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Carcinogenesis Advance Access published online on November 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn230
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aberrant activation of hedgehog signaling pathway in ovarian cancers: Effect on prognosis, cell invasion and differentiation

Xiaoyun Liao1, Michelle KY Siu1, Christy WH Au1, Esther Wong1, Hoi Yan Chan1, Philip Ip1, Hextan YS Ngan2 and Annie NY Cheung1,*

1 Department of Pathology
2 Department of Obstetrics and Gynecology, Queen Mary Hospital, the University of Hong Kong, Pokfulam, Hong Kong, China

* To whom correspondence should be addressed. Tel: (852) 2855-4876; Fax: (852) 2872-5197; E-mail: anycheun{at}hkucc.hku.hk

Aberrant activation of Hedgehog pathway has been implicated in the development of human malignancies. This study aimed at investigating the role of hedgehog molecules in human ovarian carcinogenesis. The expression profiles of hedgehog molecules were examined in ovarian tumor samples and ovarian cancer cell lines and the in vitro effects of hedgehog molecules on cell proliferation, apoptosis, migration, invasion and cell differentiation as well as related downstream target genes were assessed. Overexpression of Patched and Gli1 protein in ovarian cancers correlated with poor survival of the patients (P = 0.008; P = 0.004). Significantly elevated expression of Shh mRNA was observed in ovarian cancers compared with normal tissues and benign ovarian tumors and such differential expression was specific to histological types (P<0.05). Ectopic Gli1 overexpression in ovarian cancer cells conferred increased cell proliferation, cell mobility, invasiveness and change in differentiation in association with increased expression of E-cadherin, vimentin, Bcl-2, caspases as well as β1 integrin, membrane type 1 matrix metalloproteinase (MT1-MMP), and vascular endothelial growth factor (VEGF). Treatment with KAAD-cyclopamine induced cancer cell apoptosis, suppressed cell growth, mobility and invasiveness, and induced cancer cell de-differentiation with decreased expression of E-cadherin, cytokeratin 7, Snail, calretinin, vimentin, Bcl-2, caspases, β1 integrin, MT1-MMP and VEGF. Our data suggested that abnormal hedgehog signaling activation plays important roles in the development and progression of ovarian cancers. Gli1 expression is an independent prognostic marker. Inhibition of the hedgehog pathway molecules might be a valid therapeutic strategy for ovarian cancers.

Received June 11, 2008; revised September 22, 2008; accepted September 24, 2008.


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