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Effect of altered WIG-1 expression on DDP sensitivity in a DDP-resistant esophageal squamous cancer cell line
Yang Qiu1, Ying-Bo Zou, Kun Li
1Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, PR China.
Abstract:
Esophageal cancer (EC) is the most common esophageal malignancy and has a dismal prognosis. Developing novel strategies to reverse the resistance to chemotherapeutics in EC is currently of intense interest. The wide-type p53 induced gene 1 (WIG-1) is a p53-regulated transcription factor. The effect of WIG-1 on the regulation of cisplatin (DDP) sensitivity was evaluated in DDP-resistant EC cells both in vitro and in vivo. The DDP-resistant sub-line EC109/DDP was successfully selected following eight months of culture. Overexpression of WIG-1 in EC109/DDP cells significantly lowered the IC(50) of DDP to 1.11 ± 0.54 μg/ml when compared to Control cells (4.57 ± 0.98 μg/ml, P < 0.05). In addition, WIG-1 exerted a negative effect on cell proliferation and on the cloning efficiency of EC109/DDP cells. A significant increase in the apoptosis index and in TUNEL-positive nuclei was observed when the expression of WIG-1 was upregulated. Furthermore, WIG-1-overexpressing DDP-resistant EC cells exhibited suppressed xenograft tumor growth and a lower green fluorescent protein (GFP) fluorescence intensity following DDP injection. WIG-1 also reduced the expression of ERCC1 and increased the expression of Bax in DDP-resistant EC cells, while the expression of Bcl-2, P-gp and GST-π was not significantly altered after up- or down-regulation of WIG-1. In summary, these results show that WIG-1 may reverse the DDP resistance of EC cells by reducing ERCC1 expression and increasing Bax expression. This study will provide a framework for understanding the mechanism of DDP resistance by WIG-1 and will aid in the therapeutic use of DDP in ESCC.
Insights
Wide-type p53 induced gene 1 (WIG-1) can reverse cisplatin resistance in esophageal cancer. Overexpressing WIG-1 in esophageal cancer cells reduces tumor growth and increases sensitivity to chemotherapy drugs.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Esophageal cancer (EC) is a highly lethal malignancy with poor prognosis.
- Resistance to chemotherapy, particularly cisplatin (DDP), is a major challenge in EC treatment.
- Novel strategies to overcome DDP resistance in EC are urgently needed.
Purpose of the Study:
- To investigate the role of wide-type p53 induced gene 1 (WIG-1) in regulating DDP sensitivity in EC.
- To evaluate the potential of WIG-1 as a therapeutic target for overcoming DDP resistance in EC.
Main Methods:
- Development of a DDP-resistant EC cell line (EC109/DDP).
- In vitro and in vivo experiments to assess the effect of WIG-1 overexpression on DDP sensitivity, cell proliferation, apoptosis, and tumor growth.
- Analysis of key protein expression levels (ERCC1, Bax, Bcl-2, P-gp, GST-π).
Main Results:
- WIG-1 overexpression significantly reduced the IC(50) of DDP in resistant EC cells.
- WIG-1 suppressed cell proliferation, cloning efficiency, and xenograft tumor growth.
- Upregulation of WIG-1 increased apoptosis and decreased ERCC1 expression while increasing Bax expression.
Conclusions:
- WIG-1 plays a crucial role in reversing DDP resistance in esophageal cancer.
- WIG-1 may exert its effect by downregulating ERCC1 and upregulating Bax expression.
- Targeting WIG-1 presents a promising therapeutic strategy for enhancing DDP efficacy in EC treatment.