Department of Interventional Therapy, The People's Hospital of Jianhu, Jianhu, 224700, Jiangsu, P. R. China.
Department of Intensive Medicine, The People's Hospital of Jianhu, Jianhu, 224700, Jiangsu, P. R. China.
Cell Biol Int. 2020 Jul;44(7):1503-1513. doi: 10.1002/cbin.11346. Epub 2020 Apr 28.
Tripartite motif protein 25 (TRIM25) expression was altered in various human cancers. Herein, we found that the expression of TRIM25 was elevated in hepatocellular carcinoma (HCC) tissues and cell lines. Knockdown of TRIM25 increased the sensitivity of HCC HepG2 cells to epirubicin (EPI), as indicated by reduced cell viability, enhanced cell apoptosis, and downregulated P-glycoprotein (P-gp) and multiple drug-resistance protein 1 (MRP1). Moreover, TRIM25 knockdown strengthened the effects of EPI on phosphatase and tensin homolog (PTEN) and phosphorylated (p)-AKT. However, overexpression of TRIM25 exerted an opposite effect, weakening the sensitivity of Huh7 to EPI, and obviously increasing PTEN and reducing p-AKT. Most important, all the changes induced by TRIM25 overexpression in Huh7 were reversed with additional treatment of LY294002 (an AKT pathway inhibitor). Notably, coimmunoprecipitation experiments confirmed the interaction between TRIM25 and PTEN. Knockdown of TRIM25 resulted in reduced ubiquitination of PTEN protein. Collectively, our data suggested that TRIM25 enhanced EPI resistance via modulating PTEN/AKT pathway, and targeting TRIM25 may enhance the sensitivity of HCC cells toward chemotherapy drugs.
三结构域蛋白 25（TRIM25）在各种人类癌症中的表达发生改变。在此，我们发现 TRIM25 在肝癌（HCC）组织和细胞系中的表达上调。TRIM25 的敲低增加了 HCC HepG2 细胞对表柔比星（EPI）的敏感性，表现为细胞活力降低、细胞凋亡增强以及 P-糖蛋白（P-gp）和多药耐药蛋白 1（MRP1）下调。此外，TRIM25 的敲低增强了 EPI 对磷酸酶和张力蛋白同源物（PTEN）和磷酸化（p）-AKT 的作用。然而，TRIM25 的过表达则产生相反的效果，减弱 Huh7 对 EPI 的敏感性，明显增加 PTEN 并减少 p-AKT。最重要的是，Huh7 中 TRIM25 过表达引起的所有变化都随着 AKT 通路抑制剂 LY294002 的额外处理而逆转。值得注意的是，免疫共沉淀实验证实了 TRIM25 与 PTEN 之间的相互作用。TRIM25 的敲低导致 PTEN 蛋白的泛素化减少。总之，我们的数据表明，TRIM25 通过调节 PTEN/AKT 通路增强了 EPI 耐药性，靶向 TRIM25 可能增强 HCC 细胞对化疗药物的敏感性。
