{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:50:33Z","timestamp":1789685433876,"version":"4.0.1"},"reference-count":82,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T00:00:00Z","timestamp":1564531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2P01-CA19014-26"],"award-info":[{"award-number":["2P01-CA19014-26"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54CA198999"],"award-info":[{"award-number":["U54CA198999"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein\u2013Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.<\/jats:p>","DOI":"10.3390\/ijms20153733","type":"journal-article","created":{"date-parts":[[2019,7,31]],"date-time":"2019-07-31T11:37:07Z","timestamp":1564573027000},"page":"3733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells"],"prefix":"10.3390","volume":"20","author":[{"given":"Eiji","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duhyeong","family":"Hwang","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali","family":"Bheda-Malge","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Whitehurst","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Kabanov","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119992 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Kondo","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuharu","family":"Aga","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomokazu","family":"Yoshizaki","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Pagano","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Sokolsky","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery and Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Shakelford","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Department of Immunology and Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nrm3099","article-title":"The spatial and temporal organization of ubiquitin networks","volume":"12","author":"Grabbe","year":"2011","journal-title":"Nat. Rev. Mol. Cell Boil."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7298","DOI":"10.1038\/srep07298","article-title":"Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer\u2019s progression in vivo","volume":"4","author":"Zhang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s10555-017-9702-0","article-title":"Ubiquitin carboxyl-terminal hydrolases: Involvement in cancer progression and clinical implications","volume":"36","author":"Shen","year":"2017","journal-title":"Cancer Metastasis Rev."},{"key":"ref_4","first-page":"1","article-title":"The potential role of ubiquitin c-terminal hydrolases in oncogenesis","volume":"1806","author":"Fang","year":"2010","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2174\/0929866521666140403125959","article-title":"Ubiquitin carboxyl hydrolase L1 significance for human diseases","volume":"21","author":"Suong","year":"2014","journal-title":"Protein Pept. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1038\/leu.2010.138","article-title":"The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling","volume":"24","author":"Hussain","year":"2010","journal-title":"Leukemia"},{"key":"ref_8","first-page":"123706","article-title":"Ubiquitin C-Terminal Hydrolase L1 in Tumorigenesis","volume":"2012","author":"Chin","year":"2012","journal-title":"Biochem. Res. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/1476-4598-10-129","article-title":"Ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is a potential tumour suppressor in prostate cancer and is frequently silenced by promoter methylation","volume":"10","author":"Ummanni","year":"2011","journal-title":"Mol. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1038\/sj.onc.1205390","article-title":"Interaction and colocalization of PGP9.5 with JAB1 and p27Kip1","volume":"21","author":"Caballero","year":"2002","journal-title":"Oncogene"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Bheda, A., Yue, W., Gullapalli, A., Whitehurst, C., Liu, R., Pagano, J.S., and Shackelford, J. (2009). Positive Reciprocal Regulation of Ubiquitin C-Terminal Hydrolase L1 and \u03b2-Catenin\/TCF Signaling. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005955"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2564","DOI":"10.1182\/blood-2018-05-848515","article-title":"UCH-L1 bypasses mTOR to promote protein biosynthesis and is required for MYC-driven lymphomagenesis in mice","volume":"132","author":"Hussain","year":"2018","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.virol.2013.10.018","article-title":"KSHV LANA and EBV LMP1 induce the expression of UCH-L1 following viral transformation","volume":"448","author":"Bentz","year":"2014","journal-title":"Virology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bheda, A., Shackelford, J., and Pagano, J.S. (2009). Expression and Functional Studies of Ubiquitin C-Terminal Hydrolase L1 Regulated Genes. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006764"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.3109\/10428194.2011.562571","article-title":"PU.1-dependent regulation of UCH L1 expression in B-lymphoma cells","volume":"52","author":"Bheda","year":"2011","journal-title":"Leuk. Lymphoma"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1073\/pnas.0308411100","article-title":"Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells","volume":"101","author":"Ovaa","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/mc.20177","article-title":"Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines","volume":"45","author":"Kobzeva","year":"2006","journal-title":"Mol. Carcinog."