{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:47:27Z","timestamp":1760147247297,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T00:00:00Z","timestamp":1674000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP19K09776","JP20K09654","JP22K09556","19216689"],"award-info":[{"award-number":["JP19K09776","JP20K09654","JP22K09556","19216689"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JP19K09776","JP20K09654","JP22K09556","19216689"],"award-info":[{"award-number":["JP19K09776","JP20K09654","JP22K09556","19216689"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Uterine leiomyomas are smooth-muscle tumors originating in the myometrium and are the most common pelvic tumors in women of reproductive age. Symptomatic tumors may result in abnormal uterine bleeding, bladder dysfunction, pelvic discomfort, and reproductive issues, such as infertility and miscarriage. There are currently few non-invasive treatments for leiomyoma, but there are no practical early intervention or preventive methods. In this study, human uterine leiomyoma and myometrial tissues were used to detect the protein and mRNA expression levels of UCHL1. To explore the effects of UCHL1 knockdown and inhibition in leiomyoma and myometrial cells, we determined the mRNA expressions of COL1A1 and COL3A1. Collagen gel contraction and wound-healing assays were performed on myometrial and leiomyoma cells. We found that UCHL1 expression was considerably higher in uterine leiomyomas than in the myometrium. COL1A1 and COL3A1 expression levels were downregulated after inhibition of UCHL1 in human leiomyoma cells. Furthermore, the elimination of UCHL1 significantly decreased the migration and contractility of leiomyoma cells. In conclusion, these results indicate that UCHL1 is involved in the growth of leiomyoma in humans. For the treatment of uterine leiomyoma, targeting UCHL1 activity may be a unique and possible therapeutic strategy.<\/jats:p>","DOI":"10.3390\/biom13020193","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T01:57:57Z","timestamp":1674007077000},"page":"193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pivotal Role of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) in Uterine Leiomyoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Tomoo","family":"Suzuki","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0968-8492","authenticated-orcid":false,"given":"Yidan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9249-6813","authenticated-orcid":false,"given":"Masanori","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junya","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3098-9406","authenticated-orcid":false,"given":"Hiroshi","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoaki","family":"Kuji","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirotaka","family":"Nishi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1111\/1471-0528.14640","article-title":"Epidemiology of uterine fibroids: A systematic review","volume":"124","author":"Stewart","year":"2017","journal-title":"BJOG"},{"key":"ref_2","first-page":"424","article-title":"Epidemiology of Uterine Myomas: A Review","volume":"9","author":"Sparic","year":"2016","journal-title":"Int. J. Fertil. Steril."},{"key":"ref_3","first-page":"1503","article-title":"Uterine fibroid tumors: Diagnosis and treatment","volume":"75","author":"Evans","year":"2007","journal-title":"Am. Fam. Physician."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1097\/GRF.0000000000000164","article-title":"Epidemiology of Uterine Fibroids: From Menarche to Menopause","volume":"59","author":"Wise","year":"2016","journal-title":"Clin. Obstet. Gynecol."},{"key":"ref_5","first-page":"182","article-title":"Obstetric characteristics and perinatal outcome of pregnancies with uterine leiomyomas","volume":"49","author":"Sheiner","year":"2004","journal-title":"J. Reprod. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1089\/jwh.2005.14.692","article-title":"The economic impact of uterine fibroids in the United States: A summary of published estimates","volume":"14","author":"Mauskopf","year":"2005","journal-title":"J. Womens Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.fertnstert.2016.05.001","article-title":"Decreased expression of microRNA-29 family in leiomyoma contributes to increased major fibrillar collagen production","volume":"106","author":"Marsh","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.yjmcc.2006.07.015","article-title":"Into the heart: The emerging role of the ubiquitin-proteasome system","volume":"41","author":"Willis","year":"2006","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1042\/BCJ20160082","article-title":"Ubiquitin C-terminal hydrolase L1 (UCH-L1): Structure, distribution and roles in brain function and dysfunction","volume":"473","author":"Bishop","year":"2016","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/s41440-020-0486-1","article-title":"Blockage of UCHL1 activity attenuates cardiac remodeling in spontaneously hypertensive rats","volume":"43","author":"Han","year":"2020","journal-title":"Hypertens. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"174045","DOI":"10.1016\/j.ejphar.2021.174045","article-title":"UCHL1 inhibition attenuates cardiac fibrosis via modulation of nuclear factor-kappaB signaling in fibroblasts","volume":"900","author":"Gong","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1093\/biolre\/ioac086","article-title":"The requirement of ubiquitin C-terminal hydrolase L1 in mouse ovarian development and fertilitydagger","volume":"107","author":"Woodman","year":"2022","journal-title":"Biol. Reprod."},{"key":"ref_13","first-page":"175","article-title":"Ubiquitin carboxyl-terminal hydrolase L1 contributes to the oocyte selective elimination in prepubertal mouse ovaries","volume":"61","author":"Gu","year":"2009","journal-title":"Sheng Li Xue Bao"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35857","DOI":"10.1074\/jbc.R300018200","article-title":"Non-traditional functions of ubiquitin and ubiquitin-binding proteins","volume":"278","author":"Schnell","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/hep.28933","article-title":"Deregulated neddylation in liver fibrosis","volume":"65","author":"Simon","year":"2017","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41389-022-00425-3","article-title":"A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase","volume":"11","author":"Mehine","year":"2022","journal-title":"Oncogenesis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12943-017-0672-1","article-title":"Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors","volume":"16","author":"Makinen","year":"2017","journal-title":"Mol. Cancer"},{"doi-asserted-by":"crossref","unstructured":"Ono, M., Qiang, W., Serna, V.A., Yin, P., Coon, J.S.T., Navarro, A., Monsivais, D., Kakinuma, T., Dyson, M., and Druschitz, S. (2012). Role of stem cells in human uterine leiomyoma growth. PLoS ONE, 7.","key":"ref_18","DOI":"10.1371\/journal.pone.0036935"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17053","DOI":"10.1073\/pnas.1313650110","article-title":"Paracrine activation of WNT\/beta-catenin pathway in uterine leiomyoma stem cells promotes tumor growth","volume":"110","author":"Ono","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1056\/NEJMra1209993","article-title":"Uterine fibroids","volume":"369","author":"Bulun","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1177\/1933719116682878","article-title":"Tranilast Inhibits Genes Functionally Involved in Cell Proliferation, Fibrosis, and Epigenetic Regulation and Epigenetically Induces miR-29c Expression in Leiomyoma Cells","volume":"24","author":"Chuang","year":"2017","journal-title":"Reprod. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1001\/jamaneurol.2016.0039","article-title":"Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients with and Without Mild Traumatic Brain Injury","volume":"73","author":"Papa","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6153","DOI":"10.1038\/ncomms7153","article-title":"UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1alpha","volume":"6","author":"Goto","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00030-18","DOI":"10.1128\/mSphere.00030-18","article-title":"C-Terminal Farnesylation of UCH-L1 Plays a Role in Transport of Epstein-Barr Virus Primary Oncoprotein LMP1 to Exosomes","volume":"3","author":"Kobayashi","year":"2018","journal-title":"mSphere"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1210\/me.2006-0206","article-title":"Accumulation of retinoid X receptor-alpha in uterine leiomyomas is associated with a delayed ligand-dependent proteasome-mediated degradation and an alteration of its transcriptional activity","volume":"21","author":"Lattuada","year":"2007","journal-title":"Mol. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/onc.2008.364","article-title":"Ubiquitin C-terminal hydrolase-L1 is a key regulator of tumor cell invasion and metastasis","volume":"28","author":"Kim","year":"2009","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neulet.2014.02.007","article-title":"Ubiquitin C-terminal hydrolase L1 interacts with choline transporter in cholinergic cells","volume":"564","author":"Hartnett","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13256","DOI":"10.1074\/jbc.M314124200","article-title":"Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson\u2019s and Alzheimer\u2019s diseases","volume":"279","author":"Choi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"H1817","DOI":"10.1152\/ajpheart.00445.2013","article-title":"Cardiac sympathetic innervation and PGP9.5 expression by cardiomyocytes after myocardial infarction: Effects of central MR blockade","volume":"305","author":"Drobysheva","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H551","DOI":"10.1152\/ajpheart.00771.2012","article-title":"Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure","volume":"305","author":"Rajagopalan","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.1158\/0008-5472.CAN-07-6339","article-title":"Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia","volume":"68","author":"Mayer","year":"2008","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1177\/1933719118776793","article-title":"Hypoxia Induces Hypoxia-Inducible Factor 1alpha and Potential HIF-Responsive Gene Expression in Uterine Leiomyoma","volume":"26","author":"Ishikawa","year":"2019","journal-title":"Reprod. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"18700","DOI":"10.1073\/pnas.0704472104","article-title":"Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells","volume":"104","author":"Ono","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"120238","DOI":"10.1016\/j.lfs.2021.120238","article-title":"Differential response to hypoxia in leiomyoma and myometrial cells","volume":"290","author":"Reschke","year":"2022","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.mehy.2011.08.026","article-title":"Hypoxia: The driving force of uterine myometrial stem cells differentiation into leiomyoma cells","volume":"77","author":"Zhou","year":"2011","journal-title":"Med. Hypotheses"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1093\/hmg\/ddg211","article-title":"Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron","volume":"12","author":"Osaka","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"116699","DOI":"10.1016\/j.lfs.2019.116699","article-title":"UCHL1 regulates muscle fibers and mTORC1 activity in skeletal muscle","volume":"233","author":"Gao","year":"2019","journal-title":"Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.bbrc.2017.08.027","article-title":"Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation","volume":"492","author":"Gao","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"doi-asserted-by":"crossref","unstructured":"Zhang, X., Guo, L., Niu, T., Shao, L., Li, H., Wu, W., Wang, W., Lv, L., Qin, Q., and Wang, F. (2014). Ubiquitin carboxyl terminal hydrolyase L1-suppressed autophagic degradation of p21WAF1\/Cip1 as a novel feedback mechanism in the control of cardiac fibroblast proliferation. PLoS ONE, 9.","key":"ref_39","DOI":"10.1371\/journal.pone.0094658"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6879","DOI":"10.1038\/s41598-017-06605-1","article-title":"UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization","volume":"7","author":"Nakashima","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/molehr\/gal018","article-title":"In vitro culture significantly alters gene expression profiles and reduces differences between myometrial and fibroid smooth muscle cells","volume":"12","author":"Zaitseva","year":"2006","journal-title":"Mol. Hum. Reprod."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.jhep.2015.07.034","article-title":"Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease","volume":"63","author":"Wilson","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1016\/j.fertnstert.2006.08.111","article-title":"Novel method to characterize primary cultures of leiomyoma and myometrium with the use of confirmatory biomarker gene arrays","volume":"87","author":"Malik","year":"2007","journal-title":"Fertil. Steril."},{"key":"ref_44","first-page":"900","article-title":"Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle","volume":"79","author":"Stewart","year":"1994","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1016\/j.fertnstert.2016.08.010","article-title":"Locostatin, a disrupter of Raf kinase inhibitor protein, inhibits extracellular matrix production, proliferation, and migration in human uterine leiomyoma and myometrial cells","volume":"106","author":"Janjusevic","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1002\/ijc.22025","article-title":"Silencing of the UCHL1 gene in human colorectal and ovarian cancers","volume":"119","author":"Nakazawa","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5982","DOI":"10.1158\/0008-5472.CAN-04-0993","article-title":"Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing","volume":"64","author":"Tokumaru","year":"2004","journal-title":"Cancer. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/hep.22343","article-title":"Epigenetic identification of ubiquitin carboxyl-terminal hydrolase L1 as a functional tumor suppressor and biomarker for hepatocellular carcinoma and other digestive tumors","volume":"48","author":"Yu","year":"2008","journal-title":"Hepatology"},{"key":"ref_49","first-page":"3735","article-title":"Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays","volume":"63","author":"Sato","year":"2003","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrd.2017.152","article-title":"Deubiquitylating enzymes and drug discovery: Emerging opportunities","volume":"17","author":"Harrigan","year":"2018","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.bbrc.2018.02.140","article-title":"Ubiquitin C-Terminal Hydrolase L1 regulates autophagy by inhibiting autophagosome formation through its deubiquitinating enzyme activity","volume":"497","author":"Yan","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"doi-asserted-by":"crossref","unstructured":"Kobayashi, E., Hwang, D., Bheda-Malge, A., Whitehurst, C.B., Kabanov, A.V., Kondo, S., Aga, M., Yoshizaki, T., Pagano, J.S., and Sokolsky, M. (2019). Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells. Int. J. Mol. Sci., 20.","key":"ref_52","DOI":"10.3390\/ijms20153733"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/193\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:08:50Z","timestamp":1760119730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,18]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["biom13020193"],"URL":"https:\/\/doi.org\/10.3390\/biom13020193","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2023,1,18]]}}}