Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Third Central Hospital, Tianjin, China; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey.
Cell Mol Gastroenterol Hepatol. 2021;11(5):1369-1385. doi: 10.1016/j.jcmgh.2021.01.007. Epub 2021 Jan 19.
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.
TRIM21 是一种泛素 E3 连接酶，参与多种生物学过程，包括免疫反应、细胞代谢、氧化还原稳态和癌症发展。我们最近报道，TRIM21 可以通过泛素化 p62 来负调控 p62-Keap1-Nrf2 抗氧化途径，防止其寡聚化和蛋白隔离功能。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 TRIM21 在肝癌发生中的作用。
我们使用公共数据集和 49 例 HCC 临床样本检查了 TRIM21 表达与疾病之间的相关性。我们使用 TRIM21 基因敲除小鼠来确定 TRIM21 缺失如何影响 DEN 加苯巴比妥（PB）诱导的 HCC。我们探讨了 TRIM21 缺失保护细胞免受 DEN 诱导的氧化损伤和细胞死亡的机制。
TRIM21 表达与 HCC 呈正相关。一致地，TRIM21 敲除小鼠对 DEN 诱导的肝癌发生具有抗性。这伴随着 DEN 处理时细胞死亡和组织损伤减少，因此减少了肝组织修复反应和代偿性增殖。缺乏 TRIM21 的细胞显示出 Keap1 被 p62 隔离的增强，并且免受 DEN 诱导的 ROS 诱导和细胞死亡的影响。野生型而非 E3 连接酶缺陷型和 p62 结合缺陷型突变 TRIM21 的重建阻碍了 TRIM21 缺陷细胞免受 DEN 诱导的氧化损伤和细胞死亡的保护。
TRIM21 表达增加与人类 HCC 相关。TRIM21 的基因缺失导致对氧化肝损伤的保护作用降低和肝癌发生减少，表明 TRIM21 可作为预防和治疗靶点。
