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C-MET-dependent signal transduction mediates retinoblastoma growth by regulating PKM2 nuclear translocation
Hanjun Dai1, Weijuan Zeng1, Hong Luo1
1Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.
Abstract:
Mesenchymal epithelial transition (C-MET) factor overexpression has been found in many types of cancer and has served as an important molecular target for therapeutic intervention. However, the role of C-MET in retinoblastoma remains largely unclear. The present study aimed to investigate the potential role and mechanism of C-MET in Y79 retinoblastoma cells. We found that C-MET was highly expressed in Y79 retinoblastoma cells, and, in addition, the levels of C-MET were positively correlated with cell proliferation and retinoblastoma growth. Inhibition of C-MET suppressed Y79 retinoblastoma cell proliferation and tumour growth. Mechanistically, we showed that HGF-induced C-MET-dependent signal transduction resulted in ERK 1/2 phosphorylation, which subsequently promoted the nuclear translocation of PKM2. Nuclear PKM2 further interacted with histone H3 and contributed to C-MET-dependent cyclin D1 and c-Myc expression and cell proliferation. These findings highlight the role of C-MET in Y79 retinoblastoma cells and reveal a C-MET-dependent signal transduction mechanism. C-MET may be a potential therapeutic target for retinoblastoma. SIGNIFICANCE OF THE STUDY: We demonstrated a new target of retinoblastoma, C-MET. C-MET-dependent signal transduction promotes Y79 retinoblastoma cell proliferation and tumour growth through ERK 1/2/PKM2/histone H3 signalling pathway. C-MET may be a potential target for retinoblastoma therapy.
Insights
C-MET factor is highly expressed in retinoblastoma cells, driving proliferation. Inhibiting C-MET (mesenchymal-epithelial transition factor) suppressed tumor growth, revealing a new therapeutic target for retinoblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Mesenchymal-epithelial transition (C-MET) factor is overexpressed in many cancers, making it a key therapeutic target.
- The role of C-MET in retinoblastoma, a significant eye cancer, is not well understood.
Purpose of the Study:
- To investigate the role and mechanism of C-MET in Y79 retinoblastoma cells.
- To determine if C-MET is a potential therapeutic target for retinoblastoma.
Main Methods:
- Investigated C-MET expression in Y79 retinoblastoma cells.
- Assessed the impact of C-MET inhibition on cell proliferation and tumor growth.
- Elucidated the downstream signaling pathway involving ERK1/2, PKM2, and histone H3.
Main Results:
- C-MET was highly expressed in Y79 retinoblastoma cells, correlating positively with proliferation and tumor growth.
- Inhibition of C-MET significantly suppressed retinoblastoma cell proliferation and tumor growth.
- Identified a signaling cascade: HGF-induced C-MET activates ERK1/2, promoting PKM2 nuclear translocation, which interacts with histone H3 to drive cyclin D1 and c-Myc expression.
Conclusions:
- C-MET plays a crucial role in promoting retinoblastoma cell proliferation and tumor growth.
- A novel C-MET-dependent signaling pathway (ERK1/2/PKM2/histone H3) contributes to retinoblastoma progression.
- C-MET represents a promising therapeutic target for retinoblastoma treatment.
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