HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines

Abstract

HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.

Tissue expression of human epididymal secretory protein 4 may be useful in the differential diagnosis of uterine cervical tumors

“…Because CA 125 is often elevated in benign conditions or as a result of physiologic changes in premenopausal women, it has not any confirmed role in the early detection of gynecologic cancers. Since abnormal levels of HE4 have been less frequently encountered in benign gynecological conditions HE4 may have increased specificity in differentiating between benign and malignant conditions [2][3][4][5][6][7]. In the present study, we have found that HE4 tissue expression increased in carcinomas, but decreased in intraepithelial neoplasia.…”

“…Conversely, HE4 overexpression has not been detected in ovarian mucinous tumors [4][5][6], non-epithelial ovarian cancers, sex cord stromal tumors and germ cell tumors. However overexpression of HE4 has been detected in primary tuba uterina carcinomas and endometrial malignancies [2][3][4][5][6][7]. Among non-gynecological cancers, HE4 expression has been also demonstrated in various subtypes of lung cancer [12].…”

“…HE4 contains four disulfide core proteins and due to similarities with other whey acidic protein family members, it functions as a proteinase inhibitor [2,3]. Firstly, presence of HE4 in the distal regions of the epithelial cells of the epididymal duct, suggests its roles in sperm maturation [1][2][3][4][5].…”

Human Epididymis Protein 4 (HE4) mRNA as a Prognostic Marker in Ovarian Tumors in Relation to RMI and CA125

“…Tumorigenesis is an early event associated with malignant transformation and tumor growth promotion, a process more closely associated with tumor growth and metastasis, Some tumorigenic factors contribute to malignant transformation but not necessarily tumor growth and/or metastasis and vice versa (Li et al, 2013). Genetic and hormonal alterations are considered two major etiological factors for ovarian cancer development.…”

“…In humans, HE4, SLPI and several other WAP members co-locate in 20q (Bouchard et al, 2006) a region frequently amplified in a variety of cancers (Van Dekken et al, 2001). HE4, a putative protease inhibitor containing two WAP (Whey Acid Protein) domains (Li et al, 2013) has been used widely for the early screening (Winstead, 2009;Scholler et al, 2006) and for differential diagnosis (Huhtinen et al, 2009;Montagnana et al, 2009) of ovarian cancer, as well as for monitoring disease recurrence (Anastasi et al, 2010) and progression (Kobel et al, 2008). Its role in tumorogenesis is investigated by forced over expression of HE4 that promoted several malignant phenotypes including cell proliferation, cell invasion capability, anchorage independent growth and increased tumor growth (Li et al, 2013).…”