Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas

Abstract

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 B-catenin and the ability of B-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 B-catenin protein or inactivating mutations in key negative regulators of B-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 B-catenin dysregulation compared with OEAs lacking Wnt/ B-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/B-catenin pathway defects compared with OEAs lacking such defects. Evidence that B-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 B-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/ B-catenin pathway defects. (Cancer Res 2006; 66(3): 1354-62)

Relationship between the localization of fibroblast growth factor 9 in prostate cancer cells and postoperative recurrence

“…Figure 5 shows that most FGF9-positive cancer cells were detected in poorly differentiated adenocarcinoma tissues; however, FGF9 is strongly expressed in stromal cells in both benign and malignant tissues. [4][5][6]11 These findings are consistent with previous studies of other malignant diseases. There may be a significant level of FGF9 in benign tissue.…”

“…19 Furthermore, FGF9 has an important role in the progression of several malignant diseases. [4][5][6]11 However, no study has demonstrated a correlation of FGF9 with biochemical recurrence after radical prostatectomy. The present findings demonstrate that FGF9 enhances proliferation and invasiveness in prostate cancer cells in vitro and the presence of FGF9-positive cancer cells shows a positive correlation with postoperative recurrence in prostate cancer.…”

“…4 FGF9 is a downstream target of the Wnt-signaling pathway in ovarian endometrioid adenocarcinoma. 5 Lung cancer shows acceleration of tumor growth by aryl hydrocarbon receptor through upregulation of FGF9 expression aryl hydrocarbon receptor. 6 These evidences indicate that FGF9 can be one of the key molecules for development and progression of malignant diseases.…”

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

“…To determine how DMGs contribute to MuOC pathogenesis, we next used the physical and genetic interactions from the BioGRID database,33 and integrated the coexpression of mRNA profiles,34 to identify the functional network of DMGs and their interactors. The entire functional and three separately predominant functional networks are shown in Figure 3 a .…”

“…The first and second level of interactor directly interacts with DM genes and the first level of interactor, respectively. We kept the interactions as the edge of paired nodes by computing the Pearson correlation coefficient from the MuOC transcriptomic data (GSE6008) 34. The interactions were significantly coexpressed with positive correlation coefficient r  ≥ 0.55 and p values <0.05.…”