Human Epididymis Protein 4 (HE4) Is a Secreted Glycoprotein that Is Overexpressed by Serous and Endometrioid Ovarian Carcinomas

Abstract

Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4). To ascertain its clinical utility, we did a comprehensive assessment of HE4 protein expression in benign and malignant ovarian and nonovarian tissues by immunohistochemistry. In comparison with normal surface epithelium, which does not express HE4, we found that cortical inclusion cysts lined by metaplastic Mullerian epithelium abundantly express the protein. Its expression in tumors was restricted to certain histologic subtype: 93% of serous and 100% of endometrioid EOCs expressed HE4, whereas only 50% and 0% of clear cell carcinomas and mucinous tumors, respectively, were positive. Tissue microarrays revealed that the majority of nonovarian carcinomas do not express HE4, consistent with our observation that HE4 protein expression is highly restricted in normal tissue to the reproductive tracts and respiratory epithelium. HE4 is predicted to encode a secreted protein. Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4. Cultured medium from these cells revealed a secreted form of HE4 that is Nglycosylated. This observation is consistent with the recent report that HE4 circulates in the bloodstream of patients with EOC. Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs. Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs. (Cancer Res 2005; 65(6): 2162-9)

Comprehensive analysis of HE4 expression in normal and malignant human tissues

“…In agreement with other studies, 12,13,15,16 most of the ovarian surface epithelial tumors, with the exception of mucinous type, were immunoreactive for HE4. Significant staining was also identified in endometrial, lung, breast, and pancreaticobiliary carcinomas, as well as various renal, thyroid and salivary gland neoplasms, and malignant mesotheliomas.…”

“…[3][4][5] In malignant neoplasms, gene expression profiling studies have consistently identified upregulation of HE4 in carcinomas of the ovary, [6][7][8][9][10][11][12][13][14] and several studies have analyzed HE4 protein expression in ovarian neoplasms, providing the opportunity for its application in histopathologic diagnosis. 12,13,15,16 Moreover, recent studies have shown elevated HE4 protein levels in serum from patients with ovarian tumors, demonstrating a similar sensitivity to CA125, but increased specificity for malignant tumors as compared to benign disease. 17 However, the examination of HE4 in other common malignancies, benign lesions, and normal tissues has not occurred to a large scale.…”

Physiopathological factors affecting the diagnostic value of serum HE4-test for gynecologic malignancies

“…Ovarian inclusion cyst often shows positive HE4 immunostaining [27]. HE4 expression in ovarian inclusion cysts was mainly present in cysts lined by the Mullerian epithelium but not the ovarian surface epithelium [56].…”

Urinary Concentrations of Human Epidydimis Secretory Protein 4 (He4) in The Diagnosis of Ovarian Cancer: A Case-Control Study

“…Human epidydimis secretory proteins in the cell can be found in the cytoplasm perinucleary as endoplasmatic network structure. There is glycosylation and release of the HE4 in extracellular environment from ovarian cancer cells (Drapkin et al, 2005). Ovarian cancer associated antigen CA125 is increased in 40-50% of early stage ovarian cancer patients (Rosen et al, 2005), but there have been documented that human epidydimis secretory protein 4 is increased in 82.7-90.0% cases of early stage ovarian cancers (Havrilesky et al, 2008), moreover, HE4 is RESEARCH ARTICLE elevated in more than 50% of cases when the CA125 assay values are within the normal range (Moore et al, 2007).…”

“…More expressed human epidydimis secretory protein 4 has been detected in tissues of serous and endometrioid ovarian cancers (Drapkin et al, 2005). Lower serum HE4 concentrations have been observed in patients with early stage ovarian cancer.…”