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Siberian journal of oncology

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HE4 as a potential tumor-associated marker in lung cancer

https://doi.org/10.21294/1814-4861-2026-25-1-123-134

Abstract

The aim of the study was to systematize current data on the use of human epididymis protein 4 (HE4) as a tumor-associated marker for lung cancer (LC) diagnosis, prognosis of treatment response, and monitoring of this category of patients.
Material and Methods. A search and analysis of available Russian and Englishlanguage sources was performed in the RSCI and PubMed databases using keywords “lung cancer” and “HE4”. The review includes 44 papers published between 2006 and 2024.
Results. HE4 is involved in gynecological cancer progression, but its role in the development of LC remains poorly studied despite its high expression in tumor tissue. Modern studies demonstrate that diagnostic characteristics of serum HE4 are comparable to or slightly superior to other markers used in the diagnosis of LC (CYFRA21-1, CEA, NSE, ProGRP, etc.). Several studies report that the HE4 serum level can serve as a predictor of response to chemotherapy and the duration of the relapse-free interval in LC. Some studies indicate the feasibility of HE4 as a marker for monitoring patients for early detection of lung cancer relapse. The indicators of the diagnostic and prognostic signifcance of serum HE4 vary signifcantly in different studies due to the heterogeneity of the included groups, differences in the reference values and methods for assessing the HE4 levels. This does not allow us to adopt a unifed diagnostic algorithm for using HE4.
Conclusion. The accumulated data indicate the feasibility of using HE4 as a tumor-associated marker in LC. However, some aspects that are important for the practical application of HE4 remain unclear. Thus, the introduction of this marker into clinical practice requires further systematic and in-depth studies.

About the Authors

I. I. Alentov
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia
Russian Federation

Igor I. Alentov, PhD, Senior Researcher, Department of Prediction of the Effectiveness of Conservative Treatment 
Researcher ID (WOS): HPF-2560-2023. Author ID (Scopus): 54683346300.

3, 2nd Botkinsky Passage, Moscow, 125284



N. S. Sergeeva
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia
Russian Federation

Natalia S. Sergeeva, DSc, Professor, Head of the Department of Prediction of the Effectiveness of Conservative Treatment 
Researcher ID (WOS): I-2033-2014. Author ID (Scopus): 7102748586 

3, 2nd Botkinsky Passage, Moscow, 125284



D. V. Shumanskaya
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia
Russian Federation

Daria V. Shumanskaya, MD, Oncologist, Thoracic Surgical Department, Junior Researcher, Myasthenia Group, Department of Thoracoabdominal Surgery 
Researcher ID (WOS): GOG-8510-2022.

3, 2nd Botkinsky Passage, Moscow, 125284



T. A. Karmakova
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia
Russian Federation

Tatiana A. Karmakova, DSc, Leading Researcher, Department of Prediction of the Effectiveness of Conservative Treatment 
Researcher ID (WOS): L-3592-2018. Author ID (Scopus): 6603382243.

3, 2nd Botkinsky Passage, Moscow, 125284



O. V. Pikin
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia
Russian Federation

Oleg V. Pikin, MD, DSc, Professor, Department of Thoracic Surgery, Russian Medical Academy of Postgraduate Education, Ministry of Health of Russia; Head of the Department of Thoracic Surgery 

3, 2nd Botkinsky Passage, Moscow, 125284



N. V. Marshutina
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia
Russian Federation

Nina V. Marshutina, PhD, Researcher, Department of Prediction of the Effectiveness of Conservative Treatment 
Researcher ID (WOS): I-2027-2014. Author ID (Scopus): 6602904590.

3, 2nd Botkinsky Passage, Moscow, 125284



A. D. Kaprin
P.A. Herzen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Centre, Ministry of Health of Russia; National Medical Research Radiological Centre, Ministry of Health of Russia; Peoples’ Friendship University of Russia
Russian Federation

Andrey D. Kaprin, MD, DSc, Professor, Academician of the Russian Academy of Sciences, Head of Chair of Oncology and Radiology named after Kharchenko; Director; Director General 
Researcher ID (WOS): K-1445-2014.

