{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:28:57Z","timestamp":1789043337660,"version":"build-2803163510"},"reference-count":103,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T00:00:00Z","timestamp":1620604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Asparagine endopeptidase (AEP), also called legumain, is currently the only known cysteine protease that specifically cleaves peptide bonds in asparaginyl residue in the mammalian genome. Since 2003, AEP has been reported to be widely expressed in a variety of carcinomas and is considered a potential therapeutic target. In the following years, researchers intensively investigated the substrates of AEP and the mechanism of AEP in partial tumors. With the identification of substrate proteins such as P53, integrin \u03b1v\u03b23, MMP-2, and MMP-9, the biochemical mechanism of AEP in carcinomas is also more precise. This review will clarify the probable mechanisms of AEP in the progression of breast carcinoma, glioblastoma, gastric carcinoma, and epithelial ovarian carcinoma. This review will also discuss the feasibility of targeted therapy with AEP inhibitor (AEPI) in these carcinomas.<\/jats:p>","DOI":"10.3390\/cells10051153","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T10:49:51Z","timestamp":1620643791000},"page":"1153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["The Mechanism of Asparagine Endopeptidase in the Progression of Malignant Tumors: A Review"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5959-489X","authenticated-orcid":false,"given":"Wenrui","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6935-5681","authenticated-orcid":false,"given":"Yingying","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 200127, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1042\/bj2220769","article-title":"Proteinase from germinating bean cotyledons. Evidence for involvement of a thiol group in catalysis","volume":"222","author":"Csoma","year":"1984","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8090","DOI":"10.1074\/jbc.272.12.8090","article-title":"Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase","volume":"272","author":"Chen","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1159\/000134397","article-title":"Molecular cloning of a human cDNA encoding putative cysteine protease (PRSC1) and its chromosome assignment to 14q32.1","volume":"74","author":"Tanaka","year":"1996","journal-title":"Cytogenet. Cell Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1042\/bj3350111","article-title":"Cloning and expression of mouse legumain, a lysosomal endopeptidase","volume":"335","author":"Chen","year":"1998","journal-title":"Biochem. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10940","DOI":"10.1073\/pnas.1300686110","article-title":"Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation","volume":"110","author":"Dall","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/cr.2014.4","article-title":"Structural analysis of asparaginyl endopeptidase reveals the activation mechanism and a reversible intermediate maturation stage","volume":"24","author":"Zhao","year":"2014","journal-title":"Cell Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S0014-5793(98)01574-9","article-title":"Identification of the active site of legumain links it to caspases, clostripain and gingipains in a new clan of cysteine endopeptidases","volume":"441","author":"Chen","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1107\/S1744309111048020","article-title":"Activation of legumain involves proteolytic and conformational events, resulting in a context- and substrate-dependent activity profile","volume":"68","author":"Dall","year":"2012","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"38980","DOI":"10.1074\/jbc.M305930200","article-title":"Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1042\/bj3520327","article-title":"Activation of human prolegumain by cleavage at a C-terminal asparagine residue","volume":"352","author":"Chen","year":"2000","journal-title":"Biochem. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10853","DOI":"10.1074\/jbc.272.16.10853","article-title":"Cystatin E is a novel human cysteine proteinase inhibitor with structural resemblance to family 2 cystatins","volume":"272","author":"Ni","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"19195","DOI":"10.1074\/jbc.274.27.19195","article-title":"Inhibition of mammalian legumain by some cystatins is due to a novel second reactive site","volume":"274","author":"Barrett","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15893","DOI":"10.1074\/jbc.M600694200","article-title":"Cystatin M\/E is a high affinity inhibitor of cathepsin V and cathepsin L by a reactive site that is distinct from the legumain-binding site. A novel clue for the role of cystatin M\/E in epidermal cornification","volume":"281","author":"Cheng","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1016\/j.biochi.2012.07.026","article-title":"Intra- and extracellular regulation of activity and processing of legumain by cystatin