Affinage

WFDC2

WAP four-disulfide core domain protein 2 · UniProt Q14508

Length
124 aa
Mass
13.0 kDa
Annotated
2026-06-11
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WFDC2 (HE4) is a small, secreted, N-glycosylated WAP-domain protein that acts as an extracellular signaling ligand controlling epithelial homeostasis, tissue remodeling, and tumor progression (PMID:15781627, PMID:32678075). Its biology centers on engagement of cell-surface receptors and activation of downstream signaling: WFDC2 binds the extracellular domain of EGFR and, depending on context, modulates EGFR/AKT/GSK3B/Snail signaling and epithelial-mesenchymal transition (PMID:32678075), while in ovarian cancer it drives EMT and invasion through PI3K/AKT-dependent induction of MMP-2 (PMID:31118763) and activation of JAK/STAT3 signaling (PMID:31477564). WFDC2 also forms a cytoplasmic and membrane-associated ternary complex with ANXA2 and MMP-2, using ANXA2 as a bridge to promote migration (PMID:31210752). Beyond canonical surface signaling, WFDC2 undergoes importin-4-mediated nuclear and nucleolar translocation upon EGF, VEGF, insulin, or estrogen stimulation and interacts with EGFR, IGF1R, HIF1α, and ER-α (PMID:24389815, PMID:24975515). WFDC2 shapes the tumor and tissue microenvironment by activating STAT3 to induce pro-angiogenic genes (IL8, HIF1A) (PMID:32444701) and by fostering immunosuppression through PD-L1 induction, M2 macrophage recruitment, and suppression of cytotoxic lymphocyte activity (PMID:33903172, PMID:29745428). A recurring fibrotic and inflammatory axis operates through NF-κB: WFDC2 activates p65 phosphorylation and nuclear translocation to drive ECM accumulation and renal fibrosis via TIMP-1/MMP-2 (PMID:31909536), promotes IL-33-dependent gastric metaplasia and M2 polarization (PMID:34116028), and is itself induced by TNF-α and CFTR dysfunction through NF-κB (PMID:34054511). In vivo, Wfdc2 is essential for neonatal lung function: knockout mice die from respiratory failure with type-I alveolar cell apoptosis, absent mature club cells, malformed lamellar bodies, and aberrant pro-inflammatory activation (PMID:31780266, PMID:31562139). Biallelic loss-of-function variants in WFDC2 cause human nasal polyposis and bronchiectasis, with a founder p.Cys49Arg substitution that disrupts glycosylation and blocks secretion of the mature protein, establishing that secretion is required for normal airway function (PMID:38626355).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 Medium

    Established the basic biochemical identity of HE4 as a secreted, N-glycosylated protein, defining it as an extracellular factor rather than an intracellular enzyme.

    Evidence Conditioned-medium analysis and N-glycosylation characterization from HE4-overexpressing ovarian cancer lines

    PMID:15781627

    Open questions at the time
    • No receptor or binding partner identified
    • Function of the secreted protein not addressed
  2. 2013 Medium

    Showed that HE4 is not merely a biomarker but a direct driver of tumor progression, motivating mechanistic dissection of its signaling.

    Evidence Stable HE4 overexpression with proliferation, invasion, soft-agar colony and xenograft assays in endometrial cancer cells

    PMID:23502467

    Open questions at the time
    • Receptor and downstream pathway unresolved
    • Single tumor type
  3. 2014 Medium

    Revealed an unexpected intracellular dimension by showing growth-factor- and estrogen-stimulated importin-4-dependent nuclear/nucleolar translocation and interactions with EGFR, IGF1R, HIF1α and ER-α, plus a role in antiestrogen resistance.

    Evidence Co-IP, nuclear fractionation, live-cell imaging, ivermectin inhibition, and viability assays in cancer cells

    PMID:24389815 PMID:24975515

    Open questions at the time
    • Nuclear function of HE4 (transcriptional or otherwise) not defined
    • Direct vs. indirect nature of receptor interactions unclear
  4. 2014 Medium

    Demonstrated that extracellular recombinant HE4 alone is mitogenic and modulates cell-cycle regulators, confirming a ligand-like proliferative activity.

