Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.

中文翻译：

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TRIM25通过靶向Keap1-Nrf2途径促进肝细胞癌的存活和生长。

在不利条件下，肿瘤细胞通常表现出增强的维持内质网（ER）动态平衡的能力，但其潜在机制尚不清楚。在这里，通过对所有人类TRIM蛋白的评估，我们发现在ER应激下TRIM25被显着诱导。TRIM25的上调改善了氧化应激，促进了ER相关降解（ERAD），并减少了UPR途径中的IRE1信号传导。相比之下，TRIM25的耗尽会导致内质网应激，并在体外和体内减弱肿瘤细胞的生长。从机理上讲，TRIM25通过泛素化和降解直接靶向Keap1。这导致Nrf2活化，从而增强抗氧化防御和细胞存活。在肝细胞癌（HCC）异种移植物和标本中，TRIM25表达与Nrf2表达正相关，与Keap1表达负相关。此外，高TRIM25表达与肝癌患者生存不良有关。这些发现表明TRIM25是ER稳态的调节剂，是肿瘤治疗的潜在靶标。