E\/M","volume":"94","author":"Smith","year":"2012","journal-title":"Biochimie"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1002\/anie.201409135","article-title":"Structure and mechanism of an aspartimide-dependent peptide ligase in human legumain","volume":"54","author":"Dall","year":"2015","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrm2745","article-title":"Lysosome biogenesis and lysosomal membrane proteins: Trafficking meets function","volume":"10","author":"Saftig","year":"2009","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1515\/BC.2002.133","article-title":"Inhibition of mammalian legumain by Michael acceptors and AzaAsn-halomethylketones","volume":"383","author":"Niestroj","year":"2002","journal-title":"Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1096\/fj.10-172312","article-title":"Asparagine endopeptidase is required for normal kidney physiology and homeostasis","volume":"25","author":"Miller","year":"2011","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/j.immuni.2009.09.013","article-title":"Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells","volume":"31","author":"Sepulveda","year":"2009","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1073\/pnas.0809824105","article-title":"Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome","volume":"106","author":"Chan","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/25379","article-title":"An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation","volume":"396","author":"Manoury","year":"1998","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1126\/science.1080106","article-title":"Activation of lysosomal function during dendritic cell maturation","volume":"299","author":"Trombetta","year":"2003","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/ni754","article-title":"Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP","volume":"3","author":"Manoury","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Maschalidi, S., H\u00e4ssler, S., Blanc, F., Sepulveda, F., Tohme, M., Chignard, M., van Endert, P., Si-Tahar, M., Descamps, D., and Manoury, B. (2012). Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002841"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.immuni.2018.05.006","article-title":"PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells","volume":"49","author":"Stathopoulou","year":"2018","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.stemcr.2017.01.003","article-title":"Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis","volume":"8","author":"Jafari","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1074\/mcp.M111.012138","article-title":"Temporal profiling and pulsed SILAC labeling identify novel secreted proteins during ex vivo osteoblast differentiation of human stromal stem cells","volume":"11","author":"Kristensen","year":"2012","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"G548","DOI":"10.1152\/ajpgi.00047.2016","article-title":"Legumain is activated in macrophages during pancreatitis","volume":"311","author":"Wartmann","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"AbdulHameed, M., Tawa, G., Kumar, K., Ippolito, D., Lewis, J., Stallings, J., and Wallqvist, A. (2014). Systems level analysis and identification of pathways and networks associated with liver fibrosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112193"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ashley, S., Xia, M., Murray, S., O\u2019Dwyer, D., Grant, E., White, E., Flaherty, K., Martinez, F., and Moore, B. (2016). Six-SOMAmer Index Relating to Immune, Protease and Angiogenic Functions Predicts Progression in IPF. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159878"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.atherosclerosis.2016.11.026","article-title":"Increased levels of legumain in plasma and plaques from patients with carotid atherosclerosis","volume":"257","author":"Lunde","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.atherosclerosis.2017.01.003","article-title":"Clinical relevance of biomarkers for the identification of patients with carotid atherosclerotic plaque: Potential role and limitations of cysteine protease legumain","volume":"257","author":"Ammirati","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/s41380-018-0286-z","article-title":"Delta-Secretase-cleaved Tau stimulates Abeta production via upregulating STAT1-BACE1 signaling in Alzheimer\u2019s disease","volume":"26","author":"Zhang","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1084\/jem.20180539","article-title":"Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies","volume":"215","author":"Wang","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e98878","DOI":"10.15252\/embj.201798878","article-title":"Alpha-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson\u2019s disease","volume":"37","author":"Kang","year":"2018","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nrd.2018.109","article-title":"Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing","volume":"17","author":"Boland","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8762","DOI":"10.1038\/ncomms9762","article-title":"Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer\u2019s