    Evidence Recombinant HE4 treatment with BrdU, CCK-8, and PCNA/p21 readouts in pancreatic and endometrial lines

    PMID:25354091

    Open questions at the time
    • Receptor mediating the proliferative effect not identified
    • Signaling cascade not mapped
  5. 2016 Medium

    Linked HE4 to chemoresistance by showing it suppresses p38/ERK-MAPK pro-apoptotic signaling and the pro-apoptotic gene EGR1.

    Evidence Recombinant HE4 and CRISPR knockdown with MTS, microarray, and western blot in ovarian cancer cells

    PMID:27184254

    Open questions at the time
    • Direct molecular target upstream of MAPK not defined
    • Tubulin/MAPT effects mechanistically unexplained
  6. 2019 Medium

    Assembled a coherent pro-metastatic signaling network, defining PI3K/AKT-MMP-2-driven EMT, JAK/STAT3 activation, an HDAC3-HE4-PI3K/AKT axis, and an ANXA2-MMP-2 ternary complex.

    Evidence siRNA/overexpression with pharmacological rescue, Co-IP, immunofluorescence, and xenografts across ovarian cancer studies

    PMID:31118763 PMID:31210752 PMID:31302139 PMID:31477564

    Open questions at the time
    • Whether AKT and STAT3 arms are parallel or sequential is unresolved
    • Direct receptor for HE4 in these pathways not pinpointed
    • ANXA2 interaction shown by single-lab Co-IP
  7. 2019 High

    Established WFDC2 as essential for neonatal lung development, providing the first in vivo loss-of-function phenotype and shifting the picture from cancer ligand to developmental regulator.

    Evidence TALEN and null/GFP knock-in mouse lines from independent labs with histopathology, apoptosis assays, and RNA-seq

    PMID:31562139 PMID:31780266

    Open questions at the time
    • Molecular mechanism connecting WFDC2 loss to alveolar/club-cell defects not defined
    • Receptor mediating the developmental role unknown
  8. 2019 Medium

    Identified an NF-κB/TIMP-1/MMP-2 axis driving fibrosis, showing HE4 restrains ECM degradation downstream of HIF-1α.

    Evidence UUO mouse model and HK2 overexpression/silencing with phosphorylation and MMP-2 activity assays

    PMID:31909536

    Open questions at the time
    • How secreted HE4 activates intracellular NF-κB is unresolved
    • Receptor not identified
  9. 2020 Medium

    Provided reciprocal evidence that WFDC2 binds the EGFR extracellular domain and, in prostate cancer, can suppress EGFR/AKT/GSK3B/Snail-driven EMT, indicating context-dependent (suppressive vs. promoting) outputs.

    Evidence Reciprocal Co-IP, co-localization, recombinant protein, and metastasis assays in prostate cancer

    PMID:32678075

    Open questions at the time
    • Reason for opposite EMT outcomes between tumor types unexplained
    • Stoichiometry and affinity of EGFR binding not determined
  10. 2020 Medium

    Extended HE4 function to the microenvironment by showing STAT3-dependent induction of pro-angiogenic IL8 and HIF1A and promotion of endothelial tube formation.

    Evidence Gene expression, tube-formation assay, STAT3 inhibition, and patient correlation

    PMID:32444701

    Open questions at the time
    • Receptor coupling HE4 to STAT3 not defined
    • In vivo angiogenic contribution not directly tested
  11. 2021 Medium

    Defined HE4 as an immunosuppressive factor, inducing PD-L1, recruiting M2 macrophages, and dampening cytotoxic lymphocyte activity, partly via suppression of osteopontin.

    Evidence Syngeneic rat tumor model, cytokine profiling, flow cytometry, PBMC co-culture with OPN rescue, and patient samples

    PMID:29745428 PMID:33903172

    Open questions at the time
    • Posttranscriptional mechanism of PD-L1 induction undefined
    • Direct vs. indirect action on immune cells unclear
  12. 2021 Medium

    Broadened the inflammatory/fibrotic role across organs, showing WFDC2 drives IL-33-dependent gastric metaplasia, ERK-dependent cardiac fibroblast transdifferentiation, and is induced by CFTR dysfunction via NF-κB.

