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

β-catenin signaling has been shown to play a fundamental role in embryonic development and tumorigenesis. In this study, we investigated the role of β-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 β-catenin immunoreactivity. Taken together, these results argue that β-catenin activation is a crucial step during OSSN pathogenesis. Thus, inhibition of β-catenin might be beneficial for treating this disease.

[1]  R. Nusse,et al.  Wnt signaling mediates self-organization and axis formation in embryoid bodies. , 2008, Cell stem cell.

[2]  I. Komuro,et al.  IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis , 2008, Nature.

[3]  Dianqing Wu,et al.  The canonical Wnt signaling antagonist DKK2 is an essential effector of PITX2 function during normal eye development. , 2008, Developmental biology.

[4]  Chia-Yang Liu,et al.  Excess FGF-7 in corneal epithelium causes corneal intraepithelial neoplasia in young mice and epithelium hyperplasia in adult mice. , 2008, The American journal of pathology.

[5]  L. Schweizer,et al.  The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens , 2008, BMC Cell Biology.

[6]  W. Bremner,et al.  Advances in male contraception. , 2008, Endocrine reviews.

[7]  Matthias B. Wahl,et al.  FGF signaling acts upstream of the NOTCH and WNT signaling pathways to control segmentation clock oscillations in mouse somitogenesis , 2007, Development.

[8]  L. Luo,et al.  A global double‐fluorescent Cre reporter mouse , 2007, Genesis.

[9]  M. Katoh,et al.  WNT Signaling Pathway and Stem Cell Signaling Network , 2007, Clinical Cancer Research.

[10]  M. Almeida,et al.  Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting β-Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription* , 2007, Journal of Biological Chemistry.

[11]  K. Tsubota,et al.  Cytokeratin 15 can be used to identify the limbal phenotype in normal and diseased ocular surfaces. , 2006, Investigative ophthalmology & visual science.

[12]  Maria I. Morasso,et al.  Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium , 2006, Development.

[13]  Kathleen R. Cho,et al.  Fibroblast growth factor 9 has oncogenic activity and is a downstream target of Wnt signaling in ovarian endometrioid adenocarcinomas. , 2006, Cancer research.

[14]  B. Dhillon,et al.  The aetiology and associations of conjunctival intraepithelial neoplasia , 2005, British Journal of Ophthalmology.

[15]  Colleen C Nelson,et al.  Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? , 2005, Endocrine reviews.

[16]  M. Taketo,et al.  The duality of beta-catenin function: a requirement in lens morphogenesis and signaling suppression of lens fate in periocular ectoderm. , 2005, Developmental biology.

[17]  L. Hennighausen,et al.  Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits wnt-1-induced mammary tumorigenesis. , 2005, Cancer research.

[18]  Elaine Fuchs,et al.  Defining the impact of beta-catenin/Tcf transactivation on epithelial stem cells. , 2005, Genes & development.

[19]  Chia-Yang Liu,et al.  Characterization of tetracycline-inducible bitransgenic Krt12rtTA/+/tet-O-LacZ mice. , 2005, Investigative ophthalmology & visual science.

[20]  D. Dhouailly,et al.  Transdifferentiation of corneal epithelium into epidermis occurs by means of a multistep process triggered by dermal developmental signals. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  J. Pe’er.  Ocular surface squamous neoplasia. , 2005, Ophthalmology clinics of North America.

[22]  Kathleen R. Cho,et al.  FGF‐20 and DKK1 are transcriptional targets of β‐catenin and FGF‐20 is implicated in cancer and development , 2005, The EMBO journal.

[23]  Mark D Gustavson,et al.  Tcf binding sequence and position determines β‐catenin and Lef‐1 responsiveness of MMP‐7 promoters , 2004, Molecular carcinogenesis.

[24]  S. Chandrasekharan,et al.  Audit of stereotactic core biopsies for microcalcification , 2004, Breast Cancer Research.

[25]  C. Tickle,et al.  Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos , 2004, Journal of anatomy.

