Overexpression of HE4 (human epididymis protein 4) enhances proliferation, invasion and metastasis of ovarian cancer.

Liancheng Zhu,Lu Deng,Huimin Wang,Juanjuan Liu,Yingying Hao,Huiyu Zhuang,Carlton L Schwab,Bei Lin,Jian Gao,Mingzi Tan,Song Gao,Xiao Li

doi:10.18632/oncotarget.6327

Abstract

Overexpression of Human epididymis protein 4 (HE4) related with a role in ovarian cancer tumorigenesis while little is known about the molecular mechanism alteration by HE4 up regulation. Here we reported that overexpressed HE4 promoted ovarian cancer cells proliferation, invasion and metastasis. Furthermore, human whole genome gene expression profile microarrays revealed that 231 differentially expressed genes (DEGs) were altered in response to HE4, in which MAPK signaling, ECM receptor, cell cycle, steroid biosynthesis pathways were involved. The findings suggested that overexpressed HE4 played an important role in ovarian cancer progression and metastasis and that HE4 has the potential to serve as a novel therapeutic target for ovarian cancer.

Highlights

Ovarian cancer is a kind of highly aggressive tumors associated with high mortality and morbidity in gynecology, it’s the second cause of death among female reproductive malignancies and claims 140 200 lives each year [1]
More findings showed that serum Human epididymis protein 4 (HE4) during first-line chemotherapy could predict chemotherapy response [8], and it seems to be a good predictor of response and outcome in the neoadjuvant chemotherapy for those late stage high-grade serous ovarian cancer patients [9], and high HE4 serum levels correlated with chemoresistance and decreased survival rates in epithelial ovarian cancer (EOC) patients [10, 11]
Recent studies showed that HE4 is associated with ovarian cancer cell adhesion, migration, proliferation, tumor growth and chemoresistance, which can be related to the activity of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and insulin [10, 12, 13], these HE4–mediated invasion and metastasis may be promoted by its Lewis y fucosylation [14]

Summary

Introduction

Ovarian cancer is a kind of highly aggressive tumors associated with high mortality and morbidity in gynecology, it’s the second cause of death among female reproductive malignancies and claims 140 200 lives each year [1]. Human epididymis protein 4 (HE4), known as whey-acidic-protein (WAP) four-disulfide core domain protein 2 (WFDC2), is a glycoprotein highly expressed in epithelial ovarian cancer (EOC) [3] and identified as a serum marker possessing higher sensitivity, specificity than CA125 in the confirmatory early diagnosis for EOC [4,5,6] It shows better sensibility and specificity in the diagnosis of EOC recurrence with respect to CA125 and seems to be an independent predictive factor for the ideal tumor cytoreductive surgery and to maintain its prognostic role even after the recurrence [7]. The gene expression profile, especially the pathways generated from this investigation might lead to a better understanding about the molecular mechanisms associated with the HE4 in ovarian cancer

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