{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T07:33:00Z","timestamp":1762068780894,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: FK506 binding protein like (FKBPL) is a member of the immunophilin family, with anti-angiogenic effects capable of inhibiting the migration of endothelial cells and blood vessel formation. Its role as an inhibitor of tumor growth and angiogenesis has previously been shown in studies with breast and ovarian cancer. The role of FKBPL in angiogenesis, growth, and carcinogenesis of endometrioid endometrial carcinoma (EEC) is still largely unknown. The aim of this study was to examine the expression of FKBPL in EEC and benign endometrial hyperplasia (BEH) and its correlation with the expression of vascular endothelial factor-A (VEGF-A) and estrogen receptor alpha (ER\u03b1). Materials and Methods: Specimens from 89 patients with EEC and 40 patients with BEH, as well as histological, clinical, and demographic data, were obtained from the Clinical Hospital Centre Zemun, Belgrade, Serbia over a 10-year period (2010\u20132020). Immunohistochemical staining of the tissue was performed for FKBPL, VEGF-A, and ER\u03b1. Slides were analyzed blind by two pathologists, who measured the intensity of FKBPL and VEGF-A expression and used the Allred score to determine the level of ER\u03b1 expression. Results: Immunohistochemical analysis showed moderate to high intensity of FKBPL expression in 97.5% (n = 39) of samples of BEH, and low or no expression in 93.3% (n = 83) of cases of EEC. FKBPL staining showed a high positive predictive value (98.8%) and a high negative predictive value for malignant diagnosis (86.7%). The difference in FKBPL expression between EEC and BEH was statistically significant (p &lt; 0.001), showing a decrease in intensity and loss of expression in malignant tissues of the endometrium. FKBPL expression was positively correlated with ER\u03b1 expression (intensity, percentage and high Allred score values) and negatively correlated with the expression of VEGF-A (p &lt; 0.05 for all). Conclusions: FKBPL protein expression demonstrated a significant decrease in FKBPL in EEC in comparison to BEH tissue, with a high predictive value for malignancy. FKBPL might be emerging as a significant protein with antiangiogenic and antineoplastic effects, showing great promise for the diagnostic and therapeutic applications of its therapeutic derivatives in gynecological oncology.<\/jats:p>","DOI":"10.3390\/medicina58101330","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T21:10:05Z","timestamp":1663881005000},"page":"1330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Loss of Expression of Antiangiogenic Protein FKBPL in Endometrioid Endometrial Carcinoma: Implications for Clinical Practice"],"prefix":"10.3390","volume":"58","author":[{"given":"Danilo D.","family":"Obradovi\u0107","sequence":"first","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nata\u0161a M.","family":"Mili\u0107","sequence":"additional","affiliation":[{"name":"Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nenad","family":"Miladinovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathology, Clinical Hospital Centre Zemun, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lana","family":"McClements","sequence":"additional","affiliation":[{"name":"Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dejan M.","family":"Opri\u0107","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"ref_1","unstructured":"American Cancer Society (2021). Cancer Facts & Figures 2021, American Cancer Society."},{"key":"ref_2","unstructured":"Organisation Mondiale de la Sant\u00e9, and Centre International de Recherche sur le Cancer (2020). Female Genital Tumours, International Agency for Research on Cancer. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/0090-8258(83)90111-7","article-title":"Two Pathogenetic Types of Endometrial Carcinoma","volume":"15","author":"Bokhman","year":"1983","journal-title":"Gynecol. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1097\/AOG.0b013e3182605bf1","article-title":"Endometrial Cancer","volume":"120","author":"Sorosky","year":"2012","journal-title":"Obstet. Gynecol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1093\/ajcp\/aqv014","article-title":"Endometrial Carcinoma: Role of Current and Emerging Biomarkers in Resolving Persistent Clinical Dilemmas","volume":"145","author":"Buhtoiarova","year":"2016","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S64","DOI":"10.1097\/PGP.0000000000000518","article-title":"Endometrial Carcinoma Diagnosis: Use of FIGO Grading and Genomic Subcategories in Clinical Practice","volume":"38","author":"Soslow","year":"2019","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_7","first-page":"7","article-title":"Cytonuclear Estrogen Receptor Alpha Regulates Proliferation and Migration of Endometrial Carcinoma Cells","volume":"46","author":"Saimi","year":"2021","journal-title":"Tokai J. Exp. Clin. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.ygyno.2016.03.006","article-title":"Estrogen Receptor-Alpha as a Predictive Biomarker in Endometrioid Endometrial Cancer","volume":"141","author":"Backes","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ro\u0161kar, L., Ro\u0161kar, I., Ri\u017ener, T.L., and Smrkolj, \u0160. (2021). Diagnostic and Therapeutic Values of Angiogenic Factors in Endometrial Cancer. Biomolecules, 12.","DOI":"10.3390\/biom12010007"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.ygyno.2020.12.016","article-title":"Angiogenesis in Endometrial Carcinoma: Therapies and Biomarkers, Current Options, and Future Perspectives","volume":"160","author":"Berger","year":"2021","journal-title":"Gynecol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"955","DOI":"10.2174\/1389201020666190717092448","article-title":"Changes in the Expression Profile of VEGF-A, VEGF-B, VEGFR-1, VEGFR-2 in Different Grades of Endometrial Cancer","volume":"20","author":"Dziobek","year":"2019","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12209","DOI":"10.18632\/oncotarget.3528","article-title":"FKBPL: A Marker of Good Prognosis in Breast Cancer","volume":"6","author":"Nelson","year":"2015","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"McClements, L., Annett, S., Yakkundi, A., O\u2019Rourke, M., Valentine, A., Moustafa, N., Alqudah, A., Sim\u00f5es, B.M., Furlong, F., and Short, A. (2019). FKBPL and Its Peptide Derivatives Inhibit Endocrine Therapy Resistant Cancer Stem Cells and Breast Cancer Metastasis by Downregulating DLL4 and Notch4. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5500-0"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1158\/0008-5472.CAN-09-2515","article-title":"FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy","volume":"70","author":"McKeen","year":"2010","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41416-019-0649-5","article-title":"FKBPL-Based Peptide, ALM201, Targets Angiogenesis and Cancer Stem Cells in Ovarian Cancer","volume":"122","author":"Annett","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1002\/gcc.22182","article-title":"Simultaneous Analysis of the Gene Expression Profiles of Cancer and Stromal Cells in Endometrial Cancer: Stromal Gene Expression of Endometrial Cancer","volume":"53","author":"Iguchi","year":"2014","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_17","unstructured":"(2022, August 04). Tissue Expression of FKBPL-Staining in Endometrium\u2014The Human Protein Atlas. Available online: https:\/\/www.proteinatlas.org\/ENSG00000204315-FKBPL\/tissue\/endometrium."},{"key":"ref_18","unstructured":"(2022, August 04). Expression of FKBPL in Endometrial Cancer\u2014The Human Protein Atlas. Available online: https:\/\/www.proteinatlas.org\/ENSG00000204315-FKBPL\/pathology\/endometrial+cancer."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s00280-017-3342-5","article-title":"Allred Score Is a Promising Predictor of Prognosis and Medroxyprogesterone Acetate Efficacy in Patients with Endometrial Cancer","volume":"80","author":"Yunokawa","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1158\/1078-0432.CCR-10-2241","article-title":"FKBPL and Peptide Derivatives: Novel Biological Agents That Inhibit Angiogenesis by a CD44-Dependent Mechanism","volume":"17","author":"Valentine","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1161\/ATVBAHA.114.304539","article-title":"FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis","volume":"35","author":"Yakkundi","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1316","DOI":"10.1073\/pnas.1615233114","article-title":"Estrogen Receptor \u03b1 Wields Treatment-Specific Enhancers between Morphologically Similar Endometrial Tumors","volume":"114","author":"Droog","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41416-022-01780-z","article-title":"A First-in-Human Phase I Dose-Escalation Trial of the Novel Therapeutic Peptide, ALM201, Demonstrates a Favourable Safety Profile in Unselected Patients with Ovarian Cancer and Other Advanced Solid Tumours","volume":"127","author":"Plummer","year":"2022","journal-title":"Br. J. Cancer"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/10\/1330\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:37:29Z","timestamp":1760143049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/10\/1330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,22]]},"references-count":23,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["medicina58101330"],"URL":"https:\/\/doi.org\/10.3390\/medicina58101330","relation":{},"ISSN":["1648-9144"],"issn-type":[{"type":"electronic","value":"1648-9144"}],"subject":[],"published":{"date-parts":[[2022,9,22]]}}}