{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T10:09:57Z","timestamp":1775470197659,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Skin Cutaneous Melanoma (SKCM) is a highly aggressive malignant tumor with a significant increase in mortality upon metastasis. The molecular mechanisms driving melanoma progression remain largely unclear. Recent studies have highlighted the importance of epigenetic alterations, especially DNA methylation, in melanoma development. This study aims to identify and analyze methylation-regulated differentially expressed genes (MeDEGs) in genome-wide profiles between primary and metastatic melanoma.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Gene expression profiling datasets GSE8401 and gene methylation profiling datasets GSE86355 were collected from the GEO database. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were systematically identified. Integration of DEGs and DMGs yielded a set of MeDEGs, which subsequently underwent functional enrichment analysis. The protein-protein interaction (PPI) network was constructed using STRING and visualized using Cytoscape software. Survival analysis was used to select prognostic hub genes. In addition, 37 SKCM and 37 normal skin tissues from the First Affiliated Hospital of Soochow University (FAHSU) were collected for immunohistochemical (IHC) staining and evaluation. Furthermore, DNA methylation patterns of CDC6 were analyzed. To validate these findings, SKCM cell cultures were utilized to elucidate the expression and behavioral characteristics of CDC6. Additionally, gene set enrichment analysis (GSEA) and immune infiltration analysis were conducted for CDC6.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In our study, we discovered 120 hypomethylated-upregulated genes and 212 hypermethylated-downregulated genes. The hypomethylated-upregulated genes were notably associated with biological processes such as spindle assembly checkpoint signaling, mitotic spindle assembly, and negative regulation of mitotic metaphase\/anaphase transition. Our pathway analysis revealed significant enrichment in pathways related to dilated cardiomyopathy, amino sugar metabolism, progesterone-mediated oocyte maturation, and chemical carcinogenesis. Conversely, hypermethylated-downregulated genes were found to be enriched in processes like epidermis development, keratinocyte differentiation, and skin development. Additionally, pathway analysis highlighted associations with estrogen signaling, Staphylococcus aureus infection, axon guidance, and arachidonic acid metabolism. Following the establishment of PPI networks and survival analysis, we identified 11 prognostic hub genes: CCNA2, CDC6, CDCA3, CKS2, DTL, HJURP, KRT5, KRT14, KRT15, KRT16, and NEK2. Notably, among the 11 hub genes, our findings indicate that CDC6 plays a pivotal role in enhancing the proliferation, migration, and invasion capabilities of melanoma cells in vitro.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our comprehensive genomic analyses reveal that genes with aberrant methylation exhibit differential expression during the transition from primary to metastatic melanoma. The identified genes, especially CDC6, which plays a crucial role in enhancing melanoma cell proliferation, migration, and invasion, provide valuable insights into potential methylation-based biomarkers. These findings could contribute significantly to advancing precision medicine in SKCM.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-024-05851-x","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T09:02:28Z","timestamp":1721898148000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Comprehensive analysis of aberrantly methylated differentially expressed genes and validation of CDC6 in melanoma"],"prefix":"10.1007","volume":"150","author":[{"given":"Li","family":"Liao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoliang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"5851_CR6","doi-asserted-by":"crossref","unstructured":"Aleotti V et al (2021) Methylation markers in cutaneous melanoma: unravelling the potential utility of their Tracking by Liquid Biopsy. Cancers (Basel), 13(24).","DOI":"10.3390\/cancers13246217"},{"issue":"5","key":"5851_CR2","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","volume":"158","author":"M Arnold","year":"2022","unstructured":"Arnold