Abstract
BackgroundWAP four-disulfide core domain protein 2 (WFDC2) shows a tumor-restricted upregulated pattern of expression in ovarian cancer.MethodsWe investigated the role of estradiol (E2) on cell growth in estrogen-sensitive or estrogen-insensitive ovarian cancer cell lines. Real-time (RT)-PCR and western blotting were used to examine the expression of WFDC2 at RNA and protein levels. Growth traits of cells transfected with WFDC2-shRNA or blank control were assessed using MMT arrays. Cell apoptosis was analyzed using annexin V-FITC/PI and flow cytometry. Estrogen receptor expression was evaluated using RT-PCR and flow cytometry. Apoptosis-related proteins induced by E2 directly and indirectly were determined using an antibody array comparing cells transfected with WFDC2- shRNA or a blank control.ResultsHigh-dose (625 ng/ml) E2 increased the expression of WFDC2 in HO8910 cells at both the mRNA and protein levels. However, E2 had no effect on WFDC2 expression in estrogen-insensitive SKOV3 cells. Of interest, knockdown of WFDC2 enabled a considerable estrogen response in SKOV3 cells in terms of proliferation, similar to estrogen-responsive HO8910 cells. This transformation of SKOV3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor beta (ERß) and an effect on cell apoptosis under E2 treatment by regulating genes related to cell proliferation and apoptosis.ConclusionsWe postulate that increased WFDC2 expression plays an important role in altering the estrogen pathway in ovarian cancer, and the identification of WFDC2 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-015-0210-y) contains supplementary material, which is available to authorized users.
Highlights
WAP four-disulfide core domain protein 2 (WFDC2) shows a tumor-restricted upregulated pattern of expression in ovarian cancer
We investigated the regulatory effects of estrogen and estrogen antagonist on WFDC2 gene expression in estrogen sensitive HO8910 cells and estrogen insensitive SKOV3 cells, with the aim to determine whether WFDC2 is an estrogen-responsive gene
High-dose E2 induces expression of WFDC2 in HO8910 cells To determine if HE4/WFDC2 is a downstream target of E2 signaling pathways, we induced the expression of the WFDC2 gene by adding E2 into the culture of HO8910 cells using a range of concentrations (0, 5, 25, 125, 625 and 1250 ng/ml)
Summary
WAP four-disulfide core domain protein 2 (WFDC2) shows a tumor-restricted upregulated pattern of expression in ovarian cancer. The underlying causes of ovarian cancer are poorly understood and largely untested, but estrogen, as a major steroidal product of the ovary, has been shown to be associated with increased ovarian cancer risk in estrogen receptor (ER)-expressing cells [3,4,5]. HE4 exhibits a tumor-restricted, upregulated pattern of expression in ovarian cancer, making it a potential marker [12, 14, 15]. The majority of studies have focused on the potential value of HE4 as a diagnostic using various serologic tests, but very little attention has been paid to the role of HE4 in tumor development of ovarian cancer [12, 14, 17]
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