Dickkopf-related protein 1/cytoskeleton-associated protein 4 signaling activation by Helicobacter pylori-induced activator protein-1 promotes gastric tumorigenesis via the PI3K/AKT/mTOR pathway  

作　　者：Mei Luo Yuan-Jia Chen Yuan Xie Qin-Rong Wang Yi-Ning Xiang Ni-Ya Long Wen-Xiu Yang Yan Zhao Jian-Jiang Zhou 

机构地区：[1]Key Laboratory of Endemic and Ethnic Diseases,Ministry of Education&Key Laboratory of Medical Molecular Biology of Guizhou Province,Guizhou Medical University,Guiyang 550004,Guizhou Province,China [2]Department of Pathology of Affiliated Hospital,Guizhou Medical University,Guiyang 550004,Guizhou Province,China [3]Department of Neurology of Affiliated Hospital,Guizhou Medical University,Guiyang 550004,Guizhou Province,China

出　　处：《World Journal of Gastroenterology》2022年第47期6769-6787,共19页世界胃肠病学杂志（英文版）

基　　金：the National Natural Science Foundation of China,No.32160166,No.31760328,and No.31960028;Natural Science Foundation of Guizhou Province,No.ZC[2020]4Y026,No.JC[2020]1Z010,No.JC[2020]1Y333,and No.ZK[2022]041;Scientific Research Project of Guizhou Medical University,No.20NSP068.

摘　　要：BACKGROUND Gastric cancer(GC)is a common malignant tumor with high incidence and mortality rates globally,especially in East Asian countries.Helicobacter pylori(H.pylori)infection is a significant and independent risk factor for GC.However,its underlying mechanism of action is not fully understood.Dickkopf-related protein(DKK)1 is a Wnt signaling antagonist,and cytoskeleton-associated protein(CKAP)4 is a newly identified DKK1 receptor.Recent studies found that the binding of DKK1 to CAKP4 mediated the procancer signaling of DKK1 independent of Wnt signaling.We hypothesize that H.pylori-induced activation of DKK1/CKAP4 signaling contributes to the initiation and progression of GC.AIM To investigate the interaction of H.pylori infection,DKK1 and CAKP4 in GC,as well as the underlying molecular mechanisms.METHODS RNA sequencing was used to identify differentially expressed genes(DEGs)between H.pylori-infected and uninfected primary GC cells.Gain-and loss-offunction experiments were performed to verify the H.pylori-induced upregulation of activator protein-1(AP-1)in GC cells.A dual-luciferase reporter assay and co-immunoprecipitation were used to determine the binding of AP-1 to the DKK1 promoter and DKK1 to CKAP4.Western blotting and immunohistochemistry detected the expression of DKK1,CKAP4,and phosphatidylinositol 3-kinase(PI3K)pathway-related proteins in GC cells and tissues.Functional experiments and tumorigenicity in nude mice detected malignant behavior of GC cells in vitro and in vivo.RESULTS We identified 32 DEGs between primary GC cells with and without H.pylori infection,including JUN,fos-like antigen-1(FOSL1),and DKK1,and confirmed that the three proteins and CKAP4 were highly expressed in H.pylori-infected GC cells,H.pylori-infected gerbil gastric tissues,and human GC tissues.JUN and FOSL1 form AP-1 to transcriptionally activate DKK1 expression by binding to the DKK1 promoter.Activated DKK1 bound to CKAP4,but not the most common Wnt coreceptor low-density lipoprotein receptor-related protein 5/6,to promot

关 键 词：Gastric cancer Helicobacter pylori Dickkopf-related protein 1 Cytoskeleton-associated protein 4 Phosphatidylinositol 3-kinase pathway 

分 类 号：R735.2[医药卫生—肿瘤]