Disease relevance of WFDC2

• The WFDC2 (HE4) gene is amplified in ovarian carcinomas, whereas its expression in normal tissues, including ovary, is low [1].
• We also suggest that WFDC2 re-expression in lung carcinomas may prove to be associated with tumour type and should be studied in further detail [2].
• The majority of adenocarcinomas stain with WFDC2 whilst a significant minority of squamous, small cell and large cell carcinomas exhibit focal staining [2].
• Significant increases in expression and localisation of WFDC2 are seen in patients with Cystic Fibrosis [2].

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

• Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas [3].

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

• One of these proteins, which contains two WAP domains, is HE4 (also known as WFDC2), originally described as an epididymis specific protein but more recently suggested to be a putative serum tumour marker for ovarian cancer [4].
• RESULTS: WFDC2 is expressed in some epithelial cells of the upper airways as well as in mucous cells and ducts of submucosal glands [2].
• METHODS: We used immunohistochemistry to localise WFDC2 in normal tissues of the respiratory tract, naso- and oropharynx, as well as in chronically inflamed lung from Cystic Fibrosis and a range of pulmonary carcinomas [2].
• Subsequently, protein produced in mammalian cells was purified by affinity chromatography and used to immunize mice to generate hybridomas specific for HE4 [1].
• 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 [3].

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

• Two probes for the HE1 and HE4 gene products were found to recognize tissue-specific transcripts in all three species, with a regionally differential distribution within the epididymis [8].
• This approach confirmed up-regulation of WAP four-disulfide core domain 2 (WFDC2) and SLPI during the expected window of receptivity [9].

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].

References