    Evidence Wfdc2-knockout mice with three SPEM models and recombinant rescue, conditioned-media cardiac fibroblast assays with neutralizing antibody, and CFBE patch-clamp/NF-κB studies

    PMID:34054511 PMID:34116028 PMID:34320813

    Open questions at the time
    • Receptor transducing the profibrotic/metaplastic signal not identified
    • Whether NF-κB induction of HE4 and HE4 activation of NF-κB form a feedback loop is untested
  13. 2024 High

    Connected WFDC2 to a human Mendelian disease, showing biallelic loss-of-function causes nasal polyposis and bronchiectasis through a glycosylation/secretion defect, validating that mature secreted protein is required for airway function.

    Evidence Sequencing in 10 families, deglycosylation assays, western blot, immunofluorescence, and structural modeling of the p.Cys49Arg founder variant

    PMID:38626355

    Open questions at the time
    • Molecular target of secreted WFDC2 in the airway not identified
    • How loss leads to polyposis vs. bronchiectasis not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • The central unresolved question is the identity and stoichiometry of the bona fide WFDC2 receptor(s) that transduce its many context-dependent outputs (EGFR/AKT, STAT3, NF-κB, ERK), and the molecular basis of its opposite roles across tissues and tumor types.
  • No unifying receptor model across the documented pathways
  • Mechanism reconciling tumor-promoting and tumor-suppressing EMT effects unknown
  • Biochemical function of nuclear-localized WFDC2 undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2 GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2
Partners
ANXA2EGFRESR1HDAC3HIF1AIGF1RIPO4MMP2
Complex memberships
WFDC2-ANXA2-MMP2 ternary complex

