Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China and Collaborative Innovation Centre for Cancer Medicine, Guangzhou, People's Republic of China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People's Republic of China; Department of Biotechnology, Guangzhou Medical University, People's Republic of China.
J Pathol. 2015 Feb;235(3):490-501. doi: 10.1002/path.4479.
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, in which the NF-κB pathway plays an important role and is constitutively activated. Better understanding of the molecular pathogenesis of HCC and the NF-κB pathway are needed to improve patient outcomes. Herein, we identified an unappreciated protein involved in NF-κB-induced activation, Golgi phosphoprotein 3 (GOLPH3). The mRNA and protein expression levels of GOLPH3 were frequently up-regulated in HCC and GOLPH3 expression correlated closely with clinical stage and survival in both the testing and validation cohorts. Ectopic over-expression of GOLPH3 in PLC/PRF/5 (PLC) and Huh7 HCC cells protected against cisplatin-induced apoptosis, promoted angiogenesis and proliferation and increased the aggressiveness of HCC cells in vitro and in vivo, whereas inhibition of GOLPH3 led to decreased aggressiveness. Through analysis of two published HCC patient profiles, GOLPH3 expression significantly correlated with NF-κB signalling. Furthermore, we demonstrated that GOLPH3 promoted K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor interacting protein (RIP) and NF-κB essential modulator (NEMO) and substantially sustained the activation of NF-κB in HCC cells. Taken together, our findings provided evidence that GOLPH3 is a prognostic and/or potential therapeutic biomarker for HCC patients and plays an important role in activation of the NF-κB pathway during HCC progression.
肝细胞癌（HCC）是最致命的恶性肿瘤之一，其中 NF-κB 通路起着重要作用并持续激活。为了改善患者的预后，需要更好地了解 HCC 的分子发病机制和 NF-κB 通路。在此，我们鉴定出一种参与 NF-κB 诱导激活的未被认识的蛋白，即高尔基磷酸蛋白 3（GOLPH3）。GOLPH3 的 mRNA 和蛋白表达水平在 HCC 中经常上调，GOLPH3 的表达与检测和验证队列中的临床分期和生存密切相关。在 PLC/PRF/5（PLC）和 Huh7 HCC 细胞中外源性过表达 GOLPH3 可防止顺铂诱导的细胞凋亡，促进血管生成和增殖，并增加 HCC 细胞在体外和体内的侵袭性，而抑制 GOLPH3 则导致侵袭性降低。通过分析两个已发表的 HCC 患者图谱，GOLPH3 的表达与 NF-κB 信号显著相关。此外，我们证明 GOLPH3 促进肿瘤坏死因子受体相关因子 2（TRAF2）、受体相互作用蛋白（RIP）和 NF-κB 必需调节剂（NEMO）的 K63 连接多泛素化，并在 HCC 细胞中持续激活 NF-κB。总之，我们的研究结果表明，GOLPH3 是 HCC 患者的预后和/或潜在治疗生物标志物，在 HCC 进展过程中 NF-κB 通路的激活中发挥重要作用。
