WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation

Yaoyi Xiong,Huimin Xu,Yu Xiao,Lingao Ju,Song Chen,Gang Wang,Lushun Yuan,Xinghuan Wang,Tianchen Peng

doi:10.1038/s41419-020-02752-y

Abstract

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.

Highlights

Prostate cancer has the highest incidence of any malignancy in men in many regions worldwide
We further proved that WAP four-disulfide core domain 2 (WFDC2) binds to the extracellular domain of epidermal growth factor receptor (EGFR)
Our results suggest that the secreted protein WFDC2 binds to the extracellular domain of EGFR to inhibit the activation of EGFR and inhibits PCa metastasis (Fig. 4e)

Summary

Introduction

Prostate cancer has the highest incidence of any malignancy in men in many regions worldwide. Once primary prostate cancer progresses to metastatic prostate cancer, patients have a poor outcome. Metastasis is the leading cause of death in the majority of patients with cancer, including prostate cancer[3]. HE4 serves as a serum biomarker of ovarian cancer, and has better sensitivity and specificity than CA12510. Several papers have revealed that HE4 is correlated with the metastasis of ovarian cancer[11,12]. We found that WFDC2 is downregulated in prostate cancer compared to ovarian cancer. This raised our interest regarding the function of WFDC2 in prostate cancer

Methods

Results

Conclusion