epididymal secretory proteins


Summary: Proteins secreted by the epididymal epithelium. These proteins are both tissue- and species-specific. They are important molecular agents in the process of sperm maturation.

Top Publications

  1. Kirchhoff C, Habben I, Ivell R, Krull N. A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod. 1991;45:350-7 pubmed
    ..A possible function in sperm maturation as indicated by amino acid similarities to extracellular proteinase inhibitors of genital tract mucous secretions is discussed in the context of its tissue-specific transcription. ..
  2. Montagnana M, Lippi G, Ruzzenente O, Bresciani V, Danese E, Scevarolli S, et al. The utility of serum human epididymis protein 4 (HE4) in patients with a pelvic mass. J Clin Lab Anal. 2009;23:331-5 pubmed publisher
    ..99 vs. 0.91), with a sensibility and specificity of 98 and 100%, respectively. HE4 seems to be a promising ovarian cancer marker, and its measurement might improve the diagnostic approach to patients with pelvic masses. ..
  3. Huhtinen K, Suvitie P, Hiissa J, Junnila J, Huvila J, Kujari H, et al. Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer. 2009;100:1315-9 pubmed publisher
    ..Taken together, measuring both HE4 and CA125 serum concentrations increases the accuracy of ovarian cancer diagnosis and provides valuable information to discriminate ovarian tumours from ovarian endometriotic cysts. ..
  4. Nolen B, Velikokhatnaya L, Marrangoni A, De Geest K, Lomakin A, Bast R, et al. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol. 2010;117:440-5 pubmed publisher
    ..Our findings serve to advance the development of blood-based screening methods for the discrimination of benign and malignant ovarian masses by confirming and expanding upon the superior utility of the CA-125/HE4 combination. ..
  5. Moore R, McMeekin D, Brown A, Disilvestro P, Miller M, Allard W, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009;112:40-6 pubmed publisher
    ..3). An algorithm utilizing HE4 and CA125 successfully classified patients into high and low risk groups with 93.8% of EOC correctly classified as high risk. This model can be used to effectively triage patients to centers of excellence. ..
  6. Lowe K, Shah C, Wallace E, Anderson G, Paley P, McIntosh M, et al. Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:2480-7 pubmed publisher
    ..Understanding the influence of personal factors on levels of novel early detection markers in healthy, unaffected women may have clinical utility in interpreting biomarker levels. ..
  7. Dacheux J, Gatti J, Dacheux F. Contribution of epididymal secretory proteins for spermatozoa maturation. Microsc Res Tech. 2003;61:7-17 pubmed
    ..Correlations between the highly regionalized epididymal activities and sperm characteristics linked to their survival and fertility potential are presented in this review. ..
  8. Bingle L, Singleton V, Bingle C. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene. 2002;21:2768-73 pubmed
    ..These results cast doubt on the potential role of HE4 as a serum tumour marker specific for ovarian cancer and open the door to understanding the function of multiple WAP domain containing protein isoforms arising from a single gene. ..
  9. Moore R, Brown A, Miller M, Badgwell D, Lu Z, Allard W, et al. Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. Gynecol Oncol. 2008;110:196-201 pubmed publisher
    ..Further investigation of HE4 as a marker for early detection of recurrent endometrial cancer and monitoring response to therapy is warranted. ..

More Information


  1. Scholler N, Lowe K, Bergan L, Kampani A, Ng V, Forrest R, et al. Use of yeast-secreted in vivo biotinylated recombinant antibodies (Biobodies) in bead-based ELISA. Clin Cancer Res. 2008;14:2647-55 pubmed publisher
    ..88 and 0.84, respectively; P = 0.20) or mesothelin (0.74 and 0.72, respectively; P = 0.38). Yeast-secreted Bbs can be used reliably in cost-effective yet highly sensitive bead-based assays for use in large validation studies. ..
  2. Scholler N, Garvik B, Quarles T, Jiang S, Urban N. Method for generation of in vivo biotinylated recombinant antibodies by yeast mating. J Immunol Methods. 2006;317:132-43 pubmed
    ..8 x 10(-9) M and K(d)=5.1 x 10(-9) M before and after Ni-purification respectively. Thus, yeast mating permits cost-effective generation of biotinylated recombinant antibodies of high affinity. ..