disease","volume":"6","author":"Zhang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1002\/pmic.201200006","article-title":"Asparaginyl endopeptidase cleaves TDP-43 in brain","volume":"12","author":"Herskowitz","year":"2012","journal-title":"Proteomics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.4161\/auto.7.9.16436","article-title":"Autophagic activity measured in whole rat hepatocytes as the accumulation of a novel BHMT fragment (p10), generated in amphisomes by the asparaginyl proteinase, legumain","volume":"7","author":"Overbye","year":"2011","journal-title":"Autophagy"},{"key":"ref_40","first-page":"2957","article-title":"Overexpression of legumain in tumors is significant for invasion\/metastasis and a candidate enzymatic target for prodrug therapy","volume":"63","author":"Liu","year":"2003","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Guo, P., Zhu, Z., Sun, Z., Wang, Z., Zheng, X., and Xu, H. (2013). Expression of legumain correlates with prognosis and metastasis in gastric carcinoma. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073090"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.jhep.2010.12.022","article-title":"Nucleoplasmic calcium regulates cell proliferation through legumain","volume":"55","author":"Andrade","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.2174\/1389450117666161216125344","article-title":"Targeting Legumain As a Novel Therapeutic Strategy in Cancers","volume":"18","author":"Mai","year":"2017","journal-title":"Curr. Drug Targets"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1002\/cncr.26494","article-title":"Adult glioblastoma multiforme survival in the temozolomide era: A population-based analysis of Surveillance, Epidemiology, and End Results registries","volume":"118","author":"Darefsky","year":"2012","journal-title":"Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.cell.2017.08.028","article-title":"Putting p53 in Context","volume":"170","author":"Kastenhuber","year":"2017","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"189","DOI":"10.2486\/indhealth.22.189","article-title":"Electrocorticogram (ECoG) and auditory evoked potential (AEP) in rats intoxicated with lead acetate","volume":"22","author":"Takahashi","year":"1984","journal-title":"Ind. Health"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/nature11903","article-title":"Corrigendum: Comprehensive genomic characterization defines human glioblastoma genes and core pathways","volume":"494","author":"Network","year":"2013","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1101\/gad.187922.112","article-title":"Emerging insights into the molecular and cellular basis of glioblastoma","volume":"26","author":"Dunn","year":"2012","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1126\/science.1164382","article-title":"An integrated genomic analysis of human glioblastoma multiforme","volume":"321","author":"Parsons","year":"2008","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"254","DOI":"10.7555\/JBR.27.20130030","article-title":"The MDM2-p53 pathway revisited","volume":"27","author":"Nag","year":"2013","journal-title":"J. Biomed. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1242\/jcs.116392","article-title":"The tumor microenvironment at a glance","volume":"125","author":"Balkwill","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/jnci\/djz155","article-title":"Role of Asparagine Endopeptidase in Mediating Wild-Type p53 Inactivation of Glioblastoma","volume":"112","author":"Lin","year":"2020","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4566","DOI":"10.1007\/s12035-018-1385-1","article-title":"Extracellular Vesicles Released by Glioblastoma Cells Stimulate Normal Astrocytes to Acquire a Tumor-Supportive Phenotype Via p53 and MYC Signaling Pathways","volume":"56","author":"Hallal","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/s41582-018-0025-8","article-title":"Multidimensional communication in the microenvirons of glioblastoma","volume":"14","author":"Broekman","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s12943-018-0812-2","article-title":"New insights into long noncoding RNAs and their roles in glioma","volume":"17","author":"Peng","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.canlet.2020.07.012","article-title":"The LGMN pseudogene promotes tumor progression by acting as a miR-495-3p sponge in glioblastoma","volume":"490","author":"Liao","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrneurol.2012.76","article-title":"Nanotechnology-novel therapeutics for CNS disorders","volume":"8","author":"Srikanth","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"10086","DOI":"10.1021\/acsnano.6b05070","article-title":"Increased Gold Nanoparticle Retention in Brain Tumors by in Situ Enzyme-Induced Aggregation","volume":"10","author":"Ruan","year":"2016","journal-title":"ACS Nano"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"20348","DOI":"10.1021\/acsami.7b02303","article-title":"Ligand-Mediated and Enzyme-Directed Precise Targeting and Retention for the Enhanced Treatment of Glioblastoma","volume":"9","author":"Ruan","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"8318","DOI":"10.1021\/acs.nanolett.9b03968","article-title":"Aggregable Nanoparticles-Enabled Chemotherapy and Autophagy Inhibition Combined with Anti-PD-L1 Antibody for Improved Glioma Treatment","volume":"19","author":"Ruan","year":"2019","journal-title":"Nano Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6957","DOI":"10.1039\/C9CC09983B","article-title":"Dual-responsive self-assembly in lysosomes enables cell cycle arrest for locking glioma cell growth","volume":"56","author":"Zhan","year":"2020","journal-title":"Chem. