{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T21:24:48Z","timestamp":1770413088047,"version":"3.49.0"},"reference-count":37,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T00:00:00Z","timestamp":1422489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human epididymis protein 4 (HE4) is a recognized biomarker in ovarian  and endometrial cancer and over-expressed in pancreatic adenocarcinoma. The diagnostic value of HE4 in pancreatic adenocarcinoma remains unknown. Here we elucidate mRNA, protein and serum level of HE4 in pancreatic adenocarcinoma. HE4 mRNA level in tumor adjacent tissues and pancreatic adenocarcinoma tissues were tested by real time-PCR. Tissue microarray containing normal, adenocarcinoma, and adjacent pancreatic tissue was tested  by immunohistochemistry (IHC). Serum level of HE4, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3) and carbohydrate antigen 125 (CA125) were detected by ELISA assay in control and tumor patients. Further we compared the sensitivity  and specificity of determining HE4, CA19-9, CA15-3, and CA125 for diagnosis of pancreatic adenocarcinoma and assessed the complementary diagnostic value of HE4, CA19-9, CA15-3 and CA125. Real time PCR showed significantly increased HE4 mRNA level  in pancreatic adenocarcinoma compared with control. Result of IHC showed that HE4 significantly higher expressed in the human pancreatic carcinoma tissues than in both normal and adjacent non-tumorous pancreatic tissues, and the staining intensity is inversely correlated with the clinical stage. HE4 was highly expressed in early stage of pancreatic adenocarcinoma. Serum HE4 level is higher in cases with pancreatic adenocarcinoma than in the controls. Serum HE4 levels could research to a sensitivity of 45.83% and specificity  of 93.75% when the Cutoff was set at 4.59 ng\/mL. The Combined HE4 and CA19-9 increased the sensitivity to 83.33%; and interestingly, the combination of HE4 with CA15-3 led to the most powerful sensitivity of 87.5%. Combined with CA19-9 and CA15-3, HE4 could be a potential biomarker to improve the diagnostic power for pancreatic adenocarcinoma.<\/jats:p>","DOI":"10.3390\/ijms16022956","type":"journal-article","created":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T10:10:02Z","timestamp":1422526202000},"page":"2956-2970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Expression and Diagnostic Value of HE4 in  Pancreatic Adenocarcinoma"],"prefix":"10.3390","volume":"16","author":[{"given":"Tianhe","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology, the First Affiliated Hospital, Xi'an Jiaotong University,  Xi'an 710061, China"},{"name":"Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi-Wen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA"},{"name":"Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery,  Memorial Health University Medical Center, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangyi","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Shanghai YangSi Hospital, Shanghai 200135, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Senkowski","sequence":"additional","affiliation":[{"name":"Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery,  Memorial Health University Medical Center, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Lyle","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Savannah State University, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Terry","sequence":"additional","affiliation":[{"name":"Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery,  Memorial Health University Medical Center, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Brower","sequence":"additional","affiliation":[{"name":"Department of Surgery & Surgical Oncology, Mount Sinai Beth Israel Medical Center, New York, NY 10003, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haibin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Glasgow","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA"},{"name":"Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery,  Memorial Health University Medical Center, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongchang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, the First Affiliated Hospital, Xi'an Jiaotong University,  Xi'an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA"},{"name":"Curtis and Elizabeth Anderson Cancer Institute, Department of Surgery,  Memorial Health University Medical Center, Savannah, GA 31404, USA"},{"name":"Department of Obstetrics and Gynecology, Memorial Health University Medical Center, Savannah, GA 31404, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"vii33","DOI":"10.1093\/annonc\/mds224","article-title":"Pancreatic adenocarcinoma: ESMO\u2013ESDO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"23","author":"Seufferlein","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1186\/s12967-014-0289-8","article-title":"Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma","volume":"12","author":"Elebro","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_3","first-page":"464","article-title":"Detection of serum tumor markers in the diagnosis and treatment of patients with pancreatic cancer","volume":"3","author":"Jiang","year":"2004","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1007\/s00280-013-2313-8","article-title":"A retrospective analysis of early CA199 change in salvage chemotherapy for refractory pancreatic cancer","volume":"72","author":"Nakai","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_5","unstructured":"Liu, L., Xu, H., Wang, W., Wu, C., Chen, Y., Yang, J., Cen, P., Xu, J., Liu, C., and Long, J. (2014). A Preoperative serum signature of CEA\/CA125\/CA19-9 \u2265 1000 U\/mL indicates poor outcome to pancreatectomy for pancreatic cancer. Int. J. Cancer."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"643","DOI":"10.3349\/ymj.2013.54.3.643","article-title":"Serum CA19-9 and CEA levels as a prognostic factor in pancreatic adenocarcinoma","volume":"54","author":"Lee","year":"2013","journal-title":"Yonsei Med. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s12033-011-9474-7","article-title":"The efficacy evaluation of cryosurgery in pancreatic cancer patients with the expression of CD44v6, integrin-\u03b21, CA199, and CEA","volume":"52","author":"Zhou","year":"2012","journal-title":"Mol. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1200\/JCO.2005.02.8282","article-title":"New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis","volume":"24","author":"Gold","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1158\/0008-5472.CAN-13-2444","article-title":"Interactions between MUC1 and p120 catenin regulate dynamic features of cell adhesion, motility, and metastasis","volume":"74","author":"Liu","year":"2014","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1158\/0008-5472.CAN-04-3924","article-title":"Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas","volume":"65","author":"Drapkin","year":"2005","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nm.2989","article-title":"Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis","volume":"19","author":"LeBleu","year":"2013","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1053\/j.gastro.2007.11.058","article-title":"A molecular signature of gastric metaplasia arising in response to acute parietal cell loss","volume":"134","author":"Nozaki","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_13","first-page":"6281","article-title":"Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer","volume":"60","author":"Hough","year":"2000","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1515\/cclm-2014-0041","article-title":"Serum human epididymis protein 4 (HE4) as a tumor marker in men with lung cancer","volume":"52","author":"Nagy","year":"2014","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ygyno.2012.04.022","article-title":"HE4 is an independent prognostic marker in endometrial cancer patients","volume":"126","author":"Egle","year":"2012","journal-title":"Gynecol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"viii6","DOI":"10.1093\/annonc\/mdr472","article-title":"Designing early detection programs for ovarian cancer","volume":"22","author":"Urban","year":"2011","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1007\/s13277-012-0381-8","article-title":"Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer","volume":"33","author":"Granato","year":"2012","journal-title":"Tumour Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1007\/s13277-012-0376-5","article-title":"HE4 combined with MDCT imaging is a good marker in the evaluation of disease extension in advanced epithelial ovarian carcinoma","volume":"33","author":"Midulla","year":"2012","journal-title":"Tumour Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1007\/s13277-014-1898-9","article-title":"May increased CA125 in borderline ovarian tumor be indicative of a poor prognosis? A case report","volume":"35","author":"Anastasi","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ajog.2013.04.014","article-title":"Predictive value of serum human epididymis protein 4 and cancer antigen 125 concentrations in endometrial carcinoma","volume":"209","author":"Saarelainen","year":"2013","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6847","DOI":"10.1007\/s13277-014-1943-8","article-title":"Evaluating the expression and diagnostic value of human epididymis protein 4 (HE4) in small cell lung cancer","volume":"35","author":"Wang","year":"2014","journal-title":"Tumour Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.biochi.2014.06.022","article-title":"Overexpression of Lewis y antigen promotes human epididymis protein 4-mediated invasion and metastasis of ovarian cancer cells","volume":"105","author":"Zhuang","year":"2014","journal-title":"Biochimie"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.bbrc.2012.02.008","article-title":"Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility","volume":"419","author":"Lu","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6026","DOI":"10.3390\/ijms14036026","article-title":"HE4 (WFDC2) promotes tumor growth in endometrial cancer cell lines","volume":"14","author":"Li","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.humpath.2012.07.017","article-title":"Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas","volume":"44","author":"Nam","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/modpathol.3800612","article-title":"Comprehensive analysis of HE4 expression in normal and malignant human tissues","volume":"19","author":"Galgano","year":"2006","journal-title":"Mod. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e123","DOI":"10.1371\/journal.pmed.0050123","article-title":"A mouse to human search for plasma proteome changes associated with pancreatic tumor development","volume":"5","author":"Faca","year":"2008","journal-title":"PLoS Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1158\/1078-0432.CCR-10-0248","article-title":"Serum biomarker panels for the detection of pancreatic cancer","volume":"17","author":"Brand","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/MPA.0b013e3182a6867e","article-title":"Potential prognostic biomarkers of pancreatic cancer","volume":"43","author":"Chen","year":"2014","journal-title":"Pancreas"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"696","DOI":"10.7150\/jca.10094","article-title":"Circulating microRNAs in pancreatic juice as candidate biomarkers of pancreatic cancer","volume":"5","author":"Wang","year":"2014","journal-title":"J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1007\/s13277-013-1033-3","article-title":"Biomarkers for pancreatic cancer: Promising new markers and options beyond CA19-9","volume":"34","author":"Ballehaninna","year":"2013","journal-title":"Tumour Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.ygyno.2013.03.001","article-title":"Differentiating stage 1 epithelial ovarian cancer from benign ovarian tumours using a combination of tumour markers HE4, CA125, and CEA and patient\u2019s age","volume":"129","author":"Hackethal","year":"2013","journal-title":"Gynecol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/978-3-540-37696-5_9","article-title":"Prevention and early detection of ovarian cancer: Mission impossible?","volume":"174","author":"Bast","year":"2007","journal-title":"Recent Results Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5787","DOI":"10.1158\/1078-0432.CCR-14-0289","article-title":"Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer","volume":"20","author":"Chan","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fujiwara, H., Suzuki, M., Takeshima, N., Takizawa, K., Kimura, E., Nakanishi, T., Yamada, K., Takano, H., Sasaki, H., and Koyama, K. (2014). Evaluation of human epididymis protein 4 (HE4) and Risk of Ovarian Malignancy Algorithm (ROMA) as diagnostic tools of type I and type II epithelial ovarian cancer in Japanese women. Tumour Biol.","DOI":"10.1007\/s13277-014-2738-7"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1515\/CCLM.2011.709","article-title":"The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses","volume":"49","author":"Lenhard","year":"2011","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5500","DOI":"10.1038\/srep05500","article-title":"HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation","volume":"4","author":"Lokich","year":"2014","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/2\/2956\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:42:07Z","timestamp":1760215327000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/2\/2956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,29]]},"references-count":37,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,2]]}},"alternative-id":["ijms16022956"],"URL":"https:\/\/doi.org\/10.3390\/ijms16022956","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,29]]}}}