Cancer chemotherapy and pharmacology · 2025
Clinical relevance of Nectin-4 downregulation and biological changes caused by cytotoxic chemotherapy in bladder cancer.
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Miyake Makito, Owari Takuya, Iida Kota, Onishi Sayuri, Nishimura Nobutaka, Fujii Tomomi, Jinno Cynthia N, Furuya Hideki, Oda Yuki, Miyamoto Tatsuki, Tomizawa Mitsuru, Shimizu Takuto, Onishi Kenta, Hori Shunta, Morizawa Yosuke, Goto Daisuke, Nakai Yasushi, Tanaka Nobumichi, Miura Noriyoshi, Kikugawa Tadahiko, Saika Takashi, Rosser Charles, Fujimoto Kiyohide
Аннотация
INTRODUCTION: Mechanism underlying resistance to enfortumab vedotin (EV) and prognostication of Nectin-4 expression in muscle-invasive bladder cancer (MIBC) remains unclear.
METHODS: 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.
RESULTS: 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.
CONCLUSION: The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.
METHODS: 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.
RESULTS: 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.
CONCLUSION: The clinical utility of Nection-4, associated molecules, and Nectin-4-modified molecular subtype need to be studied for better management strategies for MIBC.
Предметные рубрики MeSH
HumansUrinary Bladder NeoplasmsCell Adhesion MoleculesDrug Resistance, NeoplasmEpithelial-Mesenchymal TransitionFemaleMaleDown-RegulationCell Line, TumorGemcitabineGene Expression Regulation, NeoplasticCisplatinPrognosisDeoxycytidineMiddle AgedAgedAntineoplastic AgentsCystectomyGene Expression ProfilingClinical RelevanceNectins