3, 2nd Botkinsky Passage, Moscow, 125284;
4, Koroleva St., Obninsk, 249036;
6, Miklouho-Maklaya St., Moscow, 117198



References

1. Malignant tumors in Russia in 2022 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova, I.V. Lisichnikova. Moscow, 2023. 275 p. (in Russian). ISBN: 978-5-85502-290-2.

2. Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229–63. doi: 10.3322/caac.21834.

3. Araghi M., Fidler-Benaoudia M., Arnold M., Rutherford M., Bardot A., Ferlay J., Bucher O., De P., Engholm G., Gavin A., Kozie S., Little A., Møller B., St Jacques N., Tervonen H., Walsh P., Woods R., O’Connell D.L., Baldwin D., Elwood M., Siesling S., Bray F., Soerjomataram I.; ICBP SURVMARK-2 Local Leads; ICBP SURVMARK-2 Academic Reference Group; ICBP Clinical Committee–Lung; ICBP SurvMark-2 Academic Reference GroupICBP SurvMark-2 academic reference group; ICBP Clinical Committee – LungICBP clinical Committee – lung. International diferences in lung cancer survival by sex, histological type and stage at diagnosis: an ICBP SURVMARK-2 Study. Thorax. 2022; 77(4): 378–90. doi: 10.1136/thoraxjnl-2020-216555.

4. Remon J., Soria J.C., Peters S.; ESMO Guidelines Committee. Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy. Ann Oncol. 2021; 32(12): 1637–42. doi: 10.1016/j.annonc.2021.08.1994.

5. Molina R., Marrades R.M., Augé J.M., Escudero J.M., Viñolas N., Reguart N., Ramirez J., Filella X., Molins L., Agustí A. Assessment of a combined panel of six serum tumor markers for lung cancer. Am J Respir Crit Care Med. 2016; 193(4): 427–37. doi: 10.1164/rccm.201404-0603OC.

6. de Kock R., Borne B.V.D., Soud M.Y., Belderbos H., Stege G., de Saegher M., van Dongen-Schrover C., Genet S., Brunsveld L., Scharnhorst V., Deiman B. Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients. Cancer Treat Res Commun. 2021; 28: 100410. doi: 10.1016/j.ctarc.2021.100410.

7. Du Q., Yan C., Wu S.G., Zhang W., Huang C., Yao Y., Wang L., Zhang Q., Liu Q., Guan J., Hou Y., Li Z., Soh A., Beshiri A., Wang Q., Li X., Zheng Y., Wang H. Development and validation of a novel diagnostic nomogram model based on tumor markers for assessing cancer risk of pulmonary lesions: A multicenter study in Chinese population. Cancer Lett. 2018; 420: 236–41. doi: 10.1016/j.canlet.2018.01.079.

8. Li B.T., Lou E., Hsu M., Yu H.A., Naidoo J., Zauderer M.G., Sima C., Johnson M.L., Daras M., DeAngelis L.M., Fleisher M., Kris M.G., Azzoli C.G. Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers. PLoS One. 2016; 11(1): e0146063. doi: 10.1371/journal.pone.0146063. Erratum in: PLoS One. 2016; 11(3): e0152450. doi: 10.1371/journal.pone.0152450.

9. Luo H.J., Hu Z.D., Cui M., Zhang X.F., Tian W.Y., Ma C.Q., Ren Y.N., Dong Z.L. Diagnostic performance of CA125, HE4, ROMA, and CPH-I in identifying primary ovarian cancer. J Obstet Gynaecol Res. 2023; 49(3): 998–1006. doi: 10.1111/jog.15540.

10. GeneCards. The Human Gene Database. WFDC2 Gene – WAP FourDisulfde Core Domain 2. [Internet]. [cited 02.07.2025]. URL: https://www.genecards.org/cgi-bin/carddisp.pl?gene=WFDC2&keywords=wfdc2.

