{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:12:49Z","timestamp":1769757169043,"version":"3.49.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:00:00Z","timestamp":1684454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Skin cutaneous melanoma (SKCM) is the deadliest type of cutaneous malignancy. Ubiquitination is a process of protein sorting and degradation that exhibits multiple functions in the progression of various tumors. This study aimed to characterize a set of genes for ubiquitination in SKCM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression patterns of ubiquitin-associated genes (URGs) and the corresponding clinical information in SKCM tissues were comprehensively analyzed based on The Cancer Genome Atlas (TCGA) database. We performed univariate and multivariate Cox proportional regression models to characterize the risk scores and identify four critical genes related to prognostic ubiquitination (HCLS1, CORO1A, NCF1 and CCRL2), which were used to construct the prognostic signatures. We also studied the effects of HCLS1, CORO1A and CCRL2 on tumor metastasis-related indicators at the cellular level through <jats:italic>in vitro<\/jats:italic> experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SKCM patients in the low-risk group showing a longer survival than those in the high-risk group. Characteristic risk scores correlated with several clinicopathological variables and reflected the infiltration of multiple immune cells. In addition, the knockdown of CLS1, CORO1A and CCRL2 affected cellular malignant biological behavior through the EMT signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study provides a novel and prospective strategy to improve the clinical survival of SKCM patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1170190","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T04:50:19Z","timestamp":1684471819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Ubiquitination-related biomarkers in metastatic melanoma patients and their roles in tumor microenvironment"],"prefix":"10.3389","volume":"13","author":[{"given":"Li","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhehao","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohua","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/s41420-021-00727-2","article-title":"PSMC2 knockdown suppressed tumor progression of skin cutaneous melanoma","volume":"7","author":"Yang","year":"2021","journal-title":"Cell Death Discovery"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/his.14139","article-title":"The role of cyclin D1 and ki-67 in the development and prognostication of thin melanoma","volume":"77","author":"Kaufmann","year":"2020","journal-title":"Histopathology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/s41568-022-00442-9","article-title":"Mechanisms of immune activation and regulation: lessons from melanoma","volume":"22","author":"Kalaora","year":"2022","journal-title":"Nat Rev Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12390","article-title":"The relative clinical efficacy of trametinib-dabrafenib and cobimetinib-vemurafenib in advanced melanoma: an indirect comparison","volume":"41","author":"Galv\u00e1n-Banqueri","year":"2016","journal-title":"J Clin Pharm Ther"},{"key":"B6","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41392-020-0196-9","article-title":"Regulating tumor suppressor genes: post-translational modifications","volume":"5","author":"Chen","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1252","article-title":"Post-translational modifications in the context of therapeutic proteins","volume":"24","author":"Walsh","year":"2006","journal-title":"Nat Biotechnol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/s41418-020-00708-5","article-title":"Ubiquitination in the regulation of inflammatory cell death and cancer","volume":"28","author":"Cockram","year":"2021","journal-title":"Cell Death Differ"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.06.004","article-title":"Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy","volume":"86","author":"Liu","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1123244","article-title":"The E3 ubiquitin ligases regulate PD-1\/PD-L1 protein levels in tumor microenvironment to improve immunotherapy","volume":"14","author":"Hou","year":"2023","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.semcancer.2022.11.002","article-title":"Targeting CSC-related transcription factors by E3 ubiquitin ligases for cancer therapy","volume":"87","author":"Wang","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41467-020-14324-x","article-title":"Nedd4 ubiquitylates VDAC2\/3 to suppress erastin-induced ferroptosis in melanoma","volume":"11","author":"Yang","year":"2020","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-00710-x","article-title":"FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells","volume":"28","author":"Habel","year":"2021","journal-title":"Cell Death Differ"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00732-8","article-title":"TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination","volume":"23","author":"Zhu","year":"2021","journal-title":"Nat Cell Biol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184129","article-title":"Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways","volume":"12","author":"Chen","year":"2017","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02468-7","article-title":"Fbxo45 promotes the malignant development of esophageal squamous cell carcinoma by targeting GGNBP2 for ubiquitination and degradation","volume":"41","author":"Wang","year":"2022","journal-title":"Oncogene"},{"key":"B19","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.omtm.2021.03.026","article-title":"Discovery of key genes as novel biomarkers specifically associated with HPV-negative cervical cancer","volume":"21","author":"Liu","year":"2021","journal-title":"Mol Ther Methods Clin Dev"},{"key":"B20","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/s41419-022-04675-2","article-title":"Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation","volume":"13","author":"Wu","year":"2022","journal-title":"Cell Death Dis"},{"key":"B21","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/s41419-022-05248-z","article-title":"Fbxo22 promotes cervical cancer progression via targeting p57(Kip2) for ubiquitination and degradation","volume":"13","author":"Lin","year":"2022","journal-title":"Cell Death Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1041","article-title":"iUUCD 2.0: an update with rich annotations for ubiquitin and ubiquitin-like conjugations","volume":"46","author":"Zhou","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/path.5140","article-title":"Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice","volume":"246","author":"van der Weyden","year":"2018","journal-title":"J Pathol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3760","DOI":"10.3390\/jcm10163760","article-title":"Familial