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Gene Review

WFDC2  -  WAP four-disulfide core domain 2

Homo sapiens

Synonyms: EDDM4, Epididymal secretory protein E4, HE4, Major epididymis-specific protein E4, WAP four-disulfide core domain protein 2, ...
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Disease relevance of WFDC2


High impact information on WFDC2

  • Among the genes most commonly identified in gene expression profiles of epithelial ovarian carcinomas (EOC) is the gene for human epididymis protein 4 (HE4) [3].
  • 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 [3].
  • Using reverse transcription-PCR, we identified ovarian cancer cell lines that endogenously overexpress HE4 [3].
  • Therefore, HE4 is a secreted glycoprotein that is overexpressed by serous and endometrioid EOCs [3].
  • 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 [3].

Chemical compound and disease context of WFDC2


Biological context of WFDC2

  • The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms [4].
  • We have complemented these studies with molecular analysis of WFDC2 gene expression in primary human lung cell cultures [2].
  • A fusion gene was constructed encoding the HE4 protein fused to a gene encoding the murine IgG2a Fc domain [1].
  • AIM: Identification of the rodent counterparts of human and canine epididymal cDNAs HE3, HE4 and Ce8/Ly6G5C by sequence homology and analysis of their expression patterns and regulation level in the rat [5].
  • The HE4 bead-based assay showed lower reproducibility but yielded an AUC of 0.89 in receiver operating characteristics analysis [6].

Anatomical context of WFDC2


Associations of WFDC2 with chemical compounds

  • These substances may include, but are not limited to, diazepam, oxazepam and desmethyldiazepam, but do not include substances commonly elevated in the plasma and CSF of patients with HE4 [7].

Regulatory relationships of WFDC2

  • In cultures of tracheobronchial epithelial cells, expression of WFDC2 and SLPI are differentially regulated during differentiation yet WFDC2 is not induced by pro-inflammatory mediators [2].

Other interactions of WFDC2


Analytical, diagnostic and therapeutic context of WFDC2

  • 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 [1].
  • Comparison of multiple HE4 cDNAs and RT-PCR products with genomic sequence allowed the elucidation of the genomic organization [4].
  • Northern blot and in situ transcript hybridization specifically localized the HE4 (human epididymis gene product) mRNA to the epithelial cells of the epididymal duct, predominantly within the distal sections [10].
  • Here, we examined the expression of the HE4 gene and protein in a large series of normal and malignant adult tissues by oligonucleotide microarray and tissue microarray, respectively [11].
  • METHODS: To investigate transcriptional targeting in ovarian cancer gene therapy, we isolated a region of the HE4 promoter from -530 to +122 (pHE4-652; relative to the ATG start site of HE4) and placed it upstream of a luciferase reporter gene plasmid to generate pHE4-652-luc [12].


  1. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Hellström, I., Raycraft, J., Hayden-Ledbetter, M., Ledbetter, J.A., Schummer, M., McIntosh, M., Drescher, C., Urban, N., Hellström, K.E. Cancer Res. (2003) [Pubmed]
  2. WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Bingle, L., Cross, S.S., High, A.S., Wallace, W.A., Rassl, D., Yuan, G., Hellstrom, I., Campos, M.A., Bingle, C.D. Respir. Res. (2006) [Pubmed]
  3. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Drapkin, R., von Horsten, H.H., Lin, Y., Mok, S.C., Crum, C.P., Welch, W.R., Hecht, J.L. Cancer Res. (2005) [Pubmed]
  4. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Bingle, L., Singleton, V., Bingle, C.D. Oncogene (2002) [Pubmed]
  5. Rodent epididymal cDNAs identified by sequence homology to human and canine counterparts. Kappler-Hanno, K., Kirchhoff, C. Asian J. Androl. (2003) [Pubmed]
  6. Bead-based ELISA for validation of ovarian cancer early detection markers. Scholler, N., Crawford, M., Sato, A., Drescher, C.W., O'Briant, K.C., Kiviat, N., Anderson, G.L., Urban, N. Clin. Cancer Res. (2006) [Pubmed]
  7. The involvement of the benzodiazepine receptor in hepatic encephalopathy: evidence for the presence of a benzodiazepine receptor ligand. Basile, A.S., Ostrowski, N.L., Gammal, S.H., Jones, E.A., Skolnick, P. Adv. Biochem. Psychopharmacol. (1990) [Pubmed]
  8. Tissue-specific gene expression as an indicator of epididymis-specific functional status in the boar, bull and stallion. Uhlenbruck, F., Sinowatz, F., Amselgruber, W., Kirchhoff, C., Ivell, R. Int. J. Androl. (1993) [Pubmed]
  9. Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Ace, C.I., Okulicz, W.C. Reprod. Biol. Endocrinol. (2004) [Pubmed]
  10. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Kirchhoff, C., Habben, I., Ivell, R., Krull, N. Biol. Reprod. (1991) [Pubmed]
  11. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Galgano, M.T., Hampton, G.M., Frierson, H.F. Mod. Pathol. (2006) [Pubmed]
  12. Transcriptional targeting in ovarian cancer cells using the human epididymis protein 4 promoter. Berry, N.B., Cho, Y.M., Harrington, M.A., Williams, S.D., Foley, J., Nephew, K.P. Gynecol. Oncol. (2004) [Pubmed]
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