  3. Galgano M, Hampton G, Frierson H. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 2006;19:847-53 pubmed
  4. Bouchard D, Morisset D, Bourbonnais Y, Tremblay G. Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol. 2006;7:167-74 pubmed
    ..In this review, we assess data for an association between cancer and human WAP proteins, and discuss their potential role in tumour progression. We also propose a new mechanism by which WAP proteins might have a role in carcinogenesis. ..
  5. Hellstrom I, Raycraft J, Hayden Ledbetter M, Ledbetter J, Schummer M, McIntosh M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63:3695-700 pubmed
    ..However, the HE4 assay may have an advantage over the CA125 assay in that it is less frequently positive in patients with nonmalignant disease. ..
  6. Montagnana M, Danese E, Ruzzenente O, Bresciani V, Nuzzo T, Gelati M, et al. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful?. Clin Chem Lab Med. 2011;49:521-5 pubmed publisher
    ..Moreover, the dual marker combination of HE4 and CA125 (ROMA) does not show better performance than HE4 alone. ..
  7. Schafer B, von Horsten H, Dacheux J, Holtz W, Kirchhoff C. Cloning and characterization of boar epididymal secretory proteins by homology to the human. Reprod Domest Anim. 2003;38:111-8 pubmed
    ..Both Northern and Western analyses indicated that the Se proteins were produced in a regionalized pattern and accumulated in the cauda fluid. ..
  8. Anastasi E, Granato T, Marchei G, Viggiani V, Colaprisca B, Comploj S, et al. Ovarian tumor marker HE4 is differently expressed during the phases of the menstrual cycle in healthy young women. Tumour Biol. 2010;31:411-5 pubmed publisher
  9. Andersen M, Goff B, Lowe K, Scholler N, Bergan L, Drescher C, et al. Use of a Symptom Index, CA125, and HE4 to predict ovarian cancer. Gynecol Oncol. 2010;116:378-83 pubmed publisher
    ..If positive predictive value is a high priority, testing by CA125 and HE4 prior to imaging may be warranted for women with ovarian cancer symptoms. ..
  10. Drapkin R, von Horsten H, Lin Y, Mok S, Crum C, Welch W, et al. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res. 2005;65:2162-9 pubmed
    ..Its expression in cortical inclusion cysts suggests that formation of Mullerian epithelium is a prerequisite step in the development of some types of EOCs. ..
  11. Rosen D, Wang L, Atkinson J, Yu Y, Lu K, Diamandis E, et al. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol Oncol. 2005;99:267-77 pubmed
    ..Several markers exhibited more intense expression in cancers than in normal organs. Further investigation is needed to demonstrate complementary expression of markers in serum. ..
  12. Scholler N, Crawford M, Sato A, Drescher C, O Briant K, Kiviat N, et al. Bead-based ELISA for validation of ovarian cancer early detection markers. Clin Cancer Res. 2006;12:2117-24 pubmed
  13. Moore R, Brown A, Miller M, Skates S, Allard W, Verch T, et al. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. 2008;108:402-8 pubmed
    ..As a single tumor marker, HE4 had the highest sensitivity for detecting ovarian cancer, especially Stage I disease. Combined CA125 and HE4 is a more accurate predictor of malignancy than either alone. ..
  14. Hellstrom I, Hellstrom K. SMRP and HE4 as biomarkers for ovarian carcinoma when used alone and in combination with CA125 and/or each other. Adv Exp Med Biol. 2008;622:15-21 pubmed publisher
    ..Prospective studies are needed to establish the clinical relevance of our findings. ..
  15. Van Gorp T, Cadron I, Despierre E, Daemen A, Leunen K, Amant F, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm. Br J Cancer. 2011;104:863-70 pubmed publisher
    ..Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer. ..
  16. Anastasi E, Marchei G, Viggiani V, Gennarini G, Frati L, Reale M. HE4: a new potential early biomarker for the recurrence of ovarian cancer. Tumour Biol. 2010;31:113-9 pubmed publisher
    ..In conclusion, this study showed that HE4, compared to CA125, potentially is a better marker for the diagnosis of OC and could be an important early indicator of the recurrence of the disease. ..
  17. Moore R, Jabre Raughley M, Brown A, Robison K, Miller M, Allard W, et al. Comparison of a novel multiple marker assay vs the Risk of Malignancy Index for the prediction of epithelial ovarian cancer in patients with a pelvic mass. Am J Obstet Gynecol. 2010;203:228.e1-6 pubmed publisher
    ..3% compared with 64.7% for RMI (P < .0001). The dual marker algorithm utilizing HE4 and CA125 to calculate a ROMA value achieves a significantly higher sensitivity for identifying women with EOC than does RMI. ..
