{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T18:08:47Z","timestamp":1775930927407,"version":"3.50.1"},"reference-count":53,"publisher":"Georg Thieme Verlag KG","issue":"07","funder":[{"name":"Istanbul\n                        \u00dcniversitesi-Cerrahpasa","award":["31415"],"award-info":[{"award-number":["31415"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Exp Clin Endocrinol Diabetes"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cushing\u2019s disease is a rare endocrine disorder characterized by excessive\n                        endogenous glucocorticoid production, primarily resulting from\n                        adrenocorticotropic hormone-secreting pituitary neuroendocrine tumors\n                        (ACTH-PitNETs). This study investigated the expression of several genes\n                        implicated in the development of ACTH-PitNETs, including EGFR, USP8,\n                        CABLES1, USP2, STAM2, VPS28, HDAC2, IL-6, SMARCA4, WEE1, CDKN2A, CCND1,\n                        NR4A1, NEUROD1, and RIPK1. The methylation levels of the USP8 and CDKN2A\n                        genes were also assessed for insights into their regulatory mechanisms.<\/jats:p><jats:p>Formalin-fixed paraffin-embedded pituitary tumor tissue samples from 32\n                        patients diagnosed with ACTH-PitNET and 15 anterior pituitary tissue samples\n                        were analyzed. Gene expression was analyzed through quantitative reverse\n                        transcription polymerase chain reaction, while methylation was examined\n                        through methylation-specific polymerase chain reaction. All data were\n                        analyzed with IBM SPSS Statistics 21. The relationships among gene\n                        expressions were assessed using principal component analysis.<\/jats:p><jats:p>The expression of CABLES1, NR4A1, CCND1, NEUROD1, USP2, and WEE1 differed\n                        significantly between the patient and control groups. Additionally,\n                        significant correlations were observed between the levels of RIPK1, SMARCA4,\n                        and USP2 and pre-operative cortisol levels; WEE1 expression and\n                        pre-operative ACTH levels; CDKN2A expression and urinary cortisol levels;\n                        CABLES1, NEUROD1, SMARCA4, and STAM2 expression and post-operative cortisol\n                        levels at 48 h. CCND1 expression was correlated with adenoma size, while\n                        WEE1 expression was linked to remission status. Notably, the CDKN2A gene\n                        displayed partial methylation, whereas the USP8 gene was fully\n                        unmethylated.<\/jats:p><jats:p>The altered expression levels of the USP2, CABLES1, CDKN2A, and WEE1 may be\n                        closely associated with the development of ACTH-PitNETs. Notably, WEE1\n                        emerged as a target gene for predicting clinical remission in patients with\n                        Cushing\u2019s disease.<\/jats:p>","DOI":"10.1055\/a-2633-8467","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T22:33:05Z","timestamp":1753914785000},"page":"371-381","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Gene Expression Profile and Combined Effects in the\n                    Pathogenesis of Adrenocorticotropic Hormone-Secreting Pituitary Neuroendocrine\n                    Tumors"],"prefix":"10.1055","volume":"133","author":[{"given":"Sera","family":"Kayacan","sequence":"additional","affiliation":[{"name":"Medical Biology, Istanbul University-Cerrahpasa,\n                    Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nurperi","family":"Gazioglu","sequence":"additional","affiliation":[{"name":"Cerrahpasa Pituitary Center, Istanbul\n                    University-Cerrahpasa, Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ceren","family":"Orhan","sequence":"additional","affiliation":[{"name":"Medical Biology, Istanbul University-Cerrahpasa,\n                    Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nil","family":"Comunoglu","sequence":"additional","affiliation":[{"name":"Pathology, Istanbul University-Cerrahpasa, Istanbul,\n                    Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pinar","family":"Kadioglu","sequence":"additional","affiliation":[{"name":"Cerrahpasa Pituitary Center, Istanbul\n                    University-Cerrahpasa, Istanbul, Turkey"},{"name":"Internal Medicine, Endocrinology and Metabolism,\n                    Istanbul University-Cerrahpasa, Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Necmettin","family":"Tanriover","sequence":"additional","affiliation":[{"name":"Cerrahpasa Pituitary Center, Istanbul\n                    University-Cerrahpasa, Istanbul, Turkey"},{"name":"Neurosurgery, Istanbul University-Cerrahpasa, Istanbul,\n                    Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omer","family":"Uysal","sequence":"additional","affiliation":[{"name":"Medical Biostatistics, Istanbul University-Cerrahpasa,\n                    Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatma","family":"Kaya