{"doi":"10.1007/s00280-025-04783-8","title":"Clinical relevance of Nectin-4 downregulation and biological changes caused by cytotoxic chemotherapy in bladder cancer","abstract":null,"journal":"Cancer Chemotherapy and Pharmacology","year":2025,"id":626381,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1620257,"name":"Takuya Owari","orcid":null,"position":1,"is_corresponding":false},{"id":404791,"name":"Kota Iida","orcid":"0000-0001-7804-9128","position":2,"is_corresponding":false},{"id":1620258,"name":"Sayuri Onishi","orcid":null,"position":3,"is_corresponding":false},{"id":1620259,"name":"Nobutaka Nishimura","orcid":null,"position":4,"is_corresponding":false},{"id":404796,"name":"Tomomi Fujii","orcid":"0000-0002-7207-4127","position":5,"is_corresponding":false},{"id":1620260,"name":"Cynthia N. Jinno","orcid":null,"position":6,"is_corresponding":false},{"id":341435,"name":"Hideki Furuya","orcid":"0000-0002-9536-8662","position":7,"is_corresponding":false},{"id":1620261,"name":"Yuki Oda","orcid":null,"position":8,"is_corresponding":false},{"id":1620262,"name":"Tatsuki Miyamoto","orcid":null,"position":9,"is_corresponding":false},{"id":1620263,"name":"Mitsuru Tomizawa","orcid":null,"position":10,"is_corresponding":false},{"id":1620264,"name":"Takuto Shimizu","orcid":null,"position":11,"is_corresponding":false},{"id":1620265,"name":"Kenta Onishi","orcid":null,"position":12,"is_corresponding":false},{"id":404789,"name":"Shunta Hori","orcid":"0000-0001-9514-9964","position":13,"is_corresponding":false},{"id":404790,"name":"Yosuke Morizawa","orcid":"0000-0001-7142-5901","position":14,"is_corresponding":false},{"id":530094,"name":"Daisuke Goto","orcid":"0000-0003-4921-3851","position":15,"is_corresponding":false},{"id":404792,"name":"Yasushi Nakai","orcid":"0000-0002-7579-0372","position":16,"is_corresponding":false},{"id":404795,"name":"Nobumichi Tanaka","orcid":"0000-0001-9242-7877","position":17,"is_corresponding":false},{"id":1620267,"name":"Noriyoshi Miura","orcid":null,"position":18,"is_corresponding":false},{"id":1620269,"name":"Tadahiko Kikugawa","orcid":null,"position":19,"is_corresponding":false},{"id":1620271,"name":"Takashi Saika","orcid":null,"position":20,"is_corresponding":false},{"id":1620273,"name":"Charles Rosser","orcid":null,"position":21,"is_corresponding":false},{"id":404798,"name":"Kiyohide Fujimoto","orcid":"0000-0003-1507-2464","position":22,"is_corresponding":false},{"id":404786,"name":"Makito Miyake","orcid":"0000-0001-9503-7356","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Clinical relevance of Nectin-4 downregulation and biological changes caused by cytotoxic chemotherapy in bladder cancer","abstract":"<h4>Introduction</h4>Mechanism underlying resistance to enfortumab vedotin (EV) and prognostication of Nectin-4 expression in muscle-invasive bladder cancer (MIBC) remains unclear.<h4>Methods</h4>We generated gemcitabine-resistant HT-1376 and cisplatin-resistant HT-1376 cells generated from parental HT1376 cells (derived from MIBC). Transcriptome analysis was conducted to explore the biological function of differentially expressed genes detected in chemoresistant HT-1376 cells compared to parental HT-1376. In 70 patients with MIBC undergoing radical cystectomy, unsupervised hierarchical clustering was performed using immunohistochemical staining pattern with GATA3, KRT20, KRT5/6, KRT14, and Nectin-4 expression derived from the gene expression-based Nectin-4-modified NanoString molecular classification: Luminal-Nec4-High, Luminal-Nec4-Low, Basal-Nec4-High, and Basal-Nec4-Low subgroups.<h4>Results</h4>We found significant downregulation of Nectin-4 expression along with epithelial-to-mesenchymal transition in chemoresistant HT-1376 cells. Exogenous expression of NECTIN4 in chemoresistant HT-1376 cells partially restored sensitivity to EV. RNA seq identified differentially expressed genes, including Nectin-4 and small proline-rich proteins, downregulated in chemoresistant HT-1376 cells. Over-representation analysis using GO and KEGG revealed upregulation of gene sets enriched for ribosome biogenesis-related pathways in chemoresistant HT-1376 cells. Nectin-4-modified molecular subtype resulted in better stratification of survival-the Luminal-Nec4-High subgroup had the best and the Basal-Nec4-Low subgroup had the worst prognosis. Comparing molecular subtypes of MIBC cells between transurethral resection specimens and matched radical cystectomy specimens revealed that 43% of neoadjuvant chemotherapy-treated patients with luminal subtype tumors showed a marked shift to the basal subtype in the cystectomy specimens.<h4>Conclusion</h4>The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40560260","pmcid":null,"openalex_id":"https://openalex.org/W4411654613","authors":[],"funders":[{"funder_name":"Japan Society for the Promotion of Science","grant_id":"16K20159","title":null},{"funder_name":"Japan Society for the Promotion of Science","grant_id":"15K10605","title":null}],"total_grants":2,"fwci":2.2732,"citation_percentile":0.87501244,"influential_citations":0,"citation_trend":[{"year":2026,"count":2}],"oa_status":"closed","license":"https://www.springernature.com/gp/researchers/text-and-data-mining","oa_locations":[{"url":"https://link.springer.com/content/pdf/10.1007/s00280-025-04783-8.pdf","host_type":"publisher"},{"url":"https://link.springer.com/article/10.1007/s00280-025-04783-8/fulltext.html","host_type":"publisher"},{"url":"https://doi.org/10.1007/s00280-025-04783-8","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40560260","host_type":"repository"}],"fields_of_study":["Bladder and Urothelial Cancer Treatments","Wnt/β-catenin signaling in development and cancer","Immune Cell Function and Interaction"],"mesh_terms":["Nectins","Clinical Relevance","Gemcitabine","Aged","Antineoplastic Agents","Urinary Bladder Neoplasms","Cisplatin","Deoxycytidine","Female","Humans","Male","Middle Aged","Prognosis","Down-Regulation","Cystectomy","Cell Adhesion Molecules","Gene Expression Regulation, Neoplastic","Drug Resistance, Neoplasm","Gene Expression Profiling","Cell Line, Tumor","Epithelial-Mesenchymal Transition"],"keywords":["Downregulation and upregulation","Cytotoxic T cell","Chemotherapy","Cancer","Bladder cancer","Medicine","Cancer research","Clinical significance","Cytotoxicity","Oncology","Pathology","Internal medicine","Biology","In vitro","Gene","Genetics","Bladder neoplasm","Molecular classification","Chemoresistance","Rna Seq","Enfortumab Vedotin"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-04T13:38:12.144611Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}