Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma  

作　　者：Yuri Cho Min Ji Park Koeun Kim Sun Woong Kim Wonjin Kim Sooyeon Oh Joo Ho Lee 

机构地区：[1]Department of Internal Medicine,CHA Gangnam Medical Center,CHA University School of Medicine,Seoul 06135,South Korea [2]Department of Internal Medicine,Chaum Life Center,CHA University School of Medicine,Seoul 06062,South Korea [3]Department of Internal Medicine,CHA Bundang Medical Center,CHA University School of Medicine,Seongnam 13496,Bundang gu,South Korea

出　　处：《World Journal of Gastroenterology》2020年第42期6599-6613,共15页世界胃肠病学杂志（英文版）

摘　　要：BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis.The levels of reactive oxygen species(ROS)increase during the progression from early to advanced hepatocellular carcinoma(HCC).AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.METHODS The expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761)was quantified using real-time polymerase chain reaction and immunoblotting.Human HCC cells were treated with H2O2,which is a major component of ROS in living organisms,and with either YAP-1 small interfering RNA(siRNA)or control siRNA.To investigate the role of YAP-1 in HCC cells under oxidative stress,MTS assays were performed.Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1.Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761).Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo(both P<0.05).The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway,leading to the upregulation of components of the unfolded protein response(UPR),including 78-kDa glucoseregulated protein and activating transcription factor-6(ATF-6).The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues(P<0.05)and were positively correlated with the ATF-6 Levels(Pearson’s coefficient=0.299;P<0.05).CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC.The ROS-induced activation of YAP-1 via

关 键 词：Hepatocellular carcinoma Yes-associated protein-1 C-MYC Reactive oxygen species Unfolded protein response Activating transcription factor-6 

分 类 号：R735.7[医药卫生—肿瘤]