Bai Xue-Song, Zhang Chi, Peng Rui, Jiang Guo-Qing, Jin Sheng-Jie, Wang Qian, Ke Ai-Wu, Bai Dou-Sheng
The First Clinical Medical College, Dalian Medical University, Dalian, Liaoning 116044, People's Republic of China.
Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou 225009, Jiangsu, People's Republic of China.
Onco Targets Ther. 2020 Oct 9;13:10129-10141. doi: 10.2147/OTT.S269606. eCollection 2020.
The ubiquitin-proteasome system participates in the pathogenesis and progression of hepatocellular carcinoma (HCC). As an E3 ubiquitin ligase, RNF128 has been proved vital in carcinogenesis, whereas, little is known about the oncogenic mechanisms of RNF128 in HCC.
Through tissue microarray from HCC patients, we analyzed RNF128 expression and its relationship with clinical outcomes in HCC. Western blot and quantitative realtime polymerase chain reaction (qRT-PCR) were performed to examine expression levels of RNF128 in HCC tissues and cell lines. Effects of RNF128 on HCC cellular biological functions and the potential mechanism were evaluated through knockdown and overexpression assays in vitro and in vivo methods.
RNF128 expression was found to be remarkably elevated in HCC tissues compared with adjacent normal tissues. Furthermore, the overexpression of RNF128 enhanced hepatoma cells proliferation, colony formation, migration, invasion, and apoptotic resistance both in vitro and in vivo. Mechanistically, RNF128 activated EGFR/MEK/ERK signaling pathway and the EGFR inhibitor, gefitinib partially reversed RNF128-enhanced proliferation, invasion, and migration in hepatoma cells.
RNF128 promotes HCC progression by activating EGFR/MEK/ERK signaling pathway, which might function as a novel prognostic molecular signature with the potential to be a candidate therapeutic target for HCC patients.
泛素-蛋白酶体系统参与肝细胞癌（HCC）的发病机制和进展。作为一种E3泛素连接酶，RNF128已被证明在肿瘤发生中至关重要，然而，关于RNF128在HCC中的致癌机制知之甚少。
通过对HCC患者的组织芯片分析，我们分析了RNF128的表达及其与HCC临床结局的关系。采用蛋白质免疫印迹法（Western blot）和定量实时聚合酶链反应（qRT-PCR）检测RNF128在HCC组织和细胞系中的表达水平。通过体外和体内的敲低和过表达实验，评估RNF128对HCC细胞生物学功能的影响及其潜在机制。
与相邻正常组织相比，RNF128在HCC组织中的表达显著升高。此外，RNF128的过表达在体外和体内均增强了肝癌细胞的增殖、集落形成、迁移、侵袭和抗凋亡能力。机制上，RNF128激活了表皮生长因子受体（EGFR）/丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK/ERK）信号通路，EGFR抑制剂吉非替尼部分逆转了RNF128增强的肝癌细胞增殖、侵袭和迁移。
RNF128通过激活EGFR/MEK/ERK信号通路促进HCC进展，这可能作为一种新的预后分子标志物，有潜力成为HCC患者的候选治疗靶点。
