WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway.
WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway.
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DOI：
10.1158/1541-7786.mcr-11-0177
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Hayashi K
中科院分区：
文献类型：
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作者：
Yoshioka S;King ML;Ran S;Okuda H;MacLean JA 2nd;McAsey ME;Sugino N;Brard L;Watabe K;Hayashi K
WNT/β-catenin信号通路的异常激活与卵巢癌有关，但具体的WNT配体和相关的下游机制尚不完全清楚。本研究中，我们在浆液性卵巢癌的上皮中发现了丰富的WNT7A，而在交界性和良性肿瘤、正常卵巢和子宫内膜样癌中未发现WNT7A。为了研究WNT7A在卵巢肿瘤生长和进展中的作用，我们分别向裸鼠腹腔（i.p.）或皮下（s.c.）注射敲除的WNT7A SKOV3。ip1和过表达SKOV3细胞。在i.p.组，小鼠接受SKOV3。WNT7A表达降低的ip1细胞发生的肿瘤病变明显减少。大体和组织学检查显示，与对照细胞相比，WNT7A敲低细胞对肠系膜和浆膜的侵袭大大减少。在接受sc注射的小鼠中，WNT7A的缺失或过表达也能调节肿瘤的生长。体外细胞功能分析显示，WNT7A可调节细胞增殖、粘附和侵袭。卵巢癌细胞中过表达WNT7A可刺激TCF/LEF报告基因的活性。与WNT7A和FZD5受体共转染进一步增加了活性，而与SFRP2或显性阴性TCF4共转染可抑制这种作用。过表达WNT7A刺激MMP7启动子，MMP7启动子中TCF结合位点的突变证实WNT7A激活MMP7启动子是通过β-catenin/TCF信号介导的。综上所述，这些结果表明卵巢上皮细胞恶性转化过程中WNT7A的重新表达在WNT/β-catenin信号通路介导的卵巢癌进展中起着关键作用。
Abnormal activation the WNT/β-catenin signaling pathway has been associated with ovarian carcinomas, but a specific WNT ligand and pertinent downstream mechanisms are not fully understood. In this study, we found abundant WNT7A in the epithelium of serous ovarian carcinomas, but not detected in borderline and benign tumors, normal ovary or endometrioid carcinomas. To characterize the role of WNT7A in ovarian tumor growth and progression, nude mice were injected either intraperitoneally (i.p.) or subcutaneously (s.c.) with WNT7A knocked down SKOV3.ip1 and overexpressed SKOV3 cells. In the i.p. group, mice receiving SKOV3.ip1 cells with reduced WNT7A expression developed significantly fewer tumor lesions. Gross and histological examination revealed greatly reduced invasion of WNT7A knockdown cells into intestinal mesentery and serosa compared to the control cells. Tumor growth was regulated by loss or overexpression of WNT7A in mice receiving s.c. injection as well. In vitro analysis of cell function revealed that cell proliferation, adhesion, and invasion were regulated by WNT7A. The activity of the TCF/LEF reporter was stimulated by overexpression of WNT7A in ovarian cancer cells. Co-transfection with WNT7A and FZD5 receptor further increased activity, and this effect was inhibited by co-transfection with SFRP2, or dominant-negative TCF4. Overexpression of WNT7A stimulated MMP7 promoter, and mutation of TCF binding sites in MMP7 promoter confirmed that activation of MMP7 promoter by WNT7A was mediated by β-catenin/TCF signaling. Collectively, these results suggest that re-expression of WNT7A during malignant transformation of ovarian epithelial cells plays a critical role in ovarian cancer progression mediated by WNT/β-catenin signaling pathway.