  18. Ramanathan B, Archunan G. Analysis of epididymal proteins during sexual maturation in male albino mice. Acta Physiol Hung. 2001;88:73-80 pubmed
    ..These proteins need further investigation for the purpose of immunocontraception by using them as antigens. ..
  19. Anderson G, McIntosh M, Wu L, Barnett M, Goodman G, Thorpe J, et al. Assessing lead time of selected ovarian cancer biomarkers: a nested case-control study. J Natl Cancer Inst. 2010;102:26-38 pubmed publisher
    ..Serum concentrations of CA125, HE4, and mesothelin may provide evidence of ovarian cancer 3 years before clinical diagnosis, but the likely lead time associated with these markers appears to be less than 1 year. ..
  20. Wang S, Zhao X, Khimji I, Akbas R, Qiu W, Edwards D, et al. Integration of cell phone imaging with microchip ELISA to detect ovarian cancer HE4 biomarker in urine at the point-of-care. Lab Chip. 2011;11:3411-8 pubmed publisher
  21. Chang X, Ye X, Dong L, Cheng H, Cheng Y, Zhu L, et al. Human epididymis protein 4 (HE4) as a serum tumor biomarker in patients with ovarian carcinoma. Int J Gynecol Cancer. 2011;21:852-8 pubmed publisher
    ..Human epididymis protein 4 used in conjunction with CA 125 yields improved specificity for ovarian cancer compared with the use of CA 125 alone, generally similar to results seen in non-Chinese populations. ..
  22. Joshi S, Shaikh S, Ranpura S, Khole V. Postnatal development and testosterone dependence of a rat epididymal protein identified by neonatal tolerization. Reproduction. 2003;125:495-507 pubmed
    ..The importance of epididymis-specific proteins that are regulated by androgens in sperm maturation is discussed, and the need to ascertain the sequence of the protein and clone the cognate gene is indicated. ..
  23. Yanaihara A, Otsuka Y, Iwasaki S, Koide K, Aida T, Okai T. Comparison in gene expression of secretory human endometrium using laser microdissection. Reprod Biol Endocrinol. 2004;2:66 pubmed
    ..2-fold) were verified by real-time PCR. Some of the genes we identified with differential expression are related to the immune system. These results are telling us the new information for understanding the secretory human endometrium. ..
  24. Zhang L, Hu Z, Zhu C, Liu Q, Zhou Y, Zhang Y. Identification and characterization of an epididymis-specific gene, Ces7. Acta Biochim Biophys Sin (Shanghai). 2009;41:809-15 pubmed
    ..Furthermore, Ces7 increased with age growth until sex maturation and then maintained at high level. CES7 might be one of the major CEs in male reproductive tract and contribute to the sperm fertilization...
  25. Montagnana M, Danese E, Giudici S, Franchi M, Guidi G, Plebani M, et al. HE4 in ovarian cancer: from discovery to clinical application. Adv Clin Chem. 2011;55:1-20 pubmed
    ..This chapter will review the current knowledge on biologic and clinical applications of ovarian cancer biomarkers, with particular emphasis on the newly proposed marker, HE4. ..
  26. Girotti M, Jones R, Emery D, Chia W, Hall L. Structure and expression of the rat epididymal secretory protein I gene. An androgen-regulated member of the lipocalin superfamily with a rare splice donor site. Biochem J. 1992;281 ( Pt 1):203-10 pubmed
    ..Comparison of the exon/intron organization of the ESP I gene with those of members of the lipocalin superfamily provides strong support for a common ancestral origin. ..
  27. Sipila P, Jalkanen J, Huhtaniemi I, Poutanen M. Novel epididymal proteins as targets for the development of post-testicular male contraception. Reproduction. 2009;137:379-89 pubmed publisher
  28. Klemme L, Roberts K, Hoffman L, Ensrud K, Siiteri J, Hamilton D. Cloning and characterization of the rat Crisp-1 gene. Gene. 1999;240:279-88 pubmed
    ..The Crisp-1 gene also produces an mRNA without an exon 1 sequence by utilizing a transcription start site in intron 1, 5' of the start of exon 2. All forms of the Crisp-1 mRNA are predicted to encode Protein DE. ..
