Fibroblast growth factor 9 has oncogenic activity and is a downstream target of Wnt signaling in ovarian endometrioid adenocarcinomas.
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.
Hendrix
Neali D
ND
Department of Pathology, University of Michigan Medical School, 210 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
Wu
Rong
R
Kuick
Rork
R
Schwartz
Donald R
DR
Fearon
Eric R
ER
Cho
Kathleen R
KR
D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation; D051155:Wnt1 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D012333:RNA, Messenger; D051155:Wnt1 Protein; D051176:beta Catenin