Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo.
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.
Andl
Claudia D
CD
Gastroenterology Division, Abramson Cancer Center and Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Mizushima
Takaaki
T
Nakagawa
Hiroshi
H
Oyama
Kenji
K
Harada
Hideki
H
Chruma
Katerina
K
Herlyn
Meenhard
M
Rustgi
Anil K
AK
D000818:Animals; D001483:Base Sequence; D002449:Cell Aggregation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D066246:ErbB Receptors / Q000502:physiology*; D004947:Esophagus / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D021381:Protein Transport; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
D017931:DNA Primers; D066246:ErbB Receptors