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Targeting the MCM10/p53/p21/CCND1 Axis in Colorectal Cancer: Evaluating the Therapeutic Potential of Ultrasound
Hao Wu1, Changyu Wen1, Zheng Jiang1
1Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Background:
Colorectal cancer (CRC), the second leading cause of cancer-related deaths globally, continues to lack effective early diagnostic biomarkers and therapeutic strategies. Minichromosome maintenance protein 10 (MCM10), a replication initiation factor implicated as a pan-cancer marker, remains poorly characterized in CRC. Its role within the p53/p21/Cyclin D1 (CCND1) regulatory axis and its potential as a therapeutic target, particularly under ultrasound-based modulation, warrants investigation.
Methods:
Integrated bioinformatic analyses were conducted using public databases to evaluate MCM10 expression and clinical significance. Clinical CRC specimens were analyzed via qPCR and immunohistochemistry to validate MCM10 expression. Functional assays, including colony formation, cell counting kit-8 (CCK-8), Transwell migration/invasion, and flow cytometry, assessed the biological effects of MCM10 knockdown on proliferation, apoptosis, and cell cycle. Western blotting and rescue experiments elucidated signaling pathways. A CRC mouse xenograft model was established to evaluate in vivo tumor growth. The therapeutic modulation of MCM10-related pathways using ultrasound-based interventions was preliminarily assessed.
Results:
MCM10 expression was significantly upregulated in cell lines and CRC tissues, and correlated with poor prognosis. Silencing MCM10-impaired CRC cell proliferation, invasion, migration, and induced G1/S cell cycle arrest suppressed epithelial-mesenchymal transition and increased apoptosis. Mechanistically, MCM10 knockdown activated the p53/p21 axis and downregulated CCND1 expression. In vivo, MCM10 inhibition suppressed xenograft tumor growth. Ultrasound exposure exhibited the potential to enhance the therapeutic effects of MCM10 suppression by modulating the MCM10/p53/p21/CCND1 axis.
Conclusions:
These findings reveal that MCM10 promotes CRC malignancy through inhibiting the tumor-suppressive p53/p21/CCND1 pathway. Targeting this axis, particularly through ultrasound-enhanced delivery or sensitization strategies, holds promise as a novel therapeutic approach in CRC.
Insights
Minichromosome maintenance protein 10 (MCM10) promotes colorectal cancer (CRC) malignancy by inhibiting the p53/p21/CCND1 pathway. Targeting MCM10, potentially with ultrasound, offers a novel therapeutic strategy for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Colorectal cancer (CRC) remains a leading cause of cancer mortality with limited diagnostic and therapeutic options.
- Minichromosome maintenance protein 10 (MCM10), a key replication factor, is implicated in various cancers but its role in CRC is not well understood.
- Investigating MCM10's function in the p53/p21/Cyclin D1 (CCND1) pathway and its therapeutic potential, including ultrasound modulation, is crucial.
Purpose of the Study:
- To investigate the expression and clinical significance of MCM10 in colorectal cancer.
- To elucidate the functional role of MCM10 in CRC cell proliferation, apoptosis, cell cycle, and metastasis.
- To explore the potential of targeting MCM10, in conjunction with ultrasound, as a novel therapeutic strategy for CRC.
Main Methods:
- Bioinformatic analyses of public databases and validation in clinical CRC specimens using qPCR and immunohistochemistry.
- In vitro functional assays including proliferation, apoptosis, cell cycle, and migration/invasion assays following MCM10 knockdown.
- In vivo studies using a CRC mouse xenograft model and preliminary assessment of ultrasound-based therapeutic modulation.
Main Results:
- MCM10 was significantly upregulated in CRC tissues and associated with poor prognosis.
- MCM10 knockdown inhibited CRC cell proliferation, migration, invasion, induced cell cycle arrest, and promoted apoptosis.
- MCM10 inhibition activated the p53/p21 axis, downregulated CCND1, and suppressed tumor growth in vivo. Ultrasound enhanced these therapeutic effects.
Conclusions:
- MCM10 promotes colorectal cancer malignancy by suppressing the tumor-suppressive p53/p21/CCND1 pathway.
- Targeting MCM10, especially through ultrasound-enhanced strategies, presents a promising novel therapeutic approach for CRC.
- The MCM10/p53/p21/CCND1 axis represents a critical target for CRC therapy development.
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