Aberrant expression of a beta-catenin gain-of-function mutant induces hyperplastic transformation in the mouse cornea.

Abstract

Beta-catenin signaling has been shown to play a fundamental role in embryonic development and tumorigenesis. In this study, we investigated the role of beta-catenin (Ctnnb1) in corneal homeostasis and tumorigenesis. Conditional expression of a murine Ctnnb1 gain-of-function mutation alone caused corneal neoplasia and neovascularization, resembling human ocular surface squamous neoplasia (OSSN). These corneas displayed an upregulation of cell proliferative markers (PCNA and p63), while presenting downregulation of both the Pax-6 transcription factor and the corneal differentiation marker cytokeratin 12. In addition, the expression of limbal-type keratin 15 ectopically extended to cornea, but the pattern of conjunctival keratin 4 and epidermal keratin 10 were unchanged. Moreover, epithelial E-cadherin and laminins decreased concomitantly with elevated levels of MMP-7. We also noticed a dramatic upregulation of pro-angiogenic factors (Vegf-A, Vegfr1) and angiopoietins in these corneas. Interestingly, all human OSSN specimens examined revealed nuclear beta-catenin immunoreactivity. Taken together, these results argue that beta-catenin activation is a crucial step during OSSN pathogenesis. Thus, inhibition of beta-catenin might be beneficial for treating this disease.

• Authors: Yujin Zhang, Mindy K Call, Lung-Kun Yeh, Hongshan Liu, Tyler Kochel, I-Jong Wang, Pao-Hsien Chu, Makoto M Taketo, James V Jester, Winston W-Y Kao, Chia-Yang Liu
• Journal: Journal of cell science (J Cell Sci) Vol. 123 Issue Pt 8 Pg. 1285-94 (Apr 15 2010) ISSN: 1477-9137 [Electronic] England
• PMID: 20332116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Mutant Proteins
• beta Catenin
• Matrix Metalloproteinase 7

Topics

• Aging (pathology)
• Animals
• Basement Membrane (enzymology, pathology)
• Cadherins (metabolism)
• Cell Differentiation
• Cell Membrane (metabolism, pathology)
• Cell Nucleus (metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism, pathology)
• Cornea (metabolism, pathology)
• Down-Regulation
• Epithelium, Corneal (metabolism, pathology)
• Eye Neoplasms (metabolism, pathology)
• Humans
• Hyperplasia
• Matrix Metalloproteinase 7 (metabolism)
• Mice
• Models, Biological
• Mutant Proteins (metabolism)
• Neoplasms, Squamous Cell (metabolism, pathology)
• Protein Transport
• Up-Regulation
• beta Catenin (metabolism)