DDIT4 promotes gastric cancer proliferation and tumorigenesis through the p53 and MAPK pathways  

作　　者：Feng Du Lina Sun Yi Chu Tingyu Li Chao Lei Xin Wang Mingzuo Jiang Yali Min Yuanyuan Lu Xiaodi Zhao Yongzhan Nie Daiming Fan 

机构地区：[1]State Key Laboratory of Cancer Biology,National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases,Fourth Military Medical University,127 Chang Le West Road,Xi’an 710032,China

出　　处：《Cancer Communications》2018年第1期474-487,共14页癌症通讯（英文）

基　　金：supported by the National Natural Science Foundation of China(Nos.81430072,81421003,81602641,81572929).

摘　　要：Background:Gastric cancer(GC)is one of the most common malignancies worldwide,particularly in China.DNA damage-inducible transcript 4(DDIT4)is a mammalian target of rapamycin inhibitor and is induced by various cellular stresses;however,its critical role in GC remains poorly understood.The present study aimed to investigate the poten-tial relationship and the underlying mechanism between DDIT4 and GC development.Methods:We used western blotting,real-time polymerase chain reaction,and immunohistochemical or immunoflu-orescence to determine DDIT4 expression in GC cells and tissues.High-content screening,cell counting kit-8 assays,colony formation,and in vivo tumorigenesis assays were performed to evaluate cell proliferation.Flow cytometry was used to investigate cell apoptosis and cell cycle distribution.Results:DDIT4 was upregulated in GC cells and tissue.Furthermore,downregulating DDIT4 in GC cells inhibited proliferation both in vitro and in vivo and increased 5-fluorouracil-induced apoptosis and cell cycle arrest.In contrast,ectopic expression of DDIT4 in normal gastric epithelial cells promoted proliferation and attenuated chemosensitivity.Further analysis indicated that the mitogen-activated protein kinase and p53 signaling pathways were involved in the suppression of proliferation,and increased chemosensitivity upon DDIT4 downregulation.Conclusion:DDIT4 promotes GC proliferation and tumorigenesis,providing new insights into the role of DDIT4 in the tumorigenesis of human GC.

关 键 词：DNA damage-inducible transcript 4 Gastric cancer PROLIFERATION Mitogen-activated protein kinase P53 

分 类 号：R73[医药卫生—肿瘤]