},{"key":"ref_18","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_19","first-page":"12500","article-title":"UCH-L1 involved in regulating the degradation of EGFR and promoting malignant properties in drug-resistant breast cancer","volume":"8","author":"Jin","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1002\/mc.22376","article-title":"Overexpression of ubiquitin carboxyl terminal hydrolase-L1 enhances multidrug resistance and invasion\/metastasis in breast cancer by activating the MAPK\/Erk signaling pathway","volume":"55","author":"Wang","year":"2016","journal-title":"Mol. Carcinog."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.canlet.2011.01.006","article-title":"UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction","volume":"302","author":"Jang","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16287","DOI":"10.18632\/oncotarget.3843","article-title":"Ubiquitin C-terminal hydrolase-L1 increases cancer cell invasion by modulating hydrogen peroxide generated via NADPH oxidase 4","volume":"6","author":"Kim","year":"2015","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5060","DOI":"10.1096\/fj.12-211946","article-title":"Ubiquitin C-terminal hydrolase-L1 interacts with adhesion complexes and promotes cell migration, survival, and anchorage independent growth","volume":"26","author":"Frisan","year":"2012","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.canlet.2014.12.001","article-title":"Heterogeneous expression and biological function of ubiquitin carboxy-terminal hydrolase-L1 in osteosarcoma","volume":"359","author":"Zheng","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.chembiol.2003.08.010","article-title":"Discovery of Inhibitors that Elucidate the Role of UCH-L1 Activity in the H1299 Lung Cancer Cell Line","volume":"10","author":"Liu","year":"2003","journal-title":"Chem. Boil."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.neuint.2010.01.016","article-title":"Identification of a novel chemical potentiator and inhibitors of UCH-L1 by in silico drug screening","volume":"56","author":"Mitsui","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/j.bbrc.2017.11.051","article-title":"Ubiquitin C-terminal hydrolase-L1 plays a key role in angiogenesis by regulating hydrogen peroxide generated by NADPH oxidase 4","volume":"495","author":"Song","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nrc3601","article-title":"A central role for vesicle trafficking in epithelial neoplasia: Intracellular highways to carcinogenesis","volume":"13","author":"Goldenring","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10585-006-9014-1","article-title":"Invadopodia: Specialized Cell Structures for Cancer Invasion","volume":"23","author":"Weaver","year":"2006","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1042\/EBC20170080","article-title":"Extracellular vesicles: Important collaborators in cancer progression","volume":"62","author":"Sato","year":"2018","journal-title":"Essays Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1042\/BCJ20160006","article-title":"Extracellular vesicles: Their role in cancer biology and epithelial-mesenchymal transition","volume":"474","author":"Gopal","year":"2017","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.21873\/cgp.20015","article-title":"The Multiple Roles of Exosomes in Metastasis","volume":"14","author":"Weidle","year":"2017","journal-title":"Cancer Genom. Proteom."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ceb.2014.07.003","article-title":"Illuminating breast cancer invasion: Diverse roles for cell\u2013cell interactions","volume":"30","author":"Cheung","year":"2014","journal-title":"Curr. Opin. Cell Boil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6735","DOI":"10.1021\/bi960099f","article-title":"Substrate Binding and Catalysis by Ubiquitin C-Terminal Hydrolases: Identification of Two Active Site Residues","volume":"35","author":"Larsen","year":"1996","journal-title":"Biochemistry"},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0092-8674(02)01012-7","article-title":"The UCH-L1 Gene Encodes Two Opposing Enzymatic Activities that Affect a-Synuclein Degradation and Parkinson\u2019s Disease Susceptibility","volume":"111","author":"Liu","year":"2002","journal-title":"Cell"},{"key":"ref_37","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_38","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-1\u03b1","volume":"6","author":"Goto","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1016\/j.biomaterials.2010.02.057","article-title":"Doubly-Amphiphilic Poly (2-oxazoline) s as High-Capacity Delivery Systems for Hydrophobic Drugs","volume":"31","author":"Luxenhofer","year":"2010","journal-title":"Biomaterials"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2018.10.032","article-title":"Co-delivery of paclitaxel and cisplatin in poly(2-oxazoline) polymeric micelles: Implications for drug loading, release, pharmacokinetics and outcome of ovarian