11. Samborski A., Miller M.C., Blackman A., MacLaughlan-David S., Jackson A., Lambert-Messerlian G., Rowswell-Turner R., Moore R.G. HE4 and CA125 serum biomarker monitoring in women with epithelial ovarian cancer. Tumour Biol. 2022; 44(1): 205–13. doi: 10.3233/TUB-220016.

12. Bignotti E., Ragnoli M., Zanotti L., Calza S., Falchetti M., Lonardi S., Bergamelli S., Bandiera E., Tassi R.A., Romani C., Todeschini P., Odicino F.E., Facchetti F., Pecorelli S., Ravaggi A. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer. 2011; 104(9): 1418–25. doi: 10.1038/bjc.2011.109.

13. Galgano M.T., Hampton G.M., Frierson H.F. Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol. 2006; 19(6): 847–53. doi: 10.1038/modpathol.3800612.

14. Georgakopoulos P., Mehmood S., Akalin A., Shroyer K.R. Immunohistochemical localization of HE4 in benign, borderline, and malignant lesions of the ovary. Int J Gynecol Pathol. 2012; 31(6): 517–23. doi: 10.1097/PGP.0b013e31824fe269.

15. Karlsen N.S., Karlsen M.A., Høgdall C.K., Høgdall E.V. HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: a systematic review. Cancer Epidemiol Biomarkers Prev. 2014; 23(11): 2285–95. doi: 10.1158/1055-9965.EPI14-0447.

16. Sun M.L., Yang Z.Y., Wu Q.J., Li Y.Z., Li X.Y., Liu F.H., Wei Y.F., Wen Z.Y., Lin B., Gong T.T. The Role of Human Epididymis Protein 4 in the Diagnosis and Prognosis of Diseases: An Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies. Front Med (Lausanne). 2022; 9: 842002. doi: 10.3389/fmed.2022.842002.

17. Hertlein L., Stieber P., Kirschenhofer A., Krocker K., Nagel D., Lenhard M., Burges A. Human epididymis protein 4 (HE4) in benign and malignant diseases. Clin Chem Lab Med. 2012; 50(12): 2181–88. doi: 10.1515/cclm-2012-0097.

18. Nishiyama N., Masuo M., Nukui Y., Tateishi T., Kishino M., Tateishi U., Morota K., Ohbo K., Miyazaki Y. Human epididymis protein 4 is a new biomarker to predict the prognosis of progressive fbrosing interstitial lung disease. Respir Investig. 2021; 59(1): 90–98. doi: 10.1016/j.resinv.2020.08.002.

19. Adamczyk B., Partyka R., Adamczyk-Sowa M., Wierzbicki K., Sowa P., Kokocińska D. Evaluation of serum human epididymis protein 4 in patients with relapsing-remitting multiple sclerosis. Adv Clin Exp Med. 2020; 29(8): 943–48. doi: 10.17219/acem/121006.

20. Zhong H., Qian Y., Fang S., Yang L., Li L., Gu W. HE4 expression in lung cancer, a meta-analysis. Clin Chim Acta. 2017; 470: 109–14. doi: 10.1016/j.cca.2017.05.007.

21. Dai C., Zheng Y., Li Y., Tian T., Wang M., Xu P., Deng Y., Hao Q., Wu Y., Zhai Z., Dai Z., Lyu J. Prognostic values of HE4 expression in patients with cancer: a meta-analysis. Cancer Manag Res. 2018; 10: 4491–500. doi: 10.2147/CMAR.S178345.

22. Zhang C., Hu H., Wang X., Zhu Y., Jiang M. WFDC Protein: A Promising Diagnosis Biomarker of Ovarian Cancer. J Cancer. 2021; 12(18): 5404–12. doi: 10.7150/jca.57880.

23. Small D.M., Doherty D.F., Dougan C.M., Weldon S., Taggart C.C. The role of whey acidic protein four-disulfde-core proteins in respiratory health and disease. Biol Chem. 2017; 398(4): 425–40. doi: 10.1515/hsz-2016-0262.

24. Hua L., Liu Y., Zhen S., Wan D., Cao J., Gao X. Expression and biochemical characterization of recombinant human epididymis protein 4. Protein Expr Purif. 2014;102: 52–62. doi: 10.1016/j.pep.2014.08.004.

