Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway

作者全名："Wang, Houhong; Wei, Xiaoyu; Liu, Lu; Zhang, Junfeng; Li, Heng"

作者地址："[Wang, Houhong] Fuyang Normal Univ, Hosp 1, Dept Gen Surg, Fuyang 236006, Anhui, Peoples R China; [Wei, Xiaoyu] Chongqing Med Univ, Yongchuan Hosp, Dept Infect Dis, Chongqing 402160, Peoples R China; [Liu, Lu] Shanghai Jiao Tong Univ, Affiliated Nantong Hosp, Dept Endocrinol, Nantong 226001, Jiangsu, Peoples R China; [Zhang, Junfeng] Gen Hosp Western Theater Command PLA, Dept Radiol, Chengdu 610083, Sichuan, Peoples R China; [Li, Heng] West Dist First Affiliated Hosp USTC, Anhui Prov Canc Hosp, Dept Comprehens Surg, Hefei 230031, Anhui, Peoples R China; [Wang, Houhong] Anhui Med Univ, Affiliated Bozhou Hosp, Dept Gen Surg, Bozhou 236800, Anhui, Peoples R China"

通信作者："Liu, L (通讯作者)，Shanghai Jiao Tong Univ, Affiliated Nantong Hosp, Dept Endocrinol, Nantong 226001, Jiangsu, Peoples R China.; Zhang, JF (通讯作者)，Gen Hosp Western Theater Command PLA, Dept Radiol, Chengdu 610083, Sichuan, Peoples R China.; Li, H (通讯作者)，West Dist First Affiliated Hosp USTC, Anhui Prov Canc Hosp, Dept Comprehens Surg, Hefei 230031, Anhui, Peoples R China."

来源：EXPERIMENTAL HEMATOLOGY & ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001182370100001

JCR分区：Q1

影响因子：9.4

年份：2024

卷号：13

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：ADAR1; Hepatocellular carcinoma; Oxidative stress; Survival; Keap1/Nrf2; Reactive oxygen species

摘要："BackgroundA-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investigated the effect of ADAR1 on survival and oxidative stress of HCC, and underlying mechanisms.MethodsADAR1 expression was measured in fifty HCC and normal tissues via real-time quantitative PCR, and immunohistochemistry. For stable knockdown or overexpression of ADAR1, adeno-associated virus vectors carrying sh-ADAR1 or ADAR1 overexpression were transfected into HepG2 and SMMC-7721 cells. Transfected cells were exposed to oxidative stress agonist tBHP or sorafenib Bay 43-9006. Cell proliferation, apoptosis, and oxidative stress were measured, and tumor xenograft experiment was implemented.ResultsADAR1 was up-regulated in HCC and correlated to unfavorable clinical outcomes. ADAR1 deficiency attenuated proliferation of HCC cells and tumor growth and enhanced apoptosis. Moreover, its loss facilitated intracellular ROS accumulation, and elevated Keap1 and lowered Nrf2 expression. Intracellular GSH content and SOD activity were decreased and MDA content was increased in the absence of ADAR1. The opposite results were observed when ADAR1 was overexpressed. The effects of tBHP and Bay 43-9006 on survival, apoptosis, intracellular ROS accumulation, and Keap1/Nrf2 pathway were further exacerbated by simultaneous inhibition of ADAR1.ConclusionsThe current study unveils that ADAR1 is required for survival and oxidative stress of HCC cells, and targeting ADAR1 may sensitize HCC cells to oxidative stress via modulating Keap1/Nrf2 pathway."

基金机构：Anhui Medical University Doctoral Research Fund

基金资助正文：Not applicable.