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Targeting MCM6 Enhances Melphalan Chemosensitivity in Retinoblastoma by Modulating DNA Damage Response
Meng Wang1, Junjie Tang1, Jinmiao Li1
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
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.
Insights
Minichromosome maintenance complex component 6 (MCM6) drives retinoblastoma growth and resistance to melphalan chemotherapy. Targeting MCM6 enhances melphalan
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Retinoblastoma is a pediatric eye cancer with limited treatment options.
- Melphalan is a standard chemotherapy agent, but resistance is a challenge.
- Understanding molecular drivers of retinoblastoma progression and drug resistance is crucial.
Purpose of the Study:
- To investigate the role of minichromosome maintenance complex component 6 (MCM6) in retinoblastoma.
- To determine MCM6's impact on retinoblastoma progression.
- To assess MCM6's influence on melphalan chemosensitivity.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of retinoblastoma.
- Validation in patient tumor specimens, including post-therapy samples.
- MCM6 knockdown cell lines for functional assays and in vivo xenograft models.
Main Results:
- MCM6 is highly expressed in retinoblastoma, linked to proliferation.
- Elevated MCM6 expression correlates with melphalan treatment failure.
- MCM6 knockdown reduced proliferation, increased DNA damage, and sensitized cells to melphalan.
Conclusions:
- MCM6 is a key regulator of retinoblastoma growth and melphalan response.
- Targeting MCM6 may overcome melphalan resistance in retinoblastoma.
- MCM6 inhibition offers a potential therapeutic strategy to improve retinoblastoma treatment outcomes.
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