Fibroblast growth factor 9 has oncogenic activity and is a downstream target of Wnt signaling in ovarian endometrioid adenocarcinomas
Fibroblast growth factor 9 has oncogenic activity and is a downstream target of Wnt signaling in ovarian endometrioid adenocarcinomas
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DOI：
10.1158/0008-5472.can-05-3694
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Cho, KR
中科院分区：
文献类型：
--
作者：
Hendrix, ND;Wu, R;Cho, KR
Writ信号通过影响细胞增殖、运动和分化在发育和成体组织中起关键作用。对Wnt配体的细胞应答在很大程度上取决于它们稳定β-连环蛋白的能力以及β-连环蛋白结合和激活T细胞因子（TCF）转录因子的能力。由于β-连环蛋白的致癌突变或β-连环蛋白的关键负调节因子如腺瘤性结肠息肉病和Axin肿瘤抑制蛋白的失活突变，大约40%的卵巢类腺瘤腺癌（OEA）具有Writ信号传导的组成性激活。我们使用寡核苷酸微阵列来鉴定与缺乏Wnt/β-catenin通路缺陷相比，在β-catenin失调的OEAs中表达被激活的基因。使用微阵列和基于定量PCR的方法，我们发现与缺乏Wnt/β-连环蛋白通路缺陷的OEAs相比，在具有Wnt/β-连环蛋白通路缺陷的原发性OEAs中成纤维细胞生长因子（FGF 9）表达增加> 6倍。获得了β-连环蛋白和TCFs调节几种上皮细胞系中FGF 9表达的证据。我们发现FGF 9对上皮细胞和成纤维细胞具有促有丝分裂作用，并且FGF 9可以通过Matrigel刺激上皮细胞和内皮细胞的侵袭。此外，FGF 9可以促进E1 A永生化RK 3E上皮细胞系的肿瘤转化，并且短发夹RNA介导的OEA细胞系TOV 112 D中内源性FGF 9表达的抑制，其携带β-连环蛋白突变，抑制了细胞的肿瘤生长特性。我们的研究结果支持这样的观点，即FGF 9是导致携带Wnt/β-连环蛋白通路缺陷的OEAs的癌症表型的关键因素。
Writ 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 Writ 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.