Dagistanli","sequence":"additional","affiliation":[{"name":"Medical Biology, Istanbul University-Cerrahpasa,\n                    Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melek","family":"Ozturk","sequence":"additional","affiliation":[{"name":"Medical Biology, Istanbul University-Cerrahpasa,\n                    Istanbul, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref1","volume-title":"Cushing&apos;s Disease: An Often Misdiagnosed and Not So Rare Disorder","author":"E R Laws","year":"2016"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s12022-022-09703-7","article-title":"Overview of the 2022 WHO classification of pituitary tumors","volume":"33","author":"S L Asa","year":"2022","journal-title":"Endocr Pathol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/cen.13457","article-title":"Genetics of Cushing\u2019s disease","volume":"88","author":"A Albani","year":"2018","journal-title":"Clin Endocrinol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"943","DOI":"10.2176\/nmc.ra.2014-0184","article-title":"The role of genetic and epigenetic changes in pituitary tumorigenesis","volume":"54","author":"H Fukuoka","year":"2014","journal-title":"Neurol Med Chir"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"102915","DOI":"10.1016\/j.arcmed.2023.102915","article-title":"Genomics, transcriptomics, and epigenetics of sporadic pituitary tumors","volume":"54","author":"D Marrero-Rodr\u00edguez","year":"2023","journal-title":"Arch Med Res"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"596554","DOI":"10.3389\/fendo.2020.596554","article-title":"Genetic and epigenetic causes of pituitary adenomas","volume":"11","author":"M Chang","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"785","DOI":"10.3389\/fendo.2019.00785","article-title":"Expression of EGFR in pituitary corticotroph adenomas and its relationship with\n                    tumor behavior","volume":"14","author":"X Liu","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/cr.2015.20","article-title":"Recurrent gain-of-function USP8 mutations in Cushing&apos;s disease","volume":"25","author":"Z Y Ma","year":"2015","journal-title":"Cell Res"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s12902-024-01619-z","article-title":"Targeted analysis of ubiquitin-specific peptidase (USP8) in a population of\n                    Iranian people with Cushing&apos;s disease and a systematic review of the\n                    literature","volume":"24","author":"N Hashemi-Madani","year":"2024","journal-title":"BMC Endocr Disord"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1038\/s42003-021-02802-x","article-title":"Molecular basis of ubiquitin-specific protease 8 autoinhibition by the WW-like\n                    domain","volume":"4","author":"K Kakihara","year":"2021","journal-title":"Commun Biol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/ng.3166","article-title":"Mutations in the deubiquitinase gene USP8 cause Cushing&apos;s disease","volume":"47","author":"M Reincke","year":"2015","journal-title":"Nat Genet"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"471221","DOI":"10.1172\/JCI60417","article-title":"EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting\n                    pituitary adenomas","volume":"121","author":"H Fukuoka","year":"2011","journal-title":"J Clin Investig"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"102899","DOI":"10.1016\/j.arcmed.2023.102899","article-title":"Clinical spectrum of USP8 pathogenic variants in Cushing&apos;s disease","volume":"54","author":"R G Rebollar-Vega","year":"2023","journal-title":"Arch Med Res"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1507\/endocrj.EJ19-0239","article-title":"Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone\n                    production and corticotroph tumor cell proliferation","volume":"67","author":"K Kageyama","year":"2020","journal-title":"Endocr J"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"108811","DOI":"10.1016\/j.abb.2021.108811","article-title":"The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling\n                    pathways targeting for cancer therapeutics","volume":"15","author":"M T Islam","year":"2021","journal-title":"Arch Biochem Biophys"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"5163","DOI":"10.1091\/mbc.E05- 06- 0560","article-title":"Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated\n                    deubiquitination at endosomes","author":"E Mizuno","year":"2005","journal-title":"Mol Biol Cell"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e1007456","DOI":"10.1371\/journal.pgen.1007456","article-title":"CHMP1B is a target of USP8\/UBPY regulated by ubiquitin during endocytosis","volume":"146","author":"X Crespo-Y\u00e0\u00f1ez","year":"2018","journal-title":"PLoS Genet"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1210\/js.2016-1053","article-title":"EGFR Induces E2F1-mediated corticotroph tumorigenesis","volume":"12","author":"T Araki","year":"2017","journal-title":"J Endocr Soc"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1507\/endocrj.EJ18-0491","article-title":"Lapatinib decreases the ACTH production and proliferation