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 HE4 undergoes nuclear and nucleolar translocation upon stimulation with EGF, VEGF, and insulin, and interacts with EGFR, IGF1R, and transcription factor HIF1α. This nuclear translocation is mediated by importin-4, and ivermectin (an importin inhibitor) blocks HE4/importin-4 nuclear accumulation. Co-immunoprecipitation, nuclear fractionation, live-cell imaging, pharmacological inhibition with ivermectin Scientific reports Medium 24389815 24975515
2014 HE4 interacts with estrogen receptor-α (ER-α), and HE4 overexpression results in ER-α downregulation in vitro. 17β-estradiol, tamoxifen, and fulvestrant induce nuclear and nucleolar translocation of HE4, and HE4 overexpression induces resistance to antiestrogens. Co-immunoprecipitation, western blot, cell viability assays, immunofluorescence Scientific reports Medium 24975515
2016 HE4 overexpression promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells by suppressing cisplatin-mediated upregulation of EGR1 (a MAPK-regulated pro-apoptotic gene) and suppressing p38 MAPK activation. Recombinant HE4 treatment dramatically affected ERK activation. HE4 also upregulated α-tubulin and β-tubulin levels and increased MAPT gene expression. CRISPR/Cas-mediated knockdown of HE4 partially reversed chemoresistance. MTS assays, western blot, microarray, qRT-PCR, CRISPR/Cas knockdown, treatment with recombinant HE4 Journal of ovarian research Medium 27184254
2019 HE4 overexpression activates the NF-κB pathway through phosphorylation and nuclear translocation of the P65 subunit, which upregulates TIMP-1 and thereby inhibits MMP-2 activity, leading to reduced ECM degradation and renal fibrosis. Hypoxia induces HE4 expression in renal tubular epithelial cells via a HIF-1α/HE4/NF-κB signaling axis. Silencing HE4 inhibited hypoxia-induced ECM deposition and alleviated fibrosis in UUO mice in vivo. UUO mouse model, HK2 cell line overexpression/silencing, western blot, phosphorylation assay, MMP-2 activity assay, immunofluorescence FASEB journal Medium 31909536
2020 WFDC2 binds to the extracellular domain of EGFR (shown by co-immunoprecipitation and co-localization). Overexpression of WFDC2 or addition of recombinant HE4 inactivates the EGFR/AKT/GSK3B/Snail signaling pathway and restrains epithelial-mesenchymal transition (EMT), suppressing prostate cancer metastasis. Co-immunoprecipitation, co-localization assay, immunoblot, in vivo and in vitro metastasis assays, recombinant protein addition Cell death & disease Medium 32678075
2019 WFDC2 contributes to ovarian cancer EMT by activating the AKT signaling pathway and inducing MMP-2 expression. Knockdown of WFDC2 suppresses EMT (upregulation of E-cadherin, downregulation of Vimentin) and decreases MMP-2. The EMT phenotype and invasion induced by WFDC2 overexpression can be reversed by siMMP-2 and PI3K/AKT signaling inhibitor. siRNA knockdown, overexpression constructs, western blot, in vivo xenograft, PI3K/AKT inhibitor rescue Cancer management and research Medium 31118763
2019 Knockdown of HE4 inhibits the JAK/STAT3 pathway in ovarian cancer cells, suppressing proliferation, invasion, and migration, and reducing MMP-2/MMP-9 levels and EMT markers in vitro and in vivo. siRNA knockdown, western blot, flow cytometry, xenograft model Biology open Medium 31477564
2019 HE4 forms a triple protein complex with ANXA2 (Annexin A2) and MMP2, co-localizing in the cytoplasm and membrane. HE4 mediates MMP2 expression via ANXA2 (acting as a 'bridge') to promote cancer cell migration. Co-immunoprecipitation, double-labeling immunofluorescence, Transwell assay, scratch test Cancer cell international Medium 31210752
2020 HE4 activates STAT3 signaling and promotes upregulation of pro-angiogenic STAT3 target genes IL8 and HIF1A in immune cells, ovarian cancer cells, and endothelial cells. HE4 promoted tube formation in an in vitro angiogenesis model in a STAT3-dependent manner. Gene expression analysis, in vitro tube formation assay, western blot, STAT3 pathway inhibition, patient sample correlation Scientific reports Medium 32444701
2021 HE4 promotes PD-L1 expression in tumor cells and macrophages through a novel posttranscriptional mechanism; high tumoral HE4 promotes an ascites cytokine profile rich in myeloid-recruiting factors, influx of M2 macrophages, increased arginase 1, and reduced CTL activation and NK cell recruitment. Syngeneic rat tumor model with HE4 high/low cancer cells, cytokine profiling, flow cytometry, retrospective patient sample analysis Journal of immunology Medium 33903172
2021 WFDC2 promotes spasmolytic polypeptide-expressing metaplasia (SPEM) in mouse stomach by upregulating IL-33 expression in injured mucosa, which induces M2 macrophage polarization. Wfdc2-knockout mice are resistant to SPEM development. Supplementation of recombinant WFDC2 induces IL-33 production and SPEM. Wfdc2-knockout mice, three SPEM induction models (DMP-777, L635, tamoxifen), transcriptomic analysis, recombinant WFDC2 supplementation Gastroenterology High 34116028
2019 WFDC2 (Wfdc2) knockout mice die neonatally from respiratory failure due to increased apoptosis in type-I alveolar cells, causing hypovascular lung tissue and severe dyspnea. Wfdc2 is required for normal lung organogenesis. TALEN-based gene deletion in mice, histopathology, apoptosis assays on lung tissue Biochemical and biophysical research communications Medium 31780266
