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Published on: September 18, 2020
MDM4 as a Prognostic Factor for Patients With Gastric Cancer With Low Expression of p53
Xiaochen Zhang1, Yoshiyuki Yamamoto2, Xiaoxuan Wang1
1Department of Gastroenterology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Background/Aim:
The oncoproteins murine double minute (MDM) 2 and MDM4 inactivate tumor-suppressor protein p53. Their mutual relationship with the prognosis of gastric cancer (GC) remains unknown.
Patients And Methods:
Expression of MDM2, MDM4, and p53 in tumors of 241 patients with GC were evaluated immunohistochemically. Effects of overexpression of MDM4 on tumor-growth properties and sensitivity to cytotoxic drugs were investigated using NUGC4 human GC cell line.
Results:
High expression of p53 was associated with poor overall survival in the whole population. Among 173 patients with low expression of p53 (implying nonmutation), high expression of MDM4 was an independent factor of poor prognosis in both stage I-III and IV, but of MDM2 was not. MDM4-transduced NUGC4 cells formed twice as many colonies and had a higher 50% inhibitory concentration for 5-fluorouracil and oxaliplatin than did the control cells.
Conclusion:
MDM4 expression is a factor conferring poor prognosis in patients with GC with low expression of p53 and may confer drug resistance.
Insights
Murine double minute 4 (MDM4) overexpression indicates a poor prognosis in gastric cancer (GC) patients with low p53 expression and may increase drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The oncoproteins murine double minute 2 (MDM2) and MDM4 inactivate the tumor-suppressor protein p53.
- The prognostic significance of MDM2 and MDM4 in gastric cancer (GC) is not well understood.
Purpose of the Study:
- To investigate the relationship between MDM2, MDM4, and p53 expression and the prognosis of gastric cancer.
- To evaluate the impact of MDM4 overexpression on tumor growth and drug sensitivity in GC cells.
Main Methods:
- Immunohistochemical analysis of MDM2, MDM4, and p53 expression in 241 GC patient tumors.
- In vitro study using the NUGC4 human GC cell line to assess the effects of MDM4 overexpression.
Main Results:
- High p53 expression correlated with poor overall survival in the entire cohort.
- In patients with low p53 expression (non-mutated), high MDM4 expression was an independent predictor of poor prognosis across all stages.
- MDM4 overexpression in GC cells increased colony formation and resistance to 5-fluorouracil and oxaliplatin.
Conclusions:
- MDM4 expression is a significant prognostic factor in gastric cancer patients with low p53 expression.
- MDM4 may contribute to chemoresistance in gastric cancer.
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