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s13304-017-0424-1","article-title":"Breast cancer in young women: An overview","volume":"69","author":"Anastasiadi","year":"2017","journal-title":"Updates Surg."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"dju012","DOI":"10.1093\/jnci\/dju012","article-title":"Functional role of asparaginyl endopeptidase ubiquitination by TRAF6 in tumor invasion and metastasis","volume":"106","author":"Lin","year":"2014","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"21288","DOI":"10.1073\/pnas.0908151106","article-title":"The regulatory mechanism of Hsp90alpha secretion and its function in tumor malignancy","volume":"106","author":"Wang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1172\/JCI27648","article-title":"Targeting tumor-associated macrophages as a novel strategy against breast cancer","volume":"116","author":"Luo","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cell.2010.03.015","article-title":"Matrix metalloproteinases: Regulators of the tumor microenvironment","volume":"141","author":"Kessenbrock","year":"2010","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1515\/bchm.2001.382.5.777","article-title":"Activation of progelatinase A by mammalian legumain, a recently discovered cysteine proteinase","volume":"382","author":"Chen","year":"2001","journal-title":"Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1016\/j.bbadis.2019.05.003","article-title":"Asparaginyl endopeptidase induces endothelial permeability and tumor metastasis via downregulating zonula occludens protein ZO-1","volume":"1865","author":"Kang","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"14035","DOI":"10.1038\/ncomms14035","article-title":"Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression","volume":"8","author":"Huang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ccr.2014.03.007","article-title":"Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis","volume":"25","author":"Zhou","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1021\/mp200434n","article-title":"Targeting cell surface alpha(v)beta(3) integrin increases therapeutic efficacies of a legumain protease-activated auristatin prodrug","volume":"9","author":"Liu","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1021\/acs.jmedchem.6b01711","article-title":"Emergence of Small-Molecule Non-RGD-Mimetic Inhibitors for RGD Integrins","volume":"60","author":"Miller","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1111\/cas.12202","article-title":"Selective ablation of tumor-associated macrophages suppresses metastasis and angiogenesis","volume":"104","author":"Lin","year":"2013","journal-title":"Cancer Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.canlet.2019.12.013","article-title":"Legumain-deficient macrophages promote senescence of tumor cells by sustaining JAK1\/STAT1 activation","volume":"472","author":"Shen","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41379-018-0180-x","article-title":"Legumain is an independent predictor for invasive recurrence in breast ductal carcinoma in situ","volume":"32","author":"Toss","year":"2019","journal-title":"Mod. Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nrc1611","article-title":"Ovarian cancer metastasis: Integrating insights from disparate model organisms","volume":"5","author":"Naora","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1200\/JCO.2014.56.3106","article-title":"Does aggressive surgery improve outcomes? Interaction between preoperative disease burden and complex surgery in patients with advanced-stage ovarian cancer: An analysis of GOG 182","volume":"33","author":"Horowitz","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1080\/15384047.2017.1294290","article-title":"The expression of asparaginyl endopeptidase promotes growth potential in epithelial ovarian cancer","volume":"18","author":"Zhu","year":"2017","journal-title":"Cancer Biol. Ther."},{"key":"ref_81","first-page":"839","article-title":"Integrin traffic\u2014The update","volume":"128","author":"Hamidi","year":"2015","journal-title":"J. Cell. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1006\/gyno.1999.5388","article-title":"Beta1-integrins partly mediate binding of ovarian cancer cells to peritoneal mesothelium in vitro","volume":"73","author":"Strobel","year":"1999","journal-title":"Gynecol. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s13402-019-00486-4","article-title":"The exosomal integrin alpha5beta1\/AEP complex derived from epithelial ovarian cancer cells promotes peritoneal metastasis through regulating mesothelial cell proliferation and migration","volume":"43","author":"Li","year":"2020","journal-title":"Cell Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/283139a0","article-title":"The pathogenesis of cancer metastasis","volume":"283","author":"Poste","year":"1980","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: Target recognition and regulatory functions","volume":"136","author":"Bartel","year":"2009","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"83223","DOI":"10.18632\/oncotarget.12917","article-title":"MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"966","DOI":"10.3389\/fonc.2020.00966","article-title":"High Level of Legumain Was Correlated With Worse Prognosis and Peritoneal Metastasis in Gastric Cancer Patients","volume":"10","author":"Wang","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1007\/s12032-013-0621-9","article-title":"Effects of legumain as a potential prognostic factor on gastric cancers","volume":"30","author":"Li","year":"2013","journal-title":"Med. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/sj.bjc.6603041","article-title":"Matrix metalloproteinase-2 is a consistent prognostic factor in gastric cancer","volume":"94","author":"Kubben","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1021\/ja307083b","article-title":"Functional imaging of legumain in cancer using a new quenched activity-based probe","volume":"135","author":"Edgington","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"172","DOI":"10.7150\/ijbs.36467","article-title":"Legumain Promotes Gastric Cancer Progression Through Tumor-associated Macrophages In vitro and In vivo","volume":"16","author":"Wang","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/jso.23110","article-title":"Tumor-associated macrophages promote angiogenesis and lymphangiogenesis of gastric cancer","volume":"106","author":"Wu","year":"2012","journal-title":"J. Surg. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13046-017-0528-y","article-title":"Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells","volume":"36","author":"Zheng","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1136\/gutjnl-2018-316324","article-title":"Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer","volume":"68","author":"Lin","year":"2019","journal-title":"Gut"},{"key":"ref_95","first-page":"1229","article-title":"Overexpression of asparaginyl endopeptidase is significant for esophageal carcinoma metastasis and predicts poor patient prognosis","volume":"15","author":"Liu","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3727\/096504015X14410238486649","article-title":"Knockdown of Legumain Suppresses Cervical Cancer Cell Migration and Invasion","volume":"23","author":"Meng","year":"2016","journal-title":"Oncol. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.3892\/mmr.2016.4838","article-title":"Prognostic value of legumain in uveal melanoma","volume":"13","author":"Wu","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejca.2014.10.020","article-title":"High expression of the cysteine proteinase legumain in colorectal cancer\u2014implications for therapeutic targeting","volume":"51","author":"Haugen","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Haugen, M.H., Johansen, H.T., Pettersen, S.J., Solberg, R., Brix, K., Flatmark, K., and Maelandsmo, G.M. (2013). Nuclear legumain activity in colorectal cancer. PLoS ONE, 8.","DOI":"10.1371\/annotation\/05c95441-890f-4707-a1bc-c4d386561191"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1158\/1078-0432.CCR-04-1642","article-title":"Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer","volume":"11","author":"Murthy","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.gene.2016.08.049","article-title":"Asparaginyl endopeptidase promotes proliferation and invasiveness of prostate cancer cells via PI3K\/AKT signaling pathway","volume":"594","author":"Zhu","year":"2016","journal-title":"Gene"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s00345-012-0977-z","article-title":"Association of legumain expression pattern with prostate cancer invasiveness and aggressiveness","volume":"31","author":"Ohno","year":"2013","journal-title":"World J. Urol."},{"key":"ref_103","first-page":"12815","article-title":"Up-regulation of Legumain correlates with tumor progression and poor prognosis in urothelial carcinoma of bladder","volume":"9","author":"Yan","year":"2016","journal-title":"Int. J. Clin. Exp. Pathol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:58:52Z","timestamp":1760162332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/1153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,10]]},"references-count":103,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cells10051153"],"URL":"https:\/\/doi.org\/10.3390\/cells10051153","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,10]]}}}