[26]  C. Cheng,et al.  Interactions of Proteases, Protease Inhibitors, and the β1 Integrin/Laminin γ3 Protein Complex in the Regulation of Ectoplasmic Specialization Dynamics in the Rat Testis1 , 2004, Biology of reproduction.

[27]  R. Nusse,et al.  Convergence of Wnt, ß-Catenin, and Cadherin Pathways , 2004, Science.

[28]  R. Cardiff,et al.  PPAR signaling exacerbates mammary gland tumor development , 2004 .

[29]  E. Musgrove.  Wnt signalling via the epidermal growth factor receptor: a role in breast cancer? , 2003, Breast Cancer Research.

[30]  Yusuke Nakamura,et al.  Involvement of the FGF18 gene in colorectal carcinogenesis, as a novel downstream target of the beta-catenin/T-cell factor complex. , 2003, Cancer research.

[31]  E. Fuchs,et al.  Links between signal transduction, transcription and adhesion in epithelial bud development , 2003, Nature.

[32]  K. Kratochwil,et al.  FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. , 2002, Genes & development.

[33]  Susan E. Wert,et al.  Early restriction of peripheral and proximal cell lineages during formation of the lung , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  N. Perrimon,et al.  The Promise and Perils of Wnt Signaling Through β-Catenin , 2002, Science.

[35]  P. Rennie,et al.  The Androgen Receptor Can Promote β-Catenin Nuclear Translocation Independently of Adenomatous Polyposis Coli* , 2002, The Journal of Biological Chemistry.

[36]  Christophe Héligon,et al.  The IGF pathway regulates head formation by inhibiting Wnt signaling in Xenopus. , 2002, Developmental biology.

[37]  G. Nuovo,et al.  Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia. , 2002, Ophthalmology.

[38]  D. Chung,et al.  Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. , 2001, Cancer research.

[39]  J. Regan,et al.  FP Prostanoid Receptor Activation of a T-cell Factor/β-Catenin Signaling Pathway* , 2001, The Journal of Biological Chemistry.

[40]  P. Polakis.  Wnt signaling and cancer. , 2000, Genes & development.

[41]  M. Hung,et al.  β-Catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression , 2000 .

[42]  M. Taketo,et al.  Intestinal polyposis in mice with a dominant stable mutation of the β‐catenin gene , 1999, The EMBO journal.

[43]  Wen-Hwa Lee,et al.  Temporal, spatial, and cell type–specific control of Cre-mediated DNA recombination in transgenic mice , 1999, Nature Biotechnology.

[44]  E. Fuchs,et al.  Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. , 1999, Development.

[45]  Thomas Kirchner,et al.  β-Catenin Regulates the Expression of the Matrix Metalloproteinase-7 in Human Colorectal Cancer , 1999 .

[46]  Paul Polakis,et al.  The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors , 1999, Oncogene.

[47]  S. Orsulic,et al.  E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. , 1999, Journal of cell science.

[48]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[49]  S. Dedhar,et al.  Cell adhesion and the integrin-linked kinase regulate the LEF-1 and beta-catenin signaling pathways. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[50]  W. Birchmeier,et al.  E-cadherin as a tumor (invasion) suppressor gene. , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[51]  M. Justice,et al.  Characterization and chromosomal localization of the cornea-specific murine keratin gene Krt1.12. , 1994, The Journal of biological chemistry.

[52]  T. Sun,et al.  Cornea-specific expression of K12 keratin during mouse development. , 1993, Current eye research.

[53]  R. Kemler.  From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. , 1993, Trends in genetics : TIG.

[54]  Elaine Fuchs,et al.  Defining the impact of (cid:1) -catenin/Tcf transactivation on epithelial stem cells , 2005 .

[55]  R. Nusse,et al.  Convergence of Wnt, beta-catenin, and cadherin pathways. , 2004, Science.

[56]  N. Perrimon,et al.  The promise and perils of Wnt signaling through beta-catenin. , 2002, Science.

[57]  F. McCormick,et al.  Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. , 1999, Nature.

[58]  T. Brabletz,et al.  beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. , 1999, The American journal of pathology.

[59]  S. Tseng.  Concept and application of limbal stem cells , 1989, Eye.