The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant Pathway.
The Ubiquitin E3 Ligase TRIM21 Promotes Hepatocarcinogenesis by Suppressing the p62-Keap1-Nrf2 Antioxidant Pathway.
复制标题
DOI：
10.1016/j.jcmgh.2021.01.007
复制
发表时间：
2021
影响因子：
7.2
通讯作者：
Zong WX
中科院分区：
文献类型：
--
作者：
Wang F;Zhang Y;Shen J;Yang B;Dai W;Yan J;Maimouni S;Daguplo HQ;Coppola S;Gao Y;Wang Y;Du Z;Peng K;Liu H;Zhang Q;Tang F;Wang P;Gao S;Wang Y;Ding WX;Guo G;Wang F;Zong WX
TRIM 21是一种泛素E3连接酶，涉及许多生物学过程，包括免疫应答、细胞代谢、氧化还原稳态和癌症发展。我们最近报道，TRIM 21可以通过泛素化p62来负调节p62-Keap 1-Nrf 2抗氧化途径，并阻止其寡聚化和蛋白螯合功能。由于氧化还原稳态在包括肝癌在内的许多癌症中起着关键作用，我们试图确定TRIM 21在肝癌发生中的作用。我们使用公开的数据集和49例HCC临床样本研究了TRIM 21表达与疾病之间的相关性。我们使用TRIM 21基因敲除小鼠来确定TRIM 21消融如何影响由致癌物DEN加苯巴比妥（PB）诱导的HCC。我们探讨了TRIM 21的缺失保护细胞免受DEN诱导的氧化损伤和细胞死亡的机制。TRIM 21的表达与肝癌的发生呈正相关。因此，TRIM 21基因敲除小鼠对DEN诱导的肝癌具有抗性。这伴随着DEN治疗后细胞死亡和组织损伤的减少，因此减少了肝组织修复反应和代偿性增殖。TRIM 21缺陷的细胞显示增强的Keap 1的p62螯合，并保护其免受DEN诱导的ROS诱导和细胞死亡。野生型而不是E3连接酶死亡和p62结合缺陷突变体TRIM 21的重建阻碍了TRIM 21缺陷细胞对DEN诱导的氧化损伤和细胞死亡的保护。TRIM 21表达增加与人HCC相关。TRIM 21的基因切除导致对氧化性肝损伤的保护和减少肝癌发生，表明TRIM 21作为预防和治疗靶点。
TRIM21 is a ubiquitin E3 ligase that is implicated in numerous biological processes including immune response, cell metabolism, redox homeostasis, and cancer development. We recently reported that TRIM21 can negatively regulate the p62-Keap1-Nrf2 antioxidant pathway by ubiquitylating p62 and prevents its oligomerization and protein sequestration function. As redox homeostasis plays a pivotal role in many cancers including liver cancer, we sought to determine the role of TRIM21 in hepatocarcinogenesis. We examined the correlation between TRIM21 expression and the disease using publicly available data sets and 49 cases of HCC clinical samples. We used TRIM21 genetic knockout mice to determine how TRIM21 ablation impact HCC induced by the carcinogen DEN plus phenobarbital (PB). We explored the mechanism that loss of TRIM21 protects cells from DEN-induced oxidative damage and cell death. There is a positive correlation between TRIM21 expression and HCC. Consistently, TRIM21-knockout mice are resistant to DEN-induced hepatocarcinogenesis. This is accompanied by decreased cell death and tissue damage upon DEN treatment, hence reduced hepatic tissue repair response and compensatory proliferation. Cells deficient in TRIM21 display enhanced p62 sequestration of Keap1 and are protected from DEN-induced ROS induction and cell death. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient mutant TRIM21 impedes the protection from DEN-induced oxidative damage and cell death in TRIM21-deficient cells. Increased TRIM21 expression is associated with human HCC. Genetic ablation of TRIM21 leads to protection against oxidative hepatic damage and decreased hepatocarcinogenesis, suggesting TRIM21 as a preventive and therapeutic target.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
一组新颖的生物标志物，可区分小型分化良好的 HCC 与发育不良结节及结果值
影响因子：
3.8
作者：
Jin GZ;Dong H;Yu WL;Li Y;Lu XY;Yu H;Xian ZH;Dong W;Liu YK;Cong WM;Wu MC
通讯作者：
Wu MC
P62/SQSTM1与维生素D受体结合抑制肝星细胞活性，纤维化和肝癌。
影响因子：
50.3
作者：
Duran A;Hernandez ED;Reina-Campos M;Castilla EA;Subramaniam S;Raghunandan S;Roberts LR;Kisseleva T;Karin M;Diaz-Meco MT;Moscat J
通讯作者：
Moscat J
影响因子：
10.5
作者：
Jaramillo MC;Zhang DD
通讯作者：
Zhang DD
影响因子：
25.7
作者：
Connor F;Rayner TF;Aitken SJ;Feig C;Lukk M;Santoyo-Lopez J;Odom DT
通讯作者：
Odom DT