EGFR overexpression in primary
esophageal keratinocytes resulted in the biochemical activation of Akt
and STAT pathways and induced enhanced cell migration and cell
aggregation. When established in organotypic culture,
EGFR-overexpressing cells had evidence of epithelial cell
hyperproliferation and hyperplasia. These effects were also observed in
EGFR-overexpressing transgenic mice and the esophageal cell lines
established thereof. In particular, EGFR-induced effects upon
aggregation appear to be mediated through the relocalization of p120
from the cytoplasm to the membrane and increased interaction with
E-cadherin. EGFR modulates cell migration through the up-regulation of
matrix metalloproteinase 1. Taken together, the functional effects of
EGFR overexpression help to explain its role in the initiating steps of
esophageal squamous carcinogenesis.
Epidermal Growth Factor Receptor Mediates
Increased Cell Proliferation, Migration, and Aggregation in Esophageal
Keratinocytes in Vitro and in Vivo*
§¶,§¶,§¶,§,
,,, and§**
Gastroenterology Division,
** Department of Genetics, § Abramson Cancer
Center and Family Cancer Research Institute, Wistar Institute,
University of Pennsylvania, Philadelphia, Pennsylvania 19104
*
This work was supported by National Institutes of Health
(NIH) Grants P01 DE12467 and P01 CA098101 (to A. K. R.), a
grant from the Leonard and Madlyn Abramson Family Cancer
Research Institute at the University of Pennsylvania Cancer Center (to
A. K. R.), the NIH/NIDDK Center for Molecular Studies in Digestive
and Liver Diseases (Grant P30 DK50306), and its Morphology, Molecular
Biology, Mouse, and Cell Culture Core Facilities, and NIH Grants CA
80999 and CA 25874 (both to M. H.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: 600 CRB, University
of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104. Tel.:
215-898-0154; Fax: 215-573-5412; E-mail:
anil2@mail.med.upenn.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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