Department of Pathology, Dongguan Third People's Hospital, Dongguan, China.
Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
J Cell Sci. 2017 Sep 15;130(18):3108-3115. doi: 10.1242/jcs.206623. Epub 2017 Jul 28.
Deregulation of ubiquitin ligases contributes to the malignant progression of human cancers. Tripartite motif-containing protein 65 (TRIM65) is an E3 ubiquitin ligase and has been implicated in human diseases, but its role and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we showed that TRIM65 expression was increased in HCC tissues and associated with poor outcome in two independent cohorts containing 888 patients. and data demonstrated that overexpression of TRIM65 promoted cell growth and tumor metastasis, whereas knockdown of TRIM65 resulted in opposite phenotypes. Further studies revealed that TRIM65 exerted oncogenic activities via ubiquitylation of Axin1 to activate the β-catenin signaling pathway. TRIM65 directly bound to Axin1 and accelerated its degradation through ubiquitylation. Furthermore, HMGA1 was identified as an upstream regulator of TRIM65 in HCC cells. In clinical samples, TRIM65 expression was positively correlated with the expression of HMGA1 and nuclear β-catenin. Collectively, our data indicate that TRIM65 functions as an oncogene in HCC. The newly identified HMGA1/TRIM65/β-catenin axis serves as a promising prognostic factor and therapeutic target.
泛素连接酶的失调导致人类癌症的恶性进展。三基序蛋白 65（TRIM65）是一种 E3 泛素连接酶，与人类疾病有关，但它在肝细胞癌（HCC）中的作用和临床意义尚不清楚。在这里，我们表明，TRIM65 在 HCC 组织中的表达增加，并与包含 888 名患者的两个独立队列中的不良预后相关。和数据表明，TRIM65 的过表达促进细胞生长和肿瘤转移，而 TRIM65 的敲低则导致相反的表型。进一步的研究表明，TRIM65 通过泛素化 Axin1 发挥致癌活性，从而激活 β-连环蛋白信号通路。TRIM65 直接与 Axin1 结合，并通过泛素化加速其降解。此外，HMGA1 被鉴定为 HCC 细胞中 TRIM65 的上游调节剂。在临床样本中，TRIM65 的表达与 HMGA1 和核 β-连环蛋白的表达呈正相关。总之，我们的数据表明 TRIM65 在 HCC 中作为癌基因发挥作用。新鉴定的 HMGA1/TRIM65/β-连环蛋白轴可作为有前途的预后因素和治疗靶点。