M et al (2022) Global Burden of Cutaneous Melanoma in 2020 and projections to 2040. JAMA Dermatol 158(5):495\u2013503","journal-title":"JAMA Dermatol"},{"key":"5851_CR11","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/1532-429X-14-83","volume":"14","author":"WP Bandettini","year":"2012","unstructured":"Bandettini WP et al (2012) MultiContrast delayed enhancement (MCODE) improves detection of subendocardial myocardial infarction by late gadolinium enhancement cardiovascular magnetic resonance: a clinical validation study. J Cardiovasc Magn Reson 14:83","journal-title":"J Cardiovasc Magn Reson"},{"issue":"Database issue","key":"5851_CR8","first-page":"D991","volume":"41","author":"T Barrett","year":"2013","unstructured":"Barrett T et al (2013) NCBI GEO: archive for functional genomics data sets\u2013update. Nucleic Acids Res 41(Database issue):D991\u2013D995","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"5851_CR14","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","volume":"2","author":"E Cerami","year":"2012","unstructured":"Cerami E et al (2012) The cBio Cancer Genomics Portal: an Open platform for exploring Multidimensional Cancer Genomics Data: Fig.\u00a01. Cancer Discov 2(5):401\u2013404","journal-title":"Cancer Discov"},{"key":"5851_CR12","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen EY et al (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14:128","journal-title":"BMC Bioinformatics"},{"issue":"Database issue","key":"5851_CR9","first-page":"D808","volume":"41","author":"A Franceschini","year":"2013","unstructured":"Franceschini A et al (2013) STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41(Database issue):D808\u2013D815","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"5851_CR28","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1038\/s41598-020-80336-8","volume":"11","author":"W Han","year":"2021","unstructured":"Han W et al (2021) Transcript levels of keratin 1\/5\/6\/14\/15\/16\/17 as potential prognostic indicators in melanoma patients. Sci Rep 11(1):1023","journal-title":"Sci Rep"},{"key":"5851_CR16","doi-asserted-by":"crossref","unstructured":"Hofman FM, Taylor CR (2013) Immunohistochem Curr Protoc Immunol, 103: p. 21.4.1\u201321.4.26.","DOI":"10.1002\/0471142735.im2104s103"},{"issue":"4","key":"5851_CR27","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/S0002-9440(10)63393-7","volume":"165","author":"P Karakaidos","year":"2004","unstructured":"Karakaidos P et al (2004) Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability\u2013evidence of E2F-1 transcriptional control over hCdt1. Am J Pathol 165(4):1351\u20131365","journal-title":"Am J Pathol"},{"issue":"1","key":"5851_CR22","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s40291-022-00628-9","volume":"27","author":"GT Lam","year":"2023","unstructured":"Lam GT et al (2023) Pitfalls in cutaneous melanoma diagnosis and the need for New Reliable markers. Mol Diagn Ther 27(1):49\u201360","journal-title":"Mol Diagn Ther"},{"issue":"4","key":"5851_CR3","first-page":"1071","volume":"52","author":"GC Leonardi","year":"2018","unstructured":"Leonardi GC et al (2018) Cutaneous melanoma: from pathogenesis to therapy (review). Int J Oncol 52(4):1071\u20131080","journal-title":"Int J Oncol"},{"issue":"1","key":"5851_CR17","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13072-019-0316-3","volume":"12","author":"Y Li","year":"2019","unstructured":"Li Y, Ge D, Lu C (2019) The SMART app: an interactive web application for comprehensive DNA methylation analysis and visualization. Epigenetics Chromatin 12(1):71","journal-title":"Epigenetics Chromatin"},{"issue":"W1","key":"5851_CR20","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","volume":"48","author":"T Li","year":"2020","unstructured":"Li T et al (2020) TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 48(W1):W509\u2013w514","journal-title":"Nucleic Acids Res"},{"issue":"6","key":"5851_CR26","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1002\/ijc.32900","volume":"147","author":"N Lim","year":"2020","unstructured":"Lim N, Townsend PA (2020) Cdc6 as a novel target in cancer: oncogenic potential, senescence and subcellular localisation. Int J Cancer 147(6):1528\u20131534","journal-title":"Int J Cancer"},{"issue":"10400","key":"5851_CR1","first-page":"485","volume":"402","author":"GV