The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Hellström I et al. (2003) The WFDC2 (HE4) gene is amplified in ovarian carcinomas, whereas its expression in normal tissues, including ovary, is low. Although the function of the HE4 protein is unknown,it is a member of a family of stable 4-disulfide core proteins that are secreted at high levels. We therefore performed experiments to explore whether quantitation of HE4 protein levels in serum can be used as a biomarker for ovarian carcinoma. A fusion gene was constructed encoding the HE4 protein fused to a gene encoding the murine IgG2a Fc domain. Subsequently, protein produced in mammalian cells was purified by affinity chromatography and used to immunize mice to generate hybridomas specific for HE4. Hybridoma supernatants were screened for binding to a similar fusion protein that, instead, had a human immunoglobulin tail. Two hybridomas, 2H5 and 3D8, were selected that produce monoclonal antibodies to different HE4 epitopes, and a double determinant ("Sandwich") ELISA was constructed and shown to detect a signal at the 160-pg level. Blinded studies on sera from postmenopausal patients with ovarian carcinoma and controls indicate that the specificity and sensitivity of the HE4-based ELISA is equivalent to that of the CA125 assay. However, the HE4 assay may have an advantage over the CA125 assay in that it is less frequently positive in patients with nonmalignant disease.//////////////////
NCBI Summary:
This gene encodes a protein that is a member of the WFDC domain family. The WFDC domain, or WAP Signature motif, contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor in many family members. This gene is expressed in pulmonary epithelial cells, and was also found to be expressed in some ovarian cancers. The encoded protein is a small secretory protein, which may be involved in sperm maturation. [provided by RefSeq, Jul 2008]
General function
Protease inhibitor
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Cellular localization
Secreted
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Ovarian tumor marker HE4 is differently expressed during the phases of the menstrual cycle in healthy young women. Anastasi E et al. (2010) The objective of the present study was to investigate in healthy young women the fluctuations in serum concentration of human epididymal secretory protein human epididymis-specific protein 4 (HE4) and CA125 during the phases of the menstrual cycle and the correlation between HE4 and CA125 values and age. Forty women with regular menstrual cycles were included in the study. Pelvic and transvaginal ultrasound were performed in order to exclude ovarian pathologies. Blood samples were collected at follicular (FP), ovulatory (OP), and luteal (LP) phases of the hormonal cycle. The values of HE4 (expressed as picomoles per liter) observed were (mean ± SEM) 39.1 ± 1.1 (FP), 45.3 ± 1.19 (OP), and 42.0 ± 1.3 (LP). The difference between FP and OP was statistically significant (p = 0.0002). By contrast, serum CA125 levels (expressed as units per milliliter) were 14.35 ± 0.66 (FP), 13.15 ± 0.54 (OP), and 13.70 ± 0.54 (LP), respectively. The levels of HE4 observed in serum samples of women below 35 years were 37.5 ± 1.28 in the FP, 46.6 ± 1.4 in the OP, and 42.8 ± 1.49 in the LP. In this group, a statistically significant difference was observed in the FP compared with the OP (p < 0.0001), whereas no statistically significant difference was observed during the different hormonal phases in the group of women over 35. In conclusion, the correct interpretation of laboratory data is essential to define a threshold of normality, and for what concerns HE4 levels, the menstrual cycle phase-dependent variability appears indicated in the interpretation of the results.//////////////////
Ovarian function
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Expression regulated by
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Ovarian localization
, Follicular Fluid
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Human follicular fluid proteome reveals association between overweight status and oocyte maturation abnormality. Liu X et al. (2020) Human follicular fluid (HFF), which is composed by essential proteins required for the follicle development, provides an important microenvironment for oocyte maturation. Recently, overweight status has been considered as a detrimental impact factor on oocyte maturation, but whether HFF proteome could provide protein markers for assessing overweight-based oocyte maturation deficiency is still unknown. To reveal the HFF-based molecular characteristics associated with abnormal oocyte maturation, an iTRAQ-based comparative proteomic analysis was performed to investigate different HFF protein expression profiles from normal weight women and overweight status women. Two hundred HFF proteins were quantified in our data, of which 43% have not been overlapped by two previous publications. Compared with the HFF proteins of normal weight women, 22 up-regulated HFF proteins and 21 down-regulated HFF proteins were found in the overweight status women. PANTHER database showed these altered HFF proteins participated in development, metabolism, immunity, and coagulation, and STRING database demonstrated their complicated interaction networks. The confidence of proteomic outcome was verified by Western blot analysis of WAP four-disulfide core domain protein 2 (WFDC2), lactotransferrin (LTF), prostate-specific antigen (KLK3), fibronectin (FN1), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Further, ELISA assay indicated WFDC2 might be a potentially useful candidate HFF marker for the diagnosis of oocyte maturation arrest caused by overweight status. Our work provided a new complementary high-confidence HFF dataset involved in oocyte maturation, and these altered HFF proteins might have clinical relevance and diagnostic and prognostic value for abnormal oocyte maturation in overweight status women.//////////////////