2019 Wfdc2-null mice display progressive atelectasis at birth with impaired cilia, absence of mature club cells from tracheo-bronchial airways, and malformed lamellar bodies in type II alveolar epithelial cells. RNA sequencing shows significant activation of a pro-inflammatory pathway in mutant lungs. Wfdc2-GFP knock-in and null-mutant mouse lines, histopathology, RNA sequencing, immunofluorescence Disease models & mechanisms High 31562139
2024 Biallelic pathogenic variants in WFDC2 cause nasal polyposis and bronchiectasis in humans. WFDC2 is expressed in secretory cells of airway epithelium and submucosal glands. A founder variant p.Cys49Arg structurally hampers glycosylation and thereby blocks secretion of mature WFDC2, confirming that secretion is required for normal airway function. Next-generation and Sanger sequencing, Western blotting, immunofluorescence microscopy, deglycosylation assays, computer simulations of protein structure, electrochemiluminescence immunoassay of serum American journal of respiratory and critical care medicine High 38626355
2021 CFTR dysfunction contributes to elevated HE4 expression via the NF-κB pathway in cystic fibrosis bronchial epithelial cells. CFTR modulators (lumacaftor/ivacaftor, tezacaftor/ivacaftor) partially restored CFTR activity and reduced HE4 secretion. TNF-α upregulated HE4 through NF-κB (p65 nuclear translocation), and NF-κB inhibitor BAY 11-7082 suppressed HE4 expression. CFBE cell line transfected with F508del-CFTR or wt-CFTR, whole-cell patch-clamp, immunoassay, fluorescence microscopy for p65 translocation, pharmacological inhibition Frontiers in pharmacology Medium 34054511
2019 HDAC3 interacts with HE4 protein (identified as an HDAC3-interacting protein). HDAC3 promotes ovarian carcinoma cell proliferation, invasion, and migration by increasing HE4 expression, and this axis activates the PI3K/AKT signaling pathway (elevated P-PI3K and P-AKT). Co-immunoprecipitation (HDAC3-HE4 interaction), immunohistochemistry, western blot, wound healing assay, Transwell assay, CCK8 proliferation assay, siRNA knockdown Archives of biochemistry and biophysics Medium 31302139
2018 HE4 suppresses osteopontin (OPN) expression in peripheral blood mononuclear cells (PBMCs) and compromises their cytotoxicity against ovarian cancer cells. SKOV3 and OVCAR8 cells showed enhanced proliferation in conditioned media from HE4-exposed PBMCs, an effect attenuated by recombinant OPN or OPN-inducible cytokines (IL-12 and IFN-γ). HE4-silenced SKOV3 cells were more susceptible to cytotoxic cell death upon co-culture with PBMCs. Subtractive hybridization, PBMC co-culture, conditioned media experiments, recombinant OPN rescue, siRNA knockdown of HE4, patient biopsy correlation Clinical and experimental immunology Medium 29745428
2013 HE4 overexpression in endometrial cancer cell lines significantly enhanced cell proliferation, matrigel invasion, and colony formation in soft agar, and promoted tumor growth in a mouse xenograft model, establishing a direct role for HE4 in tumor progression. Stable transfection of HE4-V0 expression construct, cell proliferation assay, matrigel invasion assay, soft agar colony formation, mouse xenograft model International journal of molecular sciences Medium 23502467
2014 Recombinant extracellular HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines, increases DNA synthesis, and modulates cell cycle markers PCNA (upregulated) and p21 (downregulated) at mRNA and protein levels. Cell viability assay (CCK-8), BrdU incorporation, western blot, qRT-PCR with purified recombinant HE4 protein Oncology reports Medium 25354091
2021 HE4 secreted from HE4-transfected HEK293T cells activates ERK signaling in cardiac fibroblasts and promotes their transdifferentiation, increasing expression of fibrosis-related genes. Treatment with an ERK upstream inhibitor or a neutralizing HE4 antibody canceled the profibrotic properties of HE4. HEK293T transfection, conditioned media treatment of rat neonatal cardiac fibroblasts, western blot for ERK signaling, fibrosis gene expression, neutralizing antibody rescue Journal of the American Heart Association Medium 34320813
2016 High-dose estradiol (E2) increases WFDC2 expression in estrogen-sensitive HO8910 ovarian cancer cells, but not in estrogen-insensitive SKOV3 cells. Knockdown of WFDC2 in SKOV3 cells confers estrogen responsiveness (proliferative response to E2), accompanied by upregulation of estrogen receptor beta (ERβ). RT-PCR, western blot, MTT proliferation assay, flow cytometry for ER expression, annexin V/PI apoptosis assay, antibody array Journal of ovarian research Medium 26928556
2011 In tammar wallaby, WFDC2 protein (comprising two 4-DSC domains: domain III at N-terminus and domain II at C-terminus) demonstrates antibacterial activity against Staphylococcus aureus, Salmonella enterica, and Pseudomonas aeruginosa, with this activity residing specifically in domain II. No antibacterial activity was detected against Enterococcus faecalis. Recombinant protein expression, antibacterial activity assays with individual domains, gene expression profiling during lactation Developmental and comparative immunology Medium 22024352
2005 HE4 is a secreted glycoprotein; conditioned media from ovarian cancer cell lines that endogenously overexpress HE4 revealed a secreted, N-glycosylated form of the protein. RT-PCR identification of HE4-expressing cell lines, conditioned medium analysis, N-glycosylation characterization Cancer research Medium 15781627

