HBx promotes hepatocarcinogenesis by enhancing phosphorylation and blocking ubiquitinylation of UHRF2

作者全名："Cheng, Fengjuan; Qian, Guanhua; Fang, Xianyun; Sun, Jingjie; Chen, Siyuan; Chen, Rongjuan; Liu, Shangjing; Li, Zhaodi; Wu, Kejia; Jiang, Shiming; Chen, Yong; Tang, Ni; Chen, Juan; Duan, Changzhu"

作者地址："[Cheng, Fengjuan; Fang, Xianyun; Sun, Jingjie; Chen, Siyuan; Chen, Rongjuan; Liu, Shangjing; Li, Zhaodi; Wu, Kejia; Duan, Changzhu] Chongqing Med Univ, Dept Cell Biol & Med Genet, Mol Med & Canc Res Ctr, Chongqing 400016, Peoples R China; [Qian, Guanhua] Chongqing Med Univ, Affiliated Hosp 2, Key Med Lab Obstet & Gynecol, Chongqing 400010, Peoples R China; [Jiang, Shiming; Chen, Yong] Chongqing Med Univ, Affiliated Hosp 1, Dept Hepatobillary Surg, Chongqing 400010, Peoples R China; [Tang, Ni; Chen, Juan] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis,Minist Educ,Dept Infe, Chongqing 400016, Peoples R China"

通信作者："Duan, CZ (corresponding author), Chongqing Med Univ, Dept Cell Biol & Med Genet, Mol Med & Canc Res Ctr, Chongqing 400016, Peoples R China."

来源：HEPATOLOGY INTERNATIONAL

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000641218000001

JCR分区：Q1

影响因子：6.6

年份：2021

卷号：15

期号：3

开始页：707

结束页：719

文献类型：Article

关键词：UHRF2; HBV; HBx; Hepatocellular carcinoma; Phosphorylation; Ubiquitination; Migration; Invasion; Proliferation; Therapeutic targets

摘要："Background and aims The major cause of Hepatocellular carcinoma (HCC) is acute or chronic infection caused by hepatotropic viruses and HBV infection is the main cause. UHRF2, a ubiquitin-protein ligase E3, is associated with cancer development. This study aimed to investigate the connection and mechanism between UHRF2 and HBV-associated HCC. Methods The expression of UHRF2 in human HBV-positive HCC tissues and paracancerous tissues was detected by western blot and tissue microarray. The effects of UHRF2 on invasion, migration and proliferation were detected in HBV-positive hepatoma cell lines. Furthermore, western blot, immunofluorescence, Co-immunoprecipitation and ubiquitination assays were used to explore the relationship and mechanism between UHRF2 and HBV-associated HCC. Results HBV-positive HCC tissues had higher UHRF2 expression levels than adjacent non-tumor tissues. The HBV-positive HCC patients with a low UHRF2 level in cancer tissues had longer overall and recurrence-free survival compared with those with a high UHRF2 level. UHRF2 induced invasion, migration and proliferation in human HBV-positive HCC cell lines HepG2.2.15 and Hep AD38(-). HBx, an encoding protein of HBV, maintained the stability of UHRF2 by blocking the ubiquitination of UHRF2. HBx up-regulated CDK2 expression through ETS1. UHRF2 bound to CDK2 directly and enhanced UHRF2 phosphorylation at serine 643. Conclusions These results suggest that HBx-ETS1-CDK2-UHRF2 pathway plays an important role in the pathogenesis of HBV-associated HCC and represents new therapeutic targets for human HCC."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81772178]; Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University

基金资助正文：This work was supported by the National Natural Science Foundation of China (Grant No. 81772178) and Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University (2019).