25. Kant K., Tomar A.K., Sharma P., Kundu B., Singh S., Yadav S. Human epididymis protein 4 quantifcation and interaction network analysis in seminal plasma. Protein Pept Lett. 2019; 26(6): 458–65. doi: 10.2174/0929866526666190327124919.

26. Cheng D., Sun Y., He H. The diagnostic accuracy of HE4 in lung cancer: a meta-analysis. Dis Markers. 2015; 2015: 352670. doi: 10.1155/2015/352670.

27. James N.E., Emerson J.B., Borgstadt A.D., Beffa L., Oliver M.T., Hovanesian V., Urh A., Singh R.K., Rowswell-Turner R., DiSilvestro P.A., Ou J., Moore R.G., Ribeiro J.R. The biomarker HE4 (WFDC2) promotes a pro-angiogenic and immunosuppressive tumor microenvironment via regulation of STAT3 target genes. Sci Rep. 2020; 10(1): 8558. doi: 10.1038/s41598-020-65353-x.

28. Tanikawa C., Kamatani Y., Takahashi A., Momozawa Y., Leveque K., Nagayama S., Mimori K., Mori M., Ishii H., Inazawa J., Yasuda J., Tsuboi A., Shimizu A., Sasaki M., Yamaji T., Sawada N., Iwasaki M., Tsugane S., Naito M., Wakai K., Koyama T., Takezaki T., Yuji K., Murakami Y., Nakamura Y., Kubo M., Matsuda K. GWAS identifes two novel colorectal cancer loci at 16q24.1 and 20q13.12. Carcinogenesis. 2018; 39(5): 652–60. doi: 10.1093/carcin/bgy026.

29. Wang D., Zhu Z.Z., Jiang H., Zhu J., Cong W.M., Wen B.J., He S.Q., Liu S.F. Multiple genes identifed as targets for 20q13.12-13.33 gain contributing to unfavorable clinical outcomes in patients with hepatocellular carcinoma. Hepatol Int. 2015; 9(3): 438–46. doi: 10.1007/s12072-015-9642-0.

30. Sud A., Thomsen H., Orlando G., Försti A., Law P.J., Broderick P., Cooke R., Hariri F., Pastinen T., Easton D.F., Pharoah P.D.P., Dunning A.M., Peto J., Canzian F., Eeles R., Kote-Jarai Z., Muir K., Pashayan N., Campa D; PRACTICAL Consortium; Hoffmann P., Nöthen M.M., Jöckel K.H., von Strandmann E.P., Swerdlow A.J., Engert A., Orr N., Hemminki K., Houlston R.S. Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood. 2018; 132(19): 2040–52. doi: 10.1182/blood-2018-06-855296.

31. Sun L., Wang C., Zhang J., Shao B., Zhao S., Guo Y., Li X., Sun Y. Genetic alterations in gastric amphicrine carcinomas and comparison with gastric mixed neuroendocrine-non-neuroendocrine neoplasms. Mod Pathol. 2022; 35(6): 808–15. doi: 10.1038/s41379-021-00978-5.

32. Li J., Chen H., Mariani A., Chen D., Klatt E., Podratz K., Drapkin R., Broaddus R., Dowdy S., Jiang S.W. HE4 (WFDC2) promotes tumor growth in endometrial cancer cell lines. Int J Mol Sci. 2013; 14(3): 6026–43. doi: 10.3390/ijms14036026.

33. Zhu L., Zhuang H., Wang H., Tan M., Schwab C.L., Deng L., Gao J., Hao Y., Li X., Gao S., Liu J., Lin B. Overexpression of HE4 (human epididymis protein 4) enhances proliferation, invasion and metastasis of ovarian cancer. Oncotarget. 2016; 7(1): 729–44. doi: 10.18632/oncotarget.6327.

34. Wang A., Jin C., Tian X., Wang Y., Li H. Knockdown of HE4 suppresses aggressive cell growth and malignant progression of ovarian cancer by inhibiting the JAK/STAT3 pathway. Biol Open. 2019; 8(9): bio043570. doi: 10.1242/bio.043570.