melanoma and susceptibility genes: a review of the most common clinical and dermoscopic phenotypic aspect, associated malignancies and practical tips for management","volume":"10","author":"Zocchi","year":"2021","journal-title":"J Clin Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(21)00545-3","article-title":"Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study","volume":"22","author":"Tawbi","year":"2021","journal-title":"Lancet Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.19750","article-title":"Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors","volume":"185","author":"Gault","year":"2021","journal-title":"Br J Dermatol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2354","DOI":"10.3390\/ijms18112354","article-title":"miRNAs, melanoma and microenvironment: an intricate network","volume":"18","author":"Romano","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"180239","DOI":"10.1098\/rsob.180239","article-title":"Post-translational modification control of RNA-binding protein hnRNPK function","volume":"9","author":"Xu","year":"2019","journal-title":"Open Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s12943-020-01262-x","article-title":"The role of ubiquitination and deubiquitination in cancer metabolism","volume":"19","author":"Sun","year":"2020","journal-title":"Mol Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.biocel.2018.06.001","article-title":"Ubiquitination: friend and foe in cancer","volume":"101","author":"Mansour","year":"2018","journal-title":"Int J Biochem Cell Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6","article-title":"The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications","volume":"17","author":"Zhang","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1590\/abd1806-4841.20176183","article-title":"Melanoma: tumor microenvironment and new treatments","volume":"92","author":"Giavina-Bianchi","year":"2017","journal-title":"Bras Dermatol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/nm730","article-title":"Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion","volume":"8","author":"Dong","year":"2002","journal-title":"Nat Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nature22991","article-title":"An immunogenic personal neoantigen vaccine for patients with melanoma","volume":"547","author":"Ott","year":"2017","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-004884","article-title":"Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites","volume":"10","author":"Conway","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B36","doi-asserted-by":"publisher","first-page":"BSR20201704","DOI":"10.1042\/BSR20201704","article-title":"Data mining of immune-related prognostic genes in metastatic melanoma microenvironment","volume":"40","author":"Han","year":"2020","journal-title":"Biosci Rep"},{"key":"B37","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.phrs.2017.07.006","article-title":"Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance","volume":"123","author":"Pulluri","year":"2017","journal-title":"Pharmacol Res"},{"key":"B38","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1186\/s12935-021-02041-4","article-title":"Ten-gene signature reveals the significance of clinical prognosis and immuno-correlation of osteosarcoma and study on novel skeleton inhibitors regarding MMP9","volume":"21","author":"Li","year":"2021","journal-title":"Cancer Cell Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-22-467","article-title":"Proteomic analysis of plasma exosomes in patients with non-small cell lung cancer","volume":"11","author":"Bao","year":"2022","journal-title":"Transl Lung Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.4095","article-title":"Immunophenotype-associated gene signature in ductal breast tumors varies by receptor subtype, but the expression of individual signature genes remains consistent","volume":"10","author":"Behring","year":"2021","journal-title":"Cancer Med"},{"key":"B41","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13578-020-00517-w","article-title":"Identification of predictors based on drug targets highlights accurate treatment of goserelin in breast and prostate cancer","volume":"11","author":"Zhao","year":"2021","journal-title":"Cell Biosci"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abl8952","article-title":"The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia","volume":"8","author":"Karantanos","year":"2022","journal-title":"Sci Adv"},{"key":"B43","doi-asserted-by":"publisher","first-page":"5000","DOI":"10.3390\/cancers13195000","article-title":"Expression of CCRL2 inhibits tumor growth by concentrating chemerin and inhibiting neoangiogenesis","volume":"13","author":"Al Delbany","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-0168","article-title":"The atypical receptor CCRL2 is essential for lung cancer immune surveillance","volume":"7","author":"Del Prete","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"17","DOI":"10.7555\/JBR.32.20170057","article-title":"Atypical chemokine receptor CCRL2 is overexpressed in prostate cancer cells","volume":"33","author":"Reyes","year":"2017","journal-title":"J BioMed Res"},{"key":"B46","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1007\/s12032-015-0696-6","article-title":"The human chemokine receptor CCRL2 suppresses chemotaxis and invasion by blocking CCL2-induced phosphorylation of p38 MAPK in human breast cancer cells","volume":"32","author":"Wang","year":"2015","journal-title":"Med Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.10.120","article-title":"Elevated chemokine CC-motif receptor-like 2 (CCRL2) promotes cell migration and invasion in glioblastoma","volume":"429","author":"Yin","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-015-4089-4","article-title":"The chemokines CCR1 and CCRL2 have a role in colorectal cancer liver metastasis","volume":"37","author":"Akram","year":"2016","journal-title":"Tumour Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024171118","article-title":"CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation","volume":"118","author":"Yin","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B50","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1038\/s42003-021-02376-8","article-title":"Neutrophil-derived reactive oxygen species promote tumor colonization","volume":"4","author":"Zhong","year":"2021","journal-title":"Commun Biol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1170190\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T04:50:22Z","timestamp":1684471822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1170190\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,19]]},"references-count":50,"alternative-id":["10.3389\/fonc.2023.1170190"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1170190","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,19]]},"article-number":"1170190"}}