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer research 552 12839961
2005 Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer research 433 15781627
2006 Comprehensive analysis of HE4 expression in normal and malignant human tissues. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 327 16607372
2009 Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. British journal of cancer 221 19337252
2006 WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respiratory research 165 16600032
2009 HE4 as a biomarker for ovarian and endometrial cancer management. Expert review of molecular diagnostics 121 19732003
2011 Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. American journal of obstetrics and gynecology 112 22301440
2014 Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 98 24627132
2012 Human epididymis protein 4 (HE4) in benign and malignant diseases. Clinical chemistry and laboratory medicine 74 23093276
2014 HE4 (WFDC2) gene overexpression promotes ovarian tumor growth. Scientific reports 69 24389815
2014 HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: a systematic review. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 67 25169975
2016 The diagnostic value of serum HE4 and CA-125 and ROMA index in ovarian cancer. Biomedical reports 62 27347403
2021 HE4 as a Biomarker for Endometrial Cancer. Cancers 61 34638250
2013 HE4 (WFDC2) Promotes Tumor Growth in Endometrial Cancer Cell Lines. International journal of molecular sciences 61 23502467
2013 Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer. Gynecologic oncology 59 23891789
2022 Dapagliflozin Attenuates Contrast-induced Acute Kidney Injury by Regulating the HIF-1α/HE4/NF-κB Pathway. Journal of cardiovascular pharmacology 57 35383661
2011 HE4 in ovarian cancer: from discovery to clinical application. Advances in clinical chemistry 57 22126021
2016 HE4 promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells. Journal of ovarian research 55 27184254
2013 The emerging role of HE4 in the evaluation of epithelial ovarian and endometrial carcinomas. Oncology (Williston Park, N.Y.) 55 23909069
2012 Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 54 22854652
2019 Hypoxia-induced HE4 in tubular epithelial cells promotes extracellular matrix accumulation and renal fibrosis via NF-κB. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 52 31909536
2012 Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 45 22962406
2018 Comparison of CA125, HE4, and ROMA index for ovarian cancer diagnosis. Current problems in cancer 42 30017407
2014 HE4, Ca125 and ROMA algorithm for differential diagnosis between benign gynaecological diseases and ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 42 24771264
2013 A critical review on HE4 performance in endometrial cancer: where are we now? Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 41 24068567
2012 Diagnostic value of HE4 for ovarian cancer: a meta-analysis. Clinical chemistry and laboratory medicine 41 22868811
2023 Recent Insight about HE4 Role in Ovarian Cancer Oncogenesis. International journal of molecular sciences 40 37445657
2021 WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury. Gastroenterology 40 34116028
2014 Serum HE4 and CA125 as predictors of response and outcome during neoadjuvant chemotherapy of advanced high-grade serous ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 25190018
2016 Overexpression of HE4 (human epididymis protein 4) enhances proliferation, invasion and metastasis of ovarian cancer. Oncotarget 38 26575020
2020 Use of a human embryonic stem cell model to discover GABRP, WFDC2, VTCN1 and ACTC1 as markers of early first trimester human trophoblast. Molecular human reproduction 37 32359161
2023 Simultaneous Detection of Ovarian Cancer-Concerned HE4 and CA125 Markers Based on Cu Single-Atom-Triggered CdS QDs and Eu MOF@Isoluminol ECL. Analytical chemistry 36 36867090
2020 WFDC2 suppresses prostate cancer metastasis by modulating EGFR signaling inactivation. Cell death & disease 35 32678075
2018 Diagnostic value of HE4 in ovarian cancer: A meta-analysis. European journal of obstetrics, gynecology, and reproductive biology 34 30317143
2012 HE4 in gynecological cancers: report of a European investigators and experts meeting. Clinical chemistry and laboratory medicine 34 23093277
2015 Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms: Clinical correlates. Gynecologic oncology 33 25866324
2015 Expression of HE4 in Endometrial Cancer and Its Clinical Significance. BioMed research international 33 26539494
2021 HE4 Predicts Progressive Fibrosis and Cardiovascular Events in Patients With Dilated Cardiomyopathy. Journal of the American Heart Association 31 34320813
