{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T09:36:13Z","timestamp":1767087373320,"version":"3.48.0"},"reference-count":51,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>HE4 is overexpressed in malignant lesions, and elevated serum HE4 levels have been applied as a biomarker for gynecologic cancers. While previous studies have demonstrated the HE4 activities in cancer biology, its role(s) in benign disease is unclear. In current study, we characterize the keratopathy phenotype of transgenic mice with HE4 overexpression (HE4-OE). HE4-OE mice started to display signs of keratitis such as eye-scratching, conjunctiva inflammation, red eyes, periocular secretions, and rough skin\/hair loss around the eyes at 3\u00a0months after birth. All the mice suffered keratitis, severe corneal opacity and ELISA results indicated HE4 overexpression, and significantly increased IL-6 and TNF-\u03b1 levels in the cornea. Immunostaining demonstrated the accumulation of disorganized collagen fibers, fibroblast activation, and the presence of vessel-like structures, indicating the progression of corneal opacification. The cornea alkali burn model showed increased HE4 expression, which was accompanied by the elevation of IL-6 and TNF-\u03b1 in the cornea. Thus, both the HE4-OE and alkali burn models have correlated increased HE4 expression to inflammatory responses. These studies indicate that HE4 may play a significant role(s) in keratopathy and other physiopathological conditions of the\u00a0eye.<\/jats:p>","DOI":"10.1515\/biol-2025-1234","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T09:30:05Z","timestamp":1767087005000},"source":"Crossref","is-referenced-by-count":0,"title":["Overexpression of HE4\/WFDC2 gene in mice leads to keratitis and corneal opacity"],"prefix":"10.1515","volume":"20","author":[{"given":"Lingjin","family":"Tuo","sequence":"first","affiliation":[{"name":"Lianyungang Research Institute for Women\u2019s and Children\u2019s Health, Lianyungang Maternal and Child Health Hospital Affiliated to Kangda College of Nanjing Medical University , Lianyungang , Jiangsu Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taojun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Interventional Imaging , The First Affiliated Hospital of Shanxi Medical University , Taiyuan , Shanxi Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolun","family":"Xu","sequence":"additional","affiliation":[{"name":"Lianyungang Research Institute for Women\u2019s and Children\u2019s Health, Lianyungang Maternal and Child Health Hospital Affiliated to Kangda College of Nanjing Medical University , Lianyungang , Jiangsu Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology , Lianyungang Maternal and Child Health Hospital Affiliated to Kangda College of Nanjing Medical University , Lianyungang , Jiangsu Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-2859","authenticated-orcid":false,"given":"Fengchao","family":"Wang","sequence":"additional","affiliation":[{"name":"National Institute of Biological Sciences , Beijing , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3733-1420","authenticated-orcid":false,"given":"Hao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Gynecology , Lianyungang Maternal and Child Health Hospital Affiliated to Kangda College of Nanjing Medical University , Lianyungang , Jiangsu Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6309-8111","authenticated-orcid":false,"given":"Shi-Wen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Lianyungang Research Institute for Women\u2019s and Children\u2019s Health, Lianyungang Maternal and Child Health Hospital Affiliated to Kangda College of Nanjing Medical University , Lianyungang , Jiangsu Province , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"2025123009295952499_j_biol-2025-1234_ref_001","doi-asserted-by":"crossref","unstructured":"Flaxman, SR, Bourne, RRA, Resnikoff, S, Ackland, P, Braithwaite, T, Cicinelli, MV, et al.. Global causes of blindness and distance vision impairment 1990\u20132020: a systematic review and meta-analysis. Lancet Glob Health 2017;5:e1221\u201334. https:\/\/doi.org\/10.1016\/s2214-109x(17)30393-5.","DOI":"10.1016\/S2214-109X(17)30393-5"},{"key":"2025123009295952499_j_biol-2025-1234_ref_002","doi-asserted-by":"crossref","unstructured":"Wang, EY, Kong, X, Wolle, M, Gasquet, N, Ssekasanvu, J, Mariotti, SP, et al.. Global trends in blindness and vision impairment resulting from corneal opacity 1984\u20132020: a meta-analysis. Ophthalmology 2023;130:863\u201371. https:\/\/doi.org\/10.1016\/j.ophtha.2023.03.012.","DOI":"10.1016\/j.ophtha.2023.03.012"},{"key":"2025123009295952499_j_biol-2025-1234_ref_003","doi-asserted-by":"crossref","unstructured":"Kim, CK, Karslioglu, MZ, Zhao, SH, Lee, OL. Infectious Keratitis in patients over 65: a review on treatment and preserving eyesight. Clin Interv Aging 2024;19:1393\u2013405. https:\/\/doi.org\/10.2147\/cia.s467262.","DOI":"10.2147\/CIA.S467262"},{"key":"2025123009295952499_j_biol-2025-1234_ref_004","doi-asserted-by":"crossref","unstructured":"Wilson, SE, Sampaio, LP, Shiju, TM, Hilgert, GSL, de Oliveira, RC. Corneal opacity: cell biological determinants of the transition from transparency to transient haze to scarring fibrosis, and resolution, after injury. Investig Ophthalmol Vis Sci 2022;63:22. https:\/\/doi.org\/10.1167\/iovs.63.1.22.","DOI":"10.1167\/iovs.63.1.22"},{"key":"2025123009295952499_j_biol-2025-1234_ref_005","doi-asserted-by":"crossref","unstructured":"Ting, DSJ, Ho, CS, Deshmukh, R, Said, DG, Dua, HS. Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance. 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HE4 (WFDC2) promotes tumor growth in endometrial cancer cell lines. Int J Mol Sci 2013;14:6026\u201343. https:\/\/doi.org\/10.3390\/ijms14036026.","DOI":"10.3390\/ijms14036026"},{"key":"2025123009295952499_j_biol-2025-1234_ref_021","doi-asserted-by":"crossref","unstructured":"Anastasi, E, Farina, A, Granato, T, Colaiacovo, F, Pucci, B, Tartaglione, S, et al.. Recent insight about HE4 role in ovarian cancer oncogenesis. Int J Mol Sci 2023;24:10479. https:\/\/doi.org\/10.3390\/ijms241310479.","DOI":"10.3390\/ijms241310479"},{"key":"2025123009295952499_j_biol-2025-1234_ref_022","doi-asserted-by":"crossref","unstructured":"Moore, RG, Hill, EK, Horan, T, Yano, N, Kim, K, MacLaughlan, S, et al.. HE4 (WFDC2) gene overexpression promotes ovarian tumor growth. 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