Long","year":"2023","unstructured":"Long GV et al (2023) Cutan Melanoma Lancet 402(10400):485\u2013502","journal-title":"Cutan Melanoma Lancet"},{"key":"5851_CR7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13148-017-0332-8","volume":"9","author":"G Micevic","year":"2017","unstructured":"Micevic G, Theodosakis N, Bosenberg M (2017) Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunities. Clin Epigenetics 9:34","journal-title":"Clin Epigenetics"},{"issue":"1","key":"5851_CR25","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1186\/s13046-023-02769-z","volume":"42","author":"I Mourkioti","year":"2023","unstructured":"Mourkioti I et al (2023) A GATA2-CDC6 axis modulates androgen receptor blockade-induced senescence in prostate cancer. J Exp Clin Cancer Res 42(1):187","journal-title":"J Exp Clin Cancer Res"},{"issue":"20","key":"5851_CR21","doi-asserted-by":"publisher","first-page":"4200","DOI":"10.1093\/bioinformatics\/btz210","volume":"35","author":"B Ru","year":"2019","unstructured":"Ru B et al (2019) TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics 35(20):4200\u20134202","journal-title":"Bioinformatics"},{"issue":"2","key":"5851_CR5","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1080\/15592294.2014.1003746","volume":"10","author":"D Sarkar","year":"2015","unstructured":"Sarkar D et al (2015) Epigenetic regulation in human melanoma: past and future. Epigenetics 10(2):103\u2013121","journal-title":"Epigenetics"},{"issue":"3","key":"5851_CR10","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1093\/bioinformatics\/btq675","volume":"27","author":"ME Smoot","year":"2011","unstructured":"Smoot ME et al (2011) Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27(3):431\u2013432","journal-title":"Bioinformatics"},{"issue":"43","key":"5851_CR19","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545\u201315550","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"5851_CR18","doi-asserted-by":"publisher","first-page":"99","DOI":"10.2144\/btn-2022-0034","volume":"75","author":"R Sule","year":"2023","unstructured":"Sule R, Rivera G, Gomes AV (2023) Western blotting (immunoblotting): history, theory, uses, protocol and problems. Biotechniques 75(3):99\u2013114","journal-title":"Biotechniques"},{"issue":"W1","key":"5851_CR13","doi-asserted-by":"publisher","first-page":"W98","DOI":"10.1093\/nar\/gkx247","volume":"45","author":"Z Tang","year":"2017","unstructured":"Tang Z et al (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98\u2013W102","journal-title":"Nucleic Acids Res"},{"issue":"6220","key":"5851_CR15","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","volume":"347","author":"M Uhl\u00e9n","year":"2015","unstructured":"Uhl\u00e9n M et al (2015) Proteomics. Tissue-based map of the human proteome. Science 347(6220):1260419","journal-title":"Science"},{"key":"5851_CR4","doi-asserted-by":"crossref","unstructured":"Villani A et al (2022) The treatment of Advanced Melanoma: therapeutic update. Int J Mol Sci, 23(12)","DOI":"10.3390\/ijms23126388"},{"issue":"1","key":"5851_CR24","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1186\/s12943-022-01623-8","volume":"21","author":"F Wang","year":"2022","unstructured":"Wang F et al (2022) CDC6 is a prognostic biomarker and correlated with immune infiltrates in glioma. Mol Cancer 21(1):153","journal-title":"Mol Cancer"},{"issue":"1","key":"5851_CR23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12916-017-0851-3","volume":"15","author":"J Wouters","year":"2017","unstructured":"Wouters J et al (2017) Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma. BMC Med 15(1):101","journal-title":"BMC Med"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-024-05851-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-024-05851-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-024-05851-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T17:10:42Z","timestamp":1723050642000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-024-05851-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,25]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["5851"],"URL":"https:\/\/doi.org\/10.1007\/s00432-024-05851-x","relation":{},"ISSN":["1432-1335"],"issn-type":[{"value":"1432-1335","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,25]]},"assertion":[{"value":"2 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"362"}}