  29. Hartge P. Designing early detection programs for ovarian cancer. J Natl Cancer Inst. 2010;102:3-4 pubmed publisher
  30. Li X, Liu Q, Liu S, Zhang J, Zhang Y. New member of the guanosine triphosphatase activating protein family in the human epididymis. Acta Biochim Biophys Sin (Shanghai). 2008;40:855-63 pubmed
    ..The results have created a foundation for further interpretation of the biological effects of GAPs in sperm maturation. ..
  31. Berry N, Cho Y, Harrington M, Williams S, Foley J, Nephew K. Transcriptional targeting in ovarian cancer cells using the human epididymis protein 4 promoter. Gynecol Oncol. 2004;92:896-904 pubmed
  32. Kamei M, Yamashita S, Tokuishi K, Hashioto T, Moroga T, Suehiro S, et al. HE4 expression can be associated with lymph node metastases and disease-free survival in breast cancer. Anticancer Res. 2010;30:4779-83 pubmed
    ..6%) was significantly worse than that in the negative group (85.6%, p=0.04). These data showed that HE4 expression is associated with lymph node involvement and is a possible predictive factor of breast cancer recurrence. ..
  33. Urban N, Thorpe J, Bergan L, Forrest R, Kampani A, Scholler N, et al. Potential role of HE4 in multimodal screening for epithelial ovarian cancer. J Natl Cancer Inst. 2011;103:1630-4 pubmed publisher
    ..03). Serum HE4 levels were found to increase with age and smoking status, suggesting that a longitudinal algorithm might improve its performance. ..
  34. Sivashanmugam P, Richardson R, Hall S, Hamil K, French F, O Rand M. Cloning and characterization of an androgen-dependent acidic epididymal glycoprotein/CRISP1-like protein from the monkey. J Androl. 1999;20:384-93 pubmed
    ..The results described in the present study suggest that mAEG (CRISP1) is secreted in the monkey epididymis, regulated by androgens and present on epididymal spermatozoa. ..
  35. Moore R, Miller M, Disilvestro P, Landrum L, Gajewski W, Ball J, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118:280-8 pubmed publisher
    ..These findings support the use of the Risk of Ovarian Malignancy Algorithm as a tool for the triage of women with an adnexal mass to gynecologic oncologists. II. ..
  36. Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, et al. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer. 2011;104:1418-25 pubmed publisher
    ..Determination of sHE4 could be clinically useful in identifying high-risk EC patients for a more aggressive adjuvant therapy. ..
  37. Ellerman D, BrantĂșa V, MartĂ­nez S, Cohen D, Conesa D, Cuasnicu P. Potential contraceptive use of epididymal proteins: immunization of male rats with epididymal protein DE inhibits sperm fusion ability. Biol Reprod. 1998;59:1029-36 pubmed
    ..Together these results indicate that immunization of male rats with epididymal protein DE specifically interferes with the sperm fertilizing ability, supporting the use of epididymal proteins for contraceptive vaccine development. ..
  38. Liu Y, Ye X, Cheng H, Cheng Y, Fu T, Chen J, et al. [Measurement of serum human epididymis secretory protein 4 combined with CA125 assay in differential diagnosis of endometriosis cyst and ovarian benign and malignant tumors]. Zhonghua Fu Chan Ke Za Zhi. 2010;45:363-6 pubmed
    ..Measurement of HE4 could be used in differential diagnosis of endometriosis cyst. And the combination of HE4 and CA(125) assay could discriminate ovarian endometriosis cysts from ovarian malignant tumors effectively. ..
  39. Busso D, Cohen D, Da Ros V, Fissore R, Cuasnicu P. Studies on the participation of epididymal sperm protein DE/CRISP-1 in egg activation. Cell Mol Biol (Noisy-le-grand). 2003;49:407-12 pubmed
    ..Together, these results argue against the participation of DE in egg activation, restricting the activity of this protein and its egg binding sites to the sperm-egg fusion process. ..
  40. Liu J, Wang H, Li J. [Advances in researches on epididymal WFDC-type serine protease inhibitors]. Zhonghua Nan Ke Xue. 2008;14:1027-30 pubmed
    ..This paper gives an overview of the structure and function of the protein and its application prospects in the development of drugs for male reproductive tract infection and immunocontraception. ..
