EYA4 inhibits hepatocellular carcinoma growth and invasion by suppressing NF-κB-dependent RAP1 transactivation
作者机构：Department of Pancreatobiliary SurgeryThe First Affiliated HospitalSun Yat-sen UniversityNo.58Zhongshan Er RoadGuangzhou 510080GuangdongP.R.China
出 版 物：《Cancer Communications》 (癌症通讯（英文）)
年 卷 期：2018年第38卷第1期
页 面：105-119页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported by National Natural Science Foundation of China(Grant Number 81472261) Natural Science Foundation of Guangdong Province(Grant Numbers 2014A030310033 and 2015A030313032) Science and Technology Planning Project of Guangdong Province(Grant Number 2013B021800122) Science and Technology Planning Projects of Guangzhou City(Grant Number 201604020044)
主 题：Eyes absent homolog 4(EYA4) RAS-related protein 1(RAP1) Nuclear factor-κB(NF-κB) Transactivation Hepatocellular carcinoma
摘 要：Background:Our previous studies demonstrated that eyes absent homolog 4(EYA4),a member of the eye devel-opment-related EYA family in Drosophila,is frequently methylated and silenced in hepatocellular carcinoma(HCC)specimens and associated with shorter *** current work aimed to explore the mechanisms through which EYA4 functions as a tumor suppressor in ***:Stable EYA4-expressing plasmid(pEYA4)transfectants of the human HCC cell lines Huh-7 and PLC/PRF/5(PLC)were *** tumors were established via subcutaneous injection of the stable transfectants into BALB/c nude *** samples were obtained from 75 pathologically diagnosed HCC *** real-time polymerase chain reaction,Western blotting and immunohistochemistry were performed to determine the expression of EYA4 in cell lines,xenografts and clinical *** cell proliferation,colony formation,invasiveness and tumor formation of stable transfectants were studied.A gene expression microarray was utilized to screen genes regulated by EYA4 *** effect of EYA4 on nuclear factor-κB(NF-κB)/RAS-related protein 1(RAP1)signaling was demonstrated through the co-transfection of pEYA4 and Flag-tagged RAS-related protein 1A gene-expressing plasmid(Flag-RAP1A),functional studies,chromatin immunoprecipitation,immunofluorescence staining and cellular ubiquitination ***:The restoration of EYA4 expression in HCC cell lines suppressed cell proliferation,inhibited clonogenic outgrowth,reduced cell invasion and restrained xenograft tumor growth,and Flag-RAP1A reversed the suppressive effects of pEYA4 in *** of NF-κB with tumor necrosis factor-α(TNF-α)increased the binding of p65 to the RAP1A gene promoter and up-regulated RAP1 protein *** inhibition of NF-κB with BAY 11-7085 and p65 siRNA successfully blocked TNF-α-induced RAP1 ***4 antagonized the TNF-α-induced phosphoryla-tion and ubiquitination of inhibitor of NF-κBα(IκB
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