2014 Human epididymis protein 4 (HE4) in laboratory medicine and an algorithm in renal disorders. Clinica chimica acta; international journal of clinical chemistry 30 25127713
2013 HE4 transcription- and splice variants-specific expression in endometrial cancer and correlation with patient survival. International journal of molecular sciences 29 24252907
2020 Endometrial cancer: A systematic review of HE4, REM and REM-B. Clinica chimica acta; international journal of clinical chemistry 28 33388311
2018 Evaluation of HE4 and TTR for diagnosis of ovarian cancer: Comparison with CA-125. Journal of gynecology obstetrics and human reproduction 28 29609043
2016 CA125 and HE4: Measurement Tools for Ovarian Cancer. Gynecologic and obstetric investigation 28 27160726
2014 HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation. Scientific reports 27 24975515
2014 Promotive role of recombinant HE4 protein in proliferation and carboplatin resistance in ovarian cancer cells. Oncology reports 27 25354091
2020 The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes. Scientific reports 26 32444701
2019 Diagnostic accuracy of CA125 and HE4 in ovarian carcinoma patients and the effect of confounders on their serum levels. Current problems in cancer 26 30670303
2018 Standard and optimal cut-off values of serum ca-125, HE4 and ROMA in preoperative prediction of ovarian cancer in Vietnam. Gynecologic oncology reports 26 30109256
2017 HE4 expression in lung cancer, a meta-analysis. Clinica chimica acta; international journal of clinical chemistry 26 28499820
2016 Physiopathological factors affecting the diagnostic value of serum HE4-test for gynecologic malignancies. Expert review of molecular diagnostics 25 27784171
2015 Expression and diagnostic value of HE4 in pancreatic adenocarcinoma. International journal of molecular sciences 25 25642754
2023 Secreted proteins MDK, WFDC2, and CXCL14 as candidate biomarkers for early diagnosis of lung adenocarcinoma. BMC cancer 23 36721112
2022 HE4 and CA125 serum biomarker monitoring in women with epithelial ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 23 36189508
2019 Knockdown of HE4 suppresses aggressive cell growth and malignant progression of ovarian cancer by inhibiting the JAK/STAT3 pathway. Biology open 22 31477564
2011 The role of HE4 in ovarian cancer: inhibiting tumour cell proliferation and metastasis. The Journal of international medical research 22 22117965
2021 HE4 Overexpression by Ovarian Cancer Promotes a Suppressive Tumor Immune Microenvironment and Enhanced Tumor and Macrophage PD-L1 Expression. Journal of immunology (Baltimore, Md. : 1950) 21 33903172
2021 The diagnostic accuracy of human epididymis protein 4 (HE4) for discriminating between benign and malignant pelvic masses: a systematic review and meta-analysis. Acta obstetricia et gynecologica Scandinavica 21 34212386
2016 The diagnosis and pathological value of combined detection of HE4 and CA125 for patients with ovarian cancer. Open medicine (Warsaw, Poland) 21 28352780
2015 Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines. Oncology reports 21 26497244
2011 WFDC2 is differentially expressed in the mammary gland of the tammar wallaby and provides immune protection to the mammary gland and the developing pouch young. Developmental and comparative immunology 21 22024352
2021 Serum HE4 and CA125 combined to predict and monitor recurrence of type II endometrial carcinoma. Scientific reports 20 34737393
2020 Increased levels of HE4 (WFDC2) in systemic sclerosis: a novel biomarker reflecting interstitial lung disease severity? Therapeutic advances in chronic disease 20 32963750
2019 WFDC2 contributes to epithelial-mesenchymal transition (EMT) by activating AKT signaling pathway and regulating MMP-2 expression. Cancer management and research 20 31118763
2021 Early diagonosis of ovarian cancer: serum HE4, CA125 and ROMA model. American journal of translational research 19 35035759
2013 HE4 combined with CA125: favorable screening tool for ovarian cancer. Medical oncology (Northwood, London, England) 19 24323399
2023 A Dual Biomarker TK1 Protein and CA125 or HE4-Based Algorithm as a Better Diagnostic Tool than ROMA Index in Early Detection of Ovarian Cancer. Cancers 18 36900385
2019 Interaction of HE4 and ANXA2 exists in various malignant cells-HE4-ANXA2-MMP2 protein complex promotes cell migration. Cancer cell international 18 31210752
2019 HE4 as a biomarker for diagnosis of lung cancer: A meta-analysis. Medicine 18 31574828