of corticotroph tumor\n                    cells","volume":"666","author":"Y Asari","year":"2019","journal-title":"Endocr J"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1124\/mol.116.107730","article-title":"The emerging role of Cables1 in cancer and other diseases","volume":"92","author":"J R Huang","year":"2017","journal-title":"Mol Pharmacol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1227\/00006123-199310000-00008","article-title":"Pituitary adenomas with invasion of the cavernous sinus space: A magnetic\n                    resonance imaging classification compared with surgical findings","volume":"33","author":"E Knosp","year":"1993","journal-title":"Neurosurgery"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1530\/EJE-10-1120","article-title":"Comparisons in the epidemiology, diagnostic features and cure rate by\n                    transsphenoidal surgery between paediatric and adult-onset Cushing&apos;s\n                    disease","volume":"164","author":"H L Storr","year":"2011","journal-title":"Eur J Endocrinol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"3097","DOI":"10.1210\/jcem.86.7.7616","article-title":"Novel patterns of gene expression in pituitary adenomas identified by\n                    complementary deoxyribonucleic acid microarrays and quantitative reverse\n                    transcription-polymerase chain reaction","volume":"86","author":"C O Evans","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/modpathol.3800965","article-title":"Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1\n                    (E-cadherin) genes correlate with aggressiveness of human pituitary\n                    adenomas","volume":"20","author":"Z R Qian","year":"2007","journal-title":"Mod Pathol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and\n                    the 2(-delta delta C(T)) method","volume":"25","author":"K J Livak","year":"2001","journal-title":"Methods"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"9821","DOI":"10.1073\/pnas.93.18.9821","article-title":"Methylation-specific PCR: A novel PCR assay for methylation status of CpG\n                    islands","volume":"93","author":"J G Herman","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"E997","DOI":"10.1210\/jc.2015-1453","article-title":"The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas\n                    causing Cushing&apos;s disease","volume":"100","author":"L G Perez-Rivas","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3892\/br.2016.729","article-title":"Gene mutations in Cushing&apos;s disease","volume":"5","author":"Q Xiong","year":"2016","journal-title":"Biomed Rep"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.cellsig.2014.11.009","article-title":"The interplay of NR4A receptors and the oncogene-tumor suppressor networks in\n                    cancer","volume":"27","author":"J A Beard","year":"2015","journal-title":"Cell Signal"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1210\/jc.2015-3324","article-title":"The Cables1 gene in glucocorticoid regulation of pituitary corticotrope growth\n                    and Cushing disease","volume":"101","author":"A Roussel-Gervais","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1507\/endocrj.EJ19-0239","article-title":"Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone\n                    production and corticotroph tumor cell proliferation","volume":"67","author":"K Kageyama","year":"2020","journal-title":"Endocr J"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"73705","DOI":"10.18632\/oncotarget.17848","article-title":"Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer\n                    cells to paclitaxel","volume":"8","author":"C W Lewis","year":"2017","journal-title":"Oncotarget"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1186\/s13045-020-00959-2","article-title":"WEE1 family business: Regulation of mitosis, cancer progression, and therapeutic\n                    target","volume":"13","author":"A Ghelli Luserna di Ror\u00e0","year":"2020","journal-title":"J Hematol Oncol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1093\/carcin\/bgad038","article-title":"Combined Wee1 and EGFR inhibition reveals synergistic antitumor effect in\n                    esophageal squamous cell carcinoma","volume":"44","author":"D Chen","year":"2023","journal-title":"Carcinogenesis"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2992","DOI":"10.1158\/1535-7163.MCT-09-0463","article-title":"Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes\n                    p53-deficient tumor cells to DNA-damaging agents","volume":"8","author":"H Hirai","year":"2009","journal-title":"Mol Cancer Ther"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"5638","DOI":"10.1158\/1078-0432.CCR-11-0650","article-title":"MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human\n                    tumor cells","volume":"17","author":"K A Bridges","year":"2011","journal-title":"Clin Cancer Res"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1158\/1535-7163","article-title":"Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics\n                    in vitro and in vivo, independent