Investigative ophthalmology & visual science · 2025
Targeting MCM6 Enhances Melphalan Chemosensitivity in Retinoblastoma by Modulating DNA Damage Response.
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Wang Meng, Tang Junjie, Li Jinmiao, Lv Jianjie, Zhang Zhihui, Liu Yaoming, Sun Hetian, Gao Yang, Chen Shuxia, Tang Lijuan, Zhang Ping, Su Shicai, Lu Rong
Аннотация
PURPOSE: This study aimed to investigate the role of minichromosome maintenance complex component 6 (MCM6), a DNA replication licensing factor, in retinoblastoma progression and its impact on melphalan chemosensitivity.
METHODS: MCM6 expression patterns were analyzed using single-cell RNA sequencing (scRNA-seq) of retinoblastoma and validated in patient tumors, including specimens obtained after failed melphalan therapy. Stable MCM6 knockdown cell lines were established for proliferation and cell-cycle assays, DNA damage analyses, and chemosensitivity testing. In vivo xenograft models were employed to evaluate the therapeutic efficacy of MCM6 knockdown combined with melphalan.
RESULTS: The scRNA-seq revealed that MCM6 was highly expressed in retinoblastoma cells and embedded in a proliferation-associated gene network. Elevated expression was also confirmed in human retinoblastoma, particularly in tumors from patients with failed melphalan therapy. MCM6 knockdown suppressed cell proliferation and cell-cycle progression while enhancing melphalan-induced DNA damage, thereby sensitizing retinoblastoma cells to melphalan. In vivo, MCM6 depletion synergized with melphalan to significantly inhibit intraocular tumor growth.
CONCLUSIONS: MCM6 acts as a critical regulator of retinoblastoma growth and modulates response to melphalan. Targeting MCM6 may offer a therapeutic approach to improve outcomes of chemotherapy in retinoblastoma.
METHODS: MCM6 expression patterns were analyzed using single-cell RNA sequencing (scRNA-seq) of retinoblastoma and validated in patient tumors, including specimens obtained after failed melphalan therapy. Stable MCM6 knockdown cell lines were established for proliferation and cell-cycle assays, DNA damage analyses, and chemosensitivity testing. In vivo xenograft models were employed to evaluate the therapeutic efficacy of MCM6 knockdown combined with melphalan.
RESULTS: The scRNA-seq revealed that MCM6 was highly expressed in retinoblastoma cells and embedded in a proliferation-associated gene network. Elevated expression was also confirmed in human retinoblastoma, particularly in tumors from patients with failed melphalan therapy. MCM6 knockdown suppressed cell proliferation and cell-cycle progression while enhancing melphalan-induced DNA damage, thereby sensitizing retinoblastoma cells to melphalan. In vivo, MCM6 depletion synergized with melphalan to significantly inhibit intraocular tumor growth.
CONCLUSIONS: MCM6 acts as a critical regulator of retinoblastoma growth and modulates response to melphalan. Targeting MCM6 may offer a therapeutic approach to improve outcomes of chemotherapy in retinoblastoma.
Предметные рубрики MeSH
RetinoblastomaMelphalanHumansAnimalsAntineoplastic Agents, AlkylatingRetinal NeoplasmsDNA DamageMinichromosome Maintenance Complex Component 6MiceCell ProliferationXenograft Model Antitumor AssaysCell Line, TumorGene Expression Regulation, NeoplasticGene Knockdown TechniquesCell CycleDrug Resistance, Neoplasm