2015 HE4, CA125, the Risk of Malignancy Algorithm and the Risk of Malignancy Index and complex pelvic masses - a prospective comparison in the pre-operative evaluation of pelvic masses in an Australian population. The Australian & New Zealand journal of obstetrics & gynaecology 18 26172511
2014 Evaluating the expression and diagnostic value of human epididymis protein 4 (HE4) in small cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 25051914
2023 Point-of-care testing: a disposable label-free electrochemical CA125 and HE4 immunosensors for early detection of ovarian cancer. Biomedical microdevices 16 37140852
2021 Enhanced Expression of Human Epididymis Protein 4 (HE4) Reflecting Pro-Inflammatory Status Is Regulated by CFTR in Cystic Fibrosis Bronchial Epithelial Cells. Frontiers in pharmacology 16 34054511
2019 WFDC2 gene deletion in mouse led to severe dyspnea and type-I alveolar cell apoptosis. Biochemical and biophysical research communications 16 31780266
2024 Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis. American journal of respiratory and critical care medicine 15 38626355
2020 Correlation analysis and clinical significance of CA125, HE4, DDI, and FDP in type II epithelial ovarian cancer. Medicine 15 33285710
2022 Urine CA125 and HE4 for the Triage of Symptomatic Women with Suspected Endometrial Cancer. Cancers 14 35884367
2019 Human epididymis protein 4 (HE4) protects against cystic pulmonary fibrosis associated-inflammation through inhibition of NF-κB and MAPK singnaling. Genes & genomics 14 31165362
2019 HDAC3 positively regulates HE4 expression to promote ovarian carcinoma progression. Archives of biochemistry and biophysics 14 31302139
2015 Value of serum marker HE4 in pulmonary carcinoma diagnosis. International journal of clinical and experimental medicine 14 26770527
2016 Human Epididymis Protein 4 (HE4) in Patients with Small-Cell Lung Cancer. Clinical laboratory 13 28164590
2022 The Diagnostic Accuracy of Serum and Urine Human Epididymis Protein 4 (HE4) in Ovarian Cancer in 15,394 Subjects: An Updated Meta-Analysis. Cureus 12 36415437
2021 Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study. Biomedicines 12 33435590
2020 Meta-analysis of the diagnostic accuracy of HE4 for endometrial carcinoma. European journal of obstetrics, gynecology, and reproductive biology 12 32711295
2019 Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice. Disease models & mechanisms 12 31562139
2020 HE4 overexpression decreases pancreatic cancer Capan-1 cell sensitivity to paclitaxel via cell cycle regulation. Cancer cell international 11 32435154
2017 Evaluation of HE4 in the Diagnosis and Follow Up of Non-Small Cell Lung Cancers. Clinical laboratory 11 28271686
2017 Measurement of HE4 and CA125 and establishment of reference intervals for the ROMA index in the sera of pregnant women. Journal of clinical laboratory analysis 11 29194801
2012 HE4 protein and SMRP: Potential novel biomarkers in ovarian cancer detection. Oncology letters 11 22984370
2023 Urine CA125 and HE4 for the Detection of Ovarian Cancer in Symptomatic Women. Cancers 10 36831601
2020 Is HE4 Superior over CA-125 in the Follow-up of Patients with Epithelial Ovarian Cancer? Current drug targets 10 32334501
2017 HE4-test of urine and body fluids for diagnosis of gynecologic cancer. Expert review of molecular diagnostics 10 28117603
2016 WAP four-disulfide core domain protein 2 gene(WFDC2) is a target of estrogen in ovarian cancer cells. Journal of ovarian research 10 26928556
2020 Role of Human Epididymis Protein 4 (HE4) in Determining Survival of Patients With Endometrial Cancer: A Meta-Analysis. Technology in cancer research & treatment 9 33148127
2023 Diagnostic performance of IOTA SR and O-RADS combined with CA125, HE4, and risk of malignancy algorithm to distinguish benign and malignant adnexal masses. European journal of radiology 8 37418798
2022 Cell-free tumor DNA, CA125 and HE4 for the objective assessment of tumor burden in patients with advanced high-grade serous ovarian cancer. PloS one 8 35130283
2021 Predictive Value of HE4 in Platinum-Based Chemotherapy for Ovarian Cancer: A Systematic Review. Frontiers in oncology 8 34307173
2019 Ovarian carcinomas express HE4 epitopes independently of each other. Cancer treatment and research communications 8 31226514
2018 HE4 suppresses the expression of osteopontin in mononuclear cells and compromises their cytotoxicity against ovarian cancer cells. Clinical and experimental immunology 8 29745428
2017 Serum HE4 Level as a Biomarker to Predict the Recurrence of Gynecologic Cancers. Current drug targets 8 28382859
2023 Combination of serum CST1 and HE4 for early diagnosis of endometrial cancer. PeerJ 7 38077439

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