of p53 functionality","volume":"12","author":"A A Van Linden","year":"2013","journal-title":"Mol Cancer Ther"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"176","DOI":"10.3892\/or.2023.8613","article-title":"Targeting the deubiquitinase USP2 for malignant tumor therapy\n                    (Review)","volume":"50","author":"S Zhang","year":"2023","journal-title":"Oncol Rep"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1016\/j.bbamcr.2012.05.022","article-title":"De-ubiquitinating proteases USP2a and USP2c cause apoptosis by stabilising\n                    RIP1","volume":"1823","author":"A L Mahul-Mellier","year":"2012","journal-title":"Biochim Biophys Acta"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1136\/jclinpath-2018-205216","article-title":"p16","volume":"71","author":"S Serra","year":"2018","journal-title":"J Clin Pathol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"5566","DOI":"10.1021\/bi200642e","article-title":"Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to\n                    cancer","volume":"50","author":"J Li","year":"2011","journal-title":"Biochemistry"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1677\/JME-08-0146","article-title":"Cell cycle control of pituitary development and disease","volume":"42","author":"V Quereda","year":"2009","journal-title":"J Mol Endocrinol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s11060-006-9316-9","article-title":"Promoter hypermethylation profile of cell cycle regulator genes in pituitary\n                    adenomas","volume":"83","author":"A Yoshino","year":"2007","journal-title":"J Neurooncol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.1002\/ijc.27316","article-title":"Cellular senescence and tumor suppressor gene p16","volume":"130","author":"H Rayess","year":"2012","journal-title":"Int J Cancer"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1158\/1078-0432.ccr-1127-3","article-title":"Molecular pathology shows p16 methylation in nonadenomatous pituitaries from\n                    patients with Cushing&apos;s disease","volume":"10","author":"D J Simpson","year":"2004","journal-title":"Clin Cancer Res"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1677\/JOE-07-0020","article-title":"Differential expression of neurogenins and NeuroD1 in human pituitary\n                    tumours","volume":"194","author":"A Fratticci","year":"2007","journal-title":"J Endocrinol"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1007\/BF03348192","article-title":"Human pituitary tumours express the bHLH transcription factors NeuroD1 and\n                    ASH1","volume":"26","author":"E Ferretti","year":"2003","journal-title":"J Endocrinol Invest"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"6673","DOI":"10.1128\/MCB.17.11.6673","article-title":"NeuroD1\/beta2 contributes to cell-specific transcription of the\n                    proopiomelanocortin gene","volume":"17","author":"G Poulin","year":"1997","journal-title":"Mol Cell Biol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"e0175435","DOI":"10.1371\/journal.pone.0175435","article-title":"Role of NeuroD1 on the negative regulation of Pomc expression by\n                    glucocorticoid","volume":"12","author":"R Parvin","year":"2017","journal-title":"PLoS One"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"e3346","DOI":"10.1210\/clinem\/dgab387","article-title":"Two distinctive POMC promoters modify gene expression in Cushing disease","volume":"106","author":"T Araki","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"289","DOI":"10.18632\/oncotarget.26513","article-title":"Analysis of pituitary adenoma expression patterns suggests a potential role for\n                    the NeuroD1 transcription factor in neuroendocrine tumor-targeting\n                    therapies","volume":"10","author":"L B Mitrofanova","year":"2019","journal-title":"Oncotarget"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"E17","DOI":"10.3171\/2014.10.FOCUS14683","article-title":"Gene and protein expression in pituitary corticotroph adenomas: A systematic\n                    review of the literature","volume":"38","author":"J Seltzer","year":"2015","journal-title":"Neurosurg Focus"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1038\/modpathol.3880408","article-title":"Expression of neuro D1 in human normal pituitaries and pituitary adenomas","volume":"14","author":"K Oyama","year":"2001","journal-title":"Mod Pathol"}],"container-title":["Experimental and Clinical Endocrinology &amp; Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2633-8467.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T22:33:10Z","timestamp":1753914790000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2633-8467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":53,"journal-issue":{"issue":"07","published-online":{"date-parts":[[2025,7,30]]},"published-print":{"date-parts":[[2025,7]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2633-8467","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0947-7349","1439-3646"],"issn-type":[{"value":"0947-7349","type":"print"},{"value":"1439-3646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]}}}