35. Lu Q., Chen H., Senkowski C., Wang J., Wang X., Brower S., Glasgow W., Byck D., Jiang S.W., Li J. Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines. Oncol Rep. 2016; 35(1): 163–70. doi: 10.3892/or.2015.4339.

36. Kim K., Khazan N., McDowell J.L., Snyder C.W.A., Miller J.P., Singh R.K., Whittum M.E., Turner R., Moore R.G. The NF-κB-HE4 axis: A novel regulator of HE4 secretion in ovarian cancer. PloS One. 2024; 19(12): e0314564. doi: 10.1371/journal.pone.0314564.

37. Xia Y., Shen S., Verma I.M. NF-κB, an active player in human cancers. Cancer Immunol Res. 2014; 2(9): 823–30. doi: 10.1158/2326-6066.CIR-14-0112.

38. Zhan Y., Chen J., Wu J., Gu Y., Huang Q., Deng Z., Chen S., Wu X., Lv Y., Zeng Z., Xie J. Human epididymis protein 4 aggravates airway infammation and remodeling in chronic obstructive pulmonary disease. Respir Res. 2022; 23(1):120. doi: 10.1186/s12931-022-02040-7.

39. Yamashita S., Tokuishi K., Hashimoto T., Moroga T., Kamei M., Ono K., Miyawaki M., Takeno S., Chujo M., Yamamoto S., Kawahara K. Prognostic signifcance of HE4 expression in pulmonary adenocarcinoma. Tumour Biol. 2011; 32(2): 265–71. doi: 10.1007/s13277-010-0118-5.

40. Zeng Q., Liu M., Zhou N., Liu L., Song X. Serum human epididymis protein 4 (HE4) may be a better tumor marker in early lung cancer. Clin Chim Acta. 2016; 455: 102–106. doi: 10.1016/j.cca.2016.02.002.

41. Wang Y., Wang Z., Ding Y., Sun F., Ding X. The application value of serum HE4 in the diagnosis of lung cancer. Asian Pac J Cancer Prev. 2019; 20(8): 2405–7. doi: 10.31557/APJCP.2019.20.8.2405.

42. Korkmaz E.T., Koksal D., Aksu F., Dikmen Z.G., Icen D., Maden E., Onder S., Akbiyik F., Emri S. Triple test with tumor markers CYFRA 21.1, HE4, and ProGRP might contribute to diagnosis and subtyping of lung cancer. Clin Biochem. 2018; 58: 15–19. doi: 10.1016/j.clinbiochem.2018.05.001.

43. Choi S.I., Jang M.A., Jeon B.R., Shin H.B., Lee Y.K., Lee Y.W. Clinical Usefulness of Human Epididymis Protein 4 in Lung Cancer. Ann Lab Med. 2017; 37(6): 526–30. doi: 10.3343/alm.2017.37.6.526..

44. Nagy B.Jr., Bhattoa H.P., Steiber Z., Csobán M., Szilasi M., Méhes G., Müller M., Lázár J., Kappelmayer J., Antal-Szalmás P. Serum human epididymis protein 4 (HE4) as a tumor marker in men with lung cancer. Clin Chem Lab Med. 2014; 52(11): 1639–48. doi: 10.1515/cclm2014-0041.

45. Visser E., Genet S.A.A.M., de Kock R.P.P.A., van den Borne B.E.E.M., Youssef-El Soud M., Belderbos H.N.A., Stege G., de Saegher M.E.A., van‘t Westeinde S.C., Brunsveld L., Broeren M.A.C., van de Kerkhof D., Deiman B.A.L.M., Eduati F., Scharnhorst V. Liquid biopsy-based decision support algorithms for diagnosis and subtyping of lung cancer. Lung Cancer. 2023; 178: 28–36. doi: 10.1016/j.lungcan.2023.01.014.

46. Li J., Li Y., Huo L., Sun R., Liu X., Gu Q., Li A., Han S., Liu H., Li Y., Zhang Y. Detection of serum HE4 levels contributes to the diagnosis of lung cancer. Oncol Lett. 2023; 25(6): 255. doi: 10.3892/ol.2023.13841.