  41. Escudero J, Auge J, Filella X, Torne A, Pahisa J, Molina R. Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. Clin Chem. 2011;57:1534-44 pubmed publisher
    ..874 vs 0.722). HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA 125 and HE4 improved the detection of ovarian cancer in all stages and histological types. ..
  42. Dong L, Chang X, Ye X, Zhu L, Zhao Y, Tian L, et al. [The values of serum human epididymis secretory protein 4 and CA(125) assay in the diagnosis of ovarian malignancy]. Zhonghua Fu Chan Ke Za Zhi. 2008;43:931-6 pubmed
    ..The set point of 150 pmol/L is advantageous for the accurate diagnosis, while the set point of 86 pmol/L is advantageous for the screening of malignant ovarian cancer. ..
  43. Tollner T, Venners S, Hollox E, Yudin A, Liu X, Tang G, et al. A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility. Sci Transl Med. 2011;3:92ra65 pubmed publisher
    ..This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility...
  44. Vrzalova J, Prazakova M, Novotny Z, Topolcan O, Casova M, Holubec L. Test of ovarian cancer multiplex xMAP technology panel. Anticancer Res. 2009;29:573-6 pubmed
    ..The panel will be tested on a larger ovarian cancer cohort and in patients with other cancer and non-cancerous diseases. ..
  45. Zou S, Chang X, Ye X, Cheng H, Cheng Y, Tang Z, et al. Effect of human epididymis protein 4 gene silencing on the malignant phenotype in ovarian cancer. Chin Med J (Engl). 2011;124:3133-40 pubmed
    ..ip1 cells. HE4 knockdown also inhibited cell proliferation, migration and invasion in SKOV3.ip1 cells in vitro. HE4 may be involved in the regulation of the cell cycle and promote ovarian cancer migration and invasion. ..
  46. Ruggeri G, Bandiera E, Zanotti L, Belloli S, Ravaggi A, Romani C, et al. HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin Chim Acta. 2011;412:1447-53 pubmed publisher
    ..The ROMA algorithm showed a good accuracy for discriminating women at high risk for EOC. ..
  47. Cohen D, Ellerman D, Cuasnicu P. Mammalian sperm-egg fusion: evidence that epididymal protein DE plays a role in mouse gamete fusion. Biol Reprod. 2000;63:462-8 pubmed
    ..The lack of disintegrin domains in DE indicates that the protein interacts with its egg-binding sites through a novel mechanism that does not involve the reported disintegrin-integrin interaction. ..
  48. Lamy P, Roques S, Viglianti C, Fabbro M, Montels F. [HE4, a novel marker for epithelial ovarian cancer: evaluation of analytical performances]. Ann Biol Clin (Paris). 2010;68:325-9 pubmed publisher
    ..Globally, the uncertainty varied from 13.1% (low values) to 28.1% (elevated values). We conclude that the HE4 EIA from Fujirebio Diagnostic Inc. displayed convenient analytical performances that allows its use it clinical practice. ..
  49. Joseph A, Shur B, Ko C, Chambon P, Hess R. Epididymal hypo-osmolality induces abnormal sperm morphology and function in the estrogen receptor alpha knockout mouse. Biol Reprod. 2010;82:958-67 pubmed publisher
  50. Huang Y, Zugates G, Peng W, Holtz D, Dunton C, Green J, et al. Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice. Cancer Res. 2009;69:6184-91 pubmed publisher
    ..administration of polymeric nanoparticles to deliver DT-A encoding DNA, combined with transcriptional regulation to target gene expression to ovarian tumor cells, holds promise as an effective therapy for advanced-stage ovarian cancer. ..
  51. Khan S, Jadhav S, Suryawanshi A, Bhonde G, Gajbhiye R, Khole V. Evaluation of contraceptive potential of a novel epididymal sperm protein SFP2 in a mouse model. Am J Reprod Immunol. 2011;66:185-98 pubmed publisher
    ..These data provide an experimental basis for the development of effective contraceptive vaccine based on new epididymal target. ..
  52. Macuks R, Baidekalna I, Donina S. Comparison of different ovarian cancer detection algorithms. Eur J Gynaecol Oncol. 2011;32:408-10 pubmed
    ..A larger sample size in both control and patient groups should be evaluated to reach clear conclusions. ..
  53. Kirchhoff C, Osterhoff C, Pera I, Schroter S. Function of human epididymal proteins in sperm maturation. Andrologia. 1998;30:225-32 pubmed