34.txt

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1: Cancer Res. 2006 Feb 1;66(3):1354-62.

Fibroblast growth factor 9 has oncogenic activity and is a downstream target of
Wnt signaling in ovarian endometrioid adenocarcinomas.

Hendrix ND, Wu R, Kuick R, Schwartz DR, Fearon ER, Cho KR.

Department of Pathology, University of Michigan Medical School, 210 Washtenaw
Avenue, Ann Arbor, MI 48109, USA.

Wnt signaling plays a key role in development and adult tissues via effects on
cell proliferation, motility, and differentiation. The cellular response to Wnt
ligands largely depends on their ability to stabilize beta-catenin and the
ability of beta-catenin to bind and activate T-cell factor (TCF) transcription
factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have
constitutive activation of Wnt signaling as a result of oncogenic mutations in
the beta-catenin protein or inactivating mutations in key negative regulators of 
beta-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor
proteins. We used oligonucleotide microarrays to identify genes of which
expression was activated in OEAs with beta-catenin dysregulation compared with
OEAs lacking Wnt/beta-catenin pathway defects. Using microarray and quantitative 
PCR-based approaches, we found that fibroblast growth factor (FGF9) expression
was increased >6-fold in primary OEAs with Wnt/beta-catenin pathway defects
compared with OEAs lacking such defects. Evidence that beta-catenin and TCFs
regulate FGF9 expression in several epithelial cell lines was obtained. We found 
FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate 
invasion of epithelial and endothelial cells through Matrigel in transwell
assays. Furthermore, FGF9 could promote neoplastic transformation of the
E1A-immortalized RK3E epithelial cell line, and short hairpin RNA-mediated
inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which
carries a beta-catenin mutation, inhibited neoplastic growth properties of the
cells. Our findings support the notion that FGF9 is a key factor contributing to 
the cancer phenotype of OEAs carrying Wnt/beta-catenin pathway defects.

PMID: 16452189 [PubMed - indexed for MEDLINE]

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