and breast cancer treatments","volume":"192","author":"Wan","year":"2019","journal-title":"Biomaterials"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1021\/acsnano.7b07878","article-title":"Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer","volume":"12","author":"Wan","year":"2018","journal-title":"ACS Nano"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.biomaterials.2016.06.002","article-title":"A High Capacity Polymeric Micelle of Paclitaxel: Implication of High Dose Drug Therapy to Safety and In Vivo Anti-Cancer Activity","volume":"101","author":"He","year":"2016","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4635","DOI":"10.1073\/pnas.0806474106","article-title":"Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson\u2019s disease","volume":"106","author":"Liu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1111\/j.1462-5822.2010.01495.x","article-title":"The ubiquitin C-terminal hydrolase UCH-L1 promotes bacterial invasion by altering the dynamics of the actin cytoskeleton","volume":"12","author":"Coppotelli","year":"2010","journal-title":"Cell. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jprot.2013.01.012","article-title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine","volume":"82","author":"Prunotto","year":"2013","journal-title":"J. Proteom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1111\/cas.13473","article-title":"Modulation of the tumor microenvironment by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma","volume":"109","author":"Yoshizaki","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5223","DOI":"10.1128\/MCB.24.12.5223-5234.2004","article-title":"Epstein-Barr Virus Latent Membrane Protein 1 Induces Synthesis of Hypoxia-Inducible Factor 1\u03b1","volume":"24","author":"Wakisaka","year":"2004","journal-title":"Mol. Cell. Boil."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9870","DOI":"10.1158\/0008-5472.CAN-06-1679","article-title":"EBV Latent Membrane Protein 1 Up-regulates Hypoxia-Inducible Factor 1A through Siah1-Mediated Down-regulation of Prolyl Hydroxylases 1 and 3 in Nasopharyngeal Epithelial Cells","volume":"66","author":"Kondo","year":"2006","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11010-008-9862-x","article-title":"Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor","volume":"318","author":"Tan","year":"2008","journal-title":"Mol. Cell. Biochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ab.2014.09.021","article-title":"Development of surface plasmon resonance imaging biosensors for detection of ubiquitin carboxyl-terminal hydrolase L1","volume":"469","author":"Sankiewicz","year":"2015","journal-title":"Anal. Biochem."},{"key":"ref_51","first-page":"195727","article-title":"Drug Solubility: Importance and Enhancement Techniques","volume":"2012","author":"Savjani","year":"2012","journal-title":"ISRN Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/ijc.20849","article-title":"Epstein-Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: Enhanced susceptibility to nasopharyngeal carcinoma","volume":"115","author":"Kondo","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1158\/0008-5472.CAN-06-3933","article-title":"Twist and Epithelial-Mesenchymal Transition Are Induced by the EBV Oncoprotein Latent Membrane Protein 1 and Are Associated with Metastatic Nasopharyngeal Carcinoma","volume":"67","author":"Horikawa","year":"2007","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1038\/onc.2009.20","article-title":"Phosphorylated ezrin is associated with EBV latent membrane protein 1 in nasopharyngeal carcinoma and induces cell migration","volume":"28","author":"Endo","year":"2009","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11255","DOI":"10.1128\/JVI.00188-11","article-title":"Epstein-Barr Virus Latent Membrane Protein 1 Induces Cancer Stem\/Progenitor-Like Cells in Nasopharyngeal Epithelial Cell Lines","volume":"85","author":"Kondo","year":"2011","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.critrevonc.2018.09.017","article-title":"Crosstalk in cancer resistance and metastasis","volume":"132","author":"Norouzi","year":"2018","journal-title":"Crit. Rev. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S1368-8375(03)00015-0","article-title":"Establishment of an oral squamous cell carcinoma cell line with high invasive and p27 degradation activities from a lymph node metastasis","volume":"39","author":"Kudo","year":"2003","journal-title":"Oral. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/j.1600-0714.1989.tb01570.x","article-title":"Variant sublines with different metastatic potentials selected in nude mice from human oral squamous cell carcinomas","volume":"18","author":"Momose","year":"1989","journal-title":"J. Oral. Pathol. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2013.05.018","article-title":"Pathogenic role of Epstein\u2013Barr virus latent membrane protein-1 in the development of nasopharyngeal carcinoma","volume":"337","author":"Yoshizaki","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"980","DOI":"10.4161\/cc.9.5.10934","article-title":"Ubiquitin editing enzyme UCH L1 and microtubule dynamics: Implication in mitosis","volume":"9","author":"Bheda","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1038\/onc.2014.66","article-title":"Exosomal HIF1\u03b1 supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes","volume":"33","author":"Aga","year":"2014","journal-title":"Oncogene"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1111\/j.1582-4934.2008.00501.x","article-title":"The ubiquitin C-terminal hydrolase UCH-L1 regulates B-cell proliferation and integrin activation","volume":"13","author":"Freda","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1182\/blood-2015-07-656678","article-title":"UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma","volume":"127","author":"Bedekovics","year":"2016","journal-title":"Blood"},{"key":"ref_64","first-page":"192","article-title":"PGP9.5 as a marker for invasive colorectal cancer","volume":"8","author":"Yamazaki","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_65","first-page":"2697","article-title":"PGP9.5 methylation as a marker for metastatic colorectal cancer","volume":"28","author":"Mizukami","year":"2008","journal-title":"Anticancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1002\/ijc.25443","article-title":"A Survey of Methylated Candidate Tumor Suppressor Genes in Nasopharyngeal Carcinoma","volume":"128","author":"Loyo","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1309\/AJCPRJP39MIDSGBH","article-title":"Significance of PGP9.5 Expression in Cancer-Associated Fibroblasts for Prognosis of Colorectal Carcinoma","volume":"134","author":"Ino","year":"2010","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.3389\/fimmu.2017.01174","article-title":"Extracellular Vesicles Arising from Apoptotic Cells in Tumors: Roles in Cancer Pathogenesis and Potential Clinical Applications","volume":"8","author":"Lynch","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_69","first-page":"538","article-title":"Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside","volume":"1868","author":"Wu","year":"2017","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mam.2017.11.009","article-title":"Extracellular vesicles compartment in liquid biopsies: Clinical application","volume":"60","author":"Rackov","year":"2018","journal-title":"Mol. Asp. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"20160479","DOI":"10.1098\/rstb.2016.0479","article-title":"Why the need and how to approach the functional diversity of extracellular vesicles","volume":"373","author":"Tkach","year":"2018","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"20160485","DOI":"10.1098\/rstb.2016.0485","article-title":"Tumour\u2013adipose tissue crosstalk: Fuelling tumour metastasis by extracellular vesicles","volume":"373","author":"Peinado","year":"2018","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.bbcan.2017.11.005","article-title":"The key role of extracellular vesicles in the metastatic process","volume":"1869","author":"Zhao","year":"2018","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"O\u2019Neill, C.P., Gilligan, K.E., and Dwyer, R.M. (2019). Role of Extracellular Vesicles (EVs) in Cell Stress Response and Resistance to Cancer Therapy. Cancers, 11.","DOI":"10.3390\/cancers11020136"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12929-019-0500-6","article-title":"Cross-talk between cancer cells and their neighbors via miRNA in extracellular vesicles: An emerging player in cancer metastasis","volume":"26","author":"Kogure","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/jso.24614","article-title":"UCH-L1-containing exosomes mediate chemotherapeutic resistance transfer in breast cancer","volume":"115","author":"Ning","year":"2017","journal-title":"J. Surg. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s10555-017-9693-x","article-title":"Progression of understanding for the role of Epstein-Barr virus and management of nasopharyngeal carcinoma","volume":"36","author":"Nakanishi","year":"2017","journal-title":"Cancer Metastasis Rev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.anl.2011.02.012","article-title":"Current understanding and management of nasopharyngeal carcinoma","volume":"39","author":"Yoshizaki","year":"2012","journal-title":"Auris Nasus Larynx"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.tim.2016.03.008","article-title":"Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers","volume":"24","author":"Pagano","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/cas.12079","article-title":"Tumor-targeted chemotherapy with the nanopolymer-based drug NC-6004 for oral squamous cell carcinoma","volume":"104","author":"Endo","year":"2013","journal-title":"Cancer Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.2147\/IJN.S60564","article-title":"Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016)","volume":"9","author":"Ueno","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transplant."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/15\/3733\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:11:28Z","timestamp":1760188288000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/15\/3733"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,31]]},"references-count":82,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["ijms20153733"],"URL":"https:\/\/doi.org\/10.3390\/ijms20153733","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,31]]}}}