Published online before print February 14, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070897

Accepted for publication November 26, 2007.

Article

Excess FGF-7 in Corneal Epithelium Causes Corneal Intraepithelial Neoplasia in Young Mice and Epithelium Hyperplasia in Adult Mice

Taiichiro Chikama^*, Chia-Yang Liu^*@, Johanna T.A. Meij^*, Yasuhito Hayashi^*, I-Jong Wang, Liu Yang, Teruo Nishida, and Winston W.Y. Kao^*¶@

From the Department of Ophthalmology,* University of Cincinnati Medical Center, Cincinnati, Ohio; the Department of Biomolecular Recognition and Ophthalmology, Yamaguchi University, Ube, Japan; the Department of Ophthalmology, Ehime University School of Medicine, Matsuyama, Japan; the Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan; and the Department of Cancer and Cell Biology,^¶ University of Cincinnati Medical Center, Cincinnati, Ohio

^@ To whom correspondence should be addressed. E-mail: liucg{at}uc.edu.

	Abstract

We hypothesized that human ocular surface squamous neoplasia (OSSN) may result from the continuous growth stimulation of corneal epithelial progenitor cells. In the present study, we analyzed the effects of excess fibroblast growth factor-7 (FGF-7) on both the proliferation and differentiation of corneal epithelium in a novel Krt12-rtTA/tet-O-FGF-7 double transgenic mouse model in which cornea-specific FGF-7 overexpression is achieved by doxycycline (Dox) treatment. When such adult mice were exposed to Dox, they exhibited epithelial hyperplasia with increases in phospho-extracellular signal-regulated kinase 1/2-, nuclear -catenin-, and 5-bromo-2'-deoxyuridine-labeled cells and altered keratin (K) 14 (K14) expression pattern, a normal K12 expression pattern, and the normal absence of K10. Hyperplasia of the adult cornea was fully reversible 2 weeks after the removal of Dox from chow. In contrast, double transgenic embryos that were exposed to Dox from embryonic day 0.5 to postnatal day 21 developed papillomatous tumors in the cornea, resembling human OSSN, and ectopic gland-like structures in the limbus, accompanied by the down-regulation of K12 and the up-regulation of K14, Pax6, and p63. These epithelial anomalies observed in young experimental mice were not fully resolved after the termination of Dox induction. Taken together, Krt12-rtTA/tet-O-FGF-7 mice may be a suitable animal model for the study of the molecular and cellular mechanisms of human OSSN.