47. He Y.P., Li L.X., Tang J.X., Yi L., Zhao Y., Zhang H.W., Wu Z.J., Lei H.K., Yu H.Q., Nian W.Q., Gan L. HE4 as a biomarker for diagnosis of lung cancer: A meta-analysis. Medicine (Baltimore). 2019; 98(39): e17198. doi: 10.1097/MD.0000000000017198.

48. Yan L., Hu Z.D. Diagnostic accuracy of human epididymis secretory protein 4 for lung cancer: a systematic review and meta-analysis. J Thorac Dis. 2019; 11(7): 2737–44. doi: 10.21037/jtd.2019.06.72.

49. Zare M.E., Nasir Kansestani A., Wu X., Zhou L., Lu J., Huang J., Wang Y., Ma Y., Gao Y., Zhang J. Serum human epididymis protein-4 outperforms conventional biomarkers in the early detection of nonsmall cell lung cancer. iScience. 2024; 27(11): 111211. doi: 10.1016/j.isci.2024.111211.

50. Tang Q.F., Zhou Z.W., Ji H.B., Pan W.H., Sun M.Z. Value of serum marker HE4 in pulmonary carcinoma diagnosis. Int J Clin Exp Med. 2015; 8: 19014–21.

51. Wojcik E., Tarapacz J., Rychlik U., Stasik Z., Sas-Korczynska B., Skotnicki P., Kulpa J.K. Human epididymis protein 4 (HE4) in patients with small-cell lung cancer. Clin Lab. 2016; 62(9): 1625–32. doi: 10.7754/Clin.Lab.2016.151212.

52. Yoon H.I., Kwon O.R., Kang K.N., Shin Y.S., Shin H.S., Yeon E.H., Kwon K.Y., Hwang I., Jeon Y.K., Kim Y., Kim C.W. Diagnostic Value of Combining Tumor and Infammatory Markers in Lung Cancer. J Cancer Prev. 2016; 21(3): 187–93. doi: 10.15430/JCP.2016.21.3.187.

53. Huang W., Wu S., Lin Z., Chen P., Wu G. Evaluation of HE4 in the diagnosis and follow up of non-small cell lung cancers. Clin Lab. 2017; 63(3): 461–67. doi: 10.7754/Clin.Lab.2016.160818.

54. Guo L., Song B., Xiao J., Lin H., Chen J., Su X. The prognostic value of biomarkers on detecting non-small cell lung cancer in a Chinese elderly population. Int J Gen Med. 2021; 14: 5279–86. doi: 10.2147/IJGM.S331311.

55. Zhang T., Chu L., Tan W., Ye C., Dong H. Human epididymis protein 4, a novel potential biomarker for diagnostic and prognosis monitoring of lung cancer. Clin Respir J. 2024; 18(5): e13774. doi: 10.1111/crj.13774.

56. Wu L., Chen X., Peng T., Tang E., Bai W., Chen L. Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study. Int J Biol Markers. 2024; 39(2): 141–48. doi: 10.1177/03936155241244802.

57. Yamashita S., Tokuishi K., Moroga T., Yamamoto S., Ohbo K., Miyahara S., Yoshida Y., Yanagisawa J., Hamatake D., Hiratsuka M., Yoshinaga Y., Shiraishi T., Iwasaki A., Kawahara K. Serum level of HE4 is closely associated with pulmonary adenocarcinoma progression. Tumour Biol. 2012; 33(6): 2365–70. doi: 10.1007/s13277-012-0499-8.

58. Iwahori K., Suzuki H., Kishi Y., Fujii Y., Uehara R., Okamoto N., Kobayashi M., Hirashima T., Kawase I., Naka T. Serum HE4 as a diagnostic and prognostic marker for lung cancer. Tumour Biol. 2012; 33: 1141–49. doi: 10.1007/s13277-012-0356-9.

