{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWFDC2 (also known as HE4) encodes a secreted glycoprotein belonging to the family of WAP (whey acidic protein)‐type four disulfide core domain proteins. Under normal physiological conditions its expression is low, being largely restricted to epithelia of the reproductive tract and respiratory system. However, multiple independent studies have shown that WFDC2 is markedly overexpressed in ovarian carcinomas and certain endometrial and other gynecological cancers, where its mRNA is often amplified. This overexpression translates into high levels of secreted HE4 protein that can be detected in body fluids such as serum and urine. Such findings have spurred extensive investigations into its utility as a diagnostic biomarker for distinguishing malignant from benign disease and for monitoring recurrence. Moreover, efforts to establish age‐ and cycle‐dependent reference ranges underscore its potential in clinical screening and risk stratification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as a biomarker, functional studies have revealed that HE4 actively contributes to tumor progression. Experimental models demonstrate that increased HE4 expression promotes cancer cell adhesion, migration, and proliferation while facilitating xenograft tumor growth and chemoresistance. Molecular investigations indicate that HE4 may modulate key signaling pathways—such as those mediated by EGFR and MAPK—and interact directly with growth factor receptors (including IGF1R) as well as transcription regulators like HIF1α. In addition, biochemical assays have characterized HE4 as a putative serine protease inhibitor that suppresses the activity of proteases (including matrix metalloproteinases and specific serine proteases) implicated in extracellular matrix remodeling and collagen degradation, a feature particularly relevant in fibrotic kidney disease. Collectively, these mechanistic insights extend the utility of HE4 beyond diagnosis, suggesting that its altered expression and activity can serve as a prognostic indicator and potential therapeutic target in ovarian, lung, endometrial, and even pancreatic cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "47"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ingegerd Hellström, John Raycraft, Martha Hayden-Ledbetter, et al. 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