Cooperation among Numb, MDM2 and p53 in the development and progression of pancreatic cancer
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We study the expression of Numb, MDM2 and p53 for clinical significance in pancreatic cancer (PC) and their functional relationship in regulating biological behaviors of PC cells. IHC, IB and qRT-PCR were used to detect Numb, MDM2 and p53 expression in PC. Transfection and drug intervention were used to investigate their functional relationship in PC cells. IHC showed that Numb expression was negatively associated with tumor size, differentiation and UICC stage, while expression of MDM2 and p53 was positively associated with tumor T and UICC stages, respectively (P < 0.05). Numb was an independent prognostic indicator in PC (P < 0.05). Patients with Numb-positive expression or combined with MDM2-negative expression had a significantly better overall survival (P < 0.05). Altered expression of Numb can regulate wild-type but not mutant p53 expression, while MDM2 knockdown increased Numb but not mutant p53 protein level. Meanwhile, Numb knockdown increased chemoresistance but decreased activated p53 and cleaved-caspase-3 protein expression in gemcitabine-treated Capan-2 cells. Moreover, Numb co-immunoprecipitated with p53 to prevent p53 ubiquitin-dependent protein degradation and this ubiquitin-dependent regulation plays an important role in the coordinate function of these three proteins on cell invasion and migration in PC cells. Our study is the first to demonstrate the clinical significance and functional cooperation among Numb, MDM2 and p53 involved in the development and progression of PC.
KeywordsNumb MDM2 p53 Pancreatic cancer Prognostic biomarker
We thank Dr. Salvatore Pece from the FIRC Institute for Molecular Oncology Foundation for PINCO-Numb-GFP plasmids and the Center of experimental medicine and laboratory technology and central laboratory of the First Hospital of China Medical University for technical support.This work was supported by a grand-in-aid for Scientific Research from the Science and Technology Committee of Liaoning Province, China (No. 2010225032) and the Social Development Program from Shenyang Science and Technology Bureau,China (No. F12-193-9-21).
The authors declare no conflict of interest.
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