59. Jiang Y., Wang C., Lv B., Ma G., Wang L. Expression level of serum human epididymis 4 and its prognostic signifcance in human non-small cell lung cancer. Int J Clin Exp Med. 2014; 7(12): 5568–72.

60. Lamy P.J., Plassot C., Pujol J.L. Serum HE4: An independent prognostic factor in non-small cell lung cancer. PloS One. 2015; 10(6): e0128836. doi: 10.1371/journal.pone.0128836.

61. Lan W.G., Hao Y.Z., Xu D.H., Wang P., Zhou Y.L., Ma L.B. Serum human epididymis protein 4 is associated with the treatment response of concurrent chemoradiotherapy and prognosis in patients with locally advanced non-small cell lung cancer. Clin Transl Oncol. 2016; 18(4): 375–80. doi: 10.1007/s12094-015-1375-y.

62. Mo D., He F. Serum human epididymis secretory protein 4 (HE4) is a potential prognostic biomarker in non-small cell lung cancer. Clin Lab. 2018; 64(9): 1421–28. doi: 10.7754/Clin.Lab.2018.180222.

63. Weissensteiner J., Babusikova E. The value of human epididymis protein 4 (HE4) as a serum tumor marker for accurate bone metastases fnding by whole-body bone scintigraphy in lung cancer patients. Neoplasma. 2019; 66(6): 1024–30. doi: 10.4149/neo_2018_181212N961.

64. Bingle L., Singleton V., Bingle C.D. 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(17): 2768–73. doi: 10.1038/sj.onc.1205363.

65. Li M., Zhang Y., Jiang L., Li Y., Li G., Zhou J., Yang C., Li X., Qu W., Chen Y., Chen Q., Wang S., Xing J., Huang H. New insights into the diagnostic characteristics and clinical application of serum biomarkers for lung cancer, and human epididymis protein 4 as a new biomarker? Neoplasma. 2022; 69(3): 729–40. doi: 10.4149/neo_2022_220207N144.

66. Yan S., Lin Y., Tian X. Significantly elevated serum human epididymis protein-4 in chronic kidney disease patients without ovarian cancer: A large-scale retrospective study. J Clin Lab Anal. 2023; 37(4): e24847. doi: 10.1002/jcla.24847.

67. Penick E.R., Beltran T.A., Choi Y.S., Wilson K.L. Human epididymis protein 4: Analysis of national health and nutrition examination survey data. Eur J Obstet Gynecol Reprod Biol. 2024; 297: 86–90. doi: 10.1016/j.ejogrb.2024.03.015.

68. Meng K., Tian M., Gui X., Xie M., Gao Y., Shi S., Zhao T., Xiao Y., Cai H., Ding J. Human epididymis protein 4 is associated with severity and poor prognosis of connective tissue disease-associated interstitial lung disease with usual interstitial pneumonia pattern. Int Immunopharmacol. 2022; 108: 108704. doi: 10.1016/j.intimp.2022.108704.

69. Schirinzi A., Cazzolla A.P., Mascolo E., Palmieri G., Pesce F., Gesualdo L., Santacroce L., Ballini A., Lovero R., Di Serio F. Determination of the upper reference limit of human epididymis secretory protein 4 (HE4) in healthy male individuals and correlation with renal and fertility markers. Endocr Metab Immune Disord Drug Targets. 2021; 21(5): 912–18. doi: 10.2174/1871530320666200807121050.

70. Geiger K., Joerger M., Roessler M., Hettwer K., Ritter C., Simon K., Uhlig S., Holdenrieder S. Relevance of tumor markers for prognosis and predicting therapy response in non-small cell lung cancer patients: A CEPAC-TDM biomarker substudy. Tumour Biol. 2024; 46(s1): 191–206. doi: 10.3233/TUB-230014.


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Alentov I.I., Sergeeva N.S., Shumanskaya D.V., Karmakova T.A., Pikin O.V., Marshutina N.V., Kaprin A.D. HE4 as a potential tumor-associated marker in lung cancer. Siberian journal of oncology. 2026;25(1):123-134. (In Russ.) https://doi.org/10.21294/1814-4861-2026-25-1-123-134

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