Esophageal cancer is a common malignancy in the United States and worldwide. A number of studies indicate that the molecular basis of esophageal squamous cancer cell carcinoma (ESCC) involves the activation of oncogenes and tumor suppressor genes, but the role of epidermal growth factor receptor (EGFR) in the very early stages of carcinogenesis remains elusive. We have overexpressed EGFR through retro-virally-mediated transduction in different primary human esophageal epithelial cells. This has led to observations that there are coordinated consequences of enhanced cell migration modulated by EGFR. In addition, when EGFR overexpressing primary human esophageal epithelial cells are placed in a novel, organotypic cell culture system, there is induction of increased epithelial thickness, hyperplasia, and hyperproliferation. Our hypothesis is that EGFR plays a critical role in the disruption of normal cellular homeostasis through induction of hyperproliferation and enhanced cell migration with impairment of differentiation. The objectives will be achieved through the following interrelated Specific Aims: (1) To determine the functional activation of Akt by EGFR and determine the possible link between upregulation of STAT-1 and matrix metalloproteinases (MMPs) as modulators of cell migration and (2) To elucidate the role of EGFR in promoting increased cell proliferation through the induction of RAD (ras like molecule), a GTP binding protein that is negatively regulated by the nm-23 metastasis suppressor gene. RAD was found to be upregulated based upon a gene array comparison of esophageal epithelial cells retrovirally transduced with green fluorescent protein (GFP) versus EGFR. ? In aggregate, the proposed studies will provide new insights into EGFR signaling and modulation of key cellular processes in the esophageal epithelium as the basis for the very early steps in esophageal squamous carcinogenesis. These data will provide a foundation for future studies in transgenic mouse models and a transition towards an R01 grant proposal. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK064249-02
Application #
6743626
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (02))
Program Officer
Hamilton, Frank A
Project Start
2003-05-01
Project End
2005-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$158,500
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Takaoka, Munenori; Smith, Caitlin E; Mashiba, Michael K et al. (2006) EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I. Am J Physiol Gastrointest Liver Physiol 290:G404-16
Takaoka, Munenori; Harada, Hideki; Andl, Claudia D et al. (2004) Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3. Cancer Res 64:7711-23
Takaoka, Munenori; Harada, Hideki; Deramaudt, Therese B et al. (2004) Ha-Ras(G12V) induces senescence in primary and immortalized human esophageal keratinocytes with p53 dysfunction. Oncogene 23:6760-8
Andl, Claudia D; Mizushima, Takaaki; Oyama, Kenji et al. (2004) EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol 287:G1227-37
Harada, Hideki; Nakagawa, Hiroshi; Oyama, Kenji et al. (2003) Telomerase induces immortalization of human esophageal keratinocytes without p16INK4a inactivation. Mol Cancer Res 1:729-38