WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation
WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation
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DOI：
10.1038/s41419-020-02752-y
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发表时间：
2020-07-16
影响因子：
9
通讯作者：
Wang, Xinghuan
中科院分区：
文献类型：
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作者：
Xiong, Yaoyi;Yuan, Lushun;Wang, Xinghuan
WAP4-二硫键核心区2(WFDC2)是一种小分子分泌型蛋白，在卵巢癌中得到了广泛的研究。已证实WFDC2促进卵巢癌的增殖和转移，是一种诊断生物标志物。然而，WFDC2在前列腺癌中的具体功能尚未见报道。在这里，我们首先通过生物信息学筛选前列腺癌的诊断标志物和有利的预后因素WFDC2。WFDC2的表达与前列腺癌的Gleason评分和转移呈负相关。然后，我们发现WFDC2的过表达和重组蛋白HE4的加入在体内和体外都能显著抑制前列腺癌的转移。通过免疫共沉淀和共定位分析，我们证明了WFDC2与表皮生长因子受体(EGFR)的胞外区结合。免疫印迹显示，WFDC2的过表达和重组蛋白HE4的加入使EGFR/AKT/GSK3B/Snail信号通路失活，从而抑制上皮细胞向间充质细胞的转化。综上所述，我们的研究证实了肿瘤抑制基因WFDC2可以通过抑制EGFR信号通路来抑制前列腺癌的转移。
WAP four-disulfide core domain 2 (WFDC2) is a small secretory protein that has been widely studied in ovarian cancer. It has been proven that WFDC2 promotes proliferation and metastasis in ovarian cancer, and serves as a diagnostic biomarker. However, the specific function of WFDC2 in prostate cancer has not been reported. Here, we first screened the diagnostic marker and favorable prognostic factor WFDC2 in prostate cancer by bioinformatics. WFDC2 expression was negatively correlated with Gleason score and metastasis in prostate cancer. Then, we revealed that overexpression of WFDC2, and addition of recombinant protein HE4 can significantly inhibit prostate cancer metastasis in vivo and in vitro. By co-immunoprecipitation and co-localization assays, we proved that WFDC2 binds to the extracellular domain of epidermal growth factor receptor (EGFR). Immunoblot showed that WFDC2 overexpression and recombinant protein HE4 addition inactivated the EGFR/AKT/GSK3B/Snail signaling pathway, and then restrained the progression of epithelial-mesenchymal transition. In conclusion, our study identified that the tumor suppressor WFDC2 can suppress prostate cancer metastasis by inactivating EGFR signaling.