Golgi phosphoprotein 3 (GOLPH3) promotes hepatocellular carcinoma cell aggressiveness by activating the NF-κB pathway
Golgi phosphoprotein 3 (GOLPH3) promotes hepatocellular carcinoma cell aggressiveness by activating the NF-κB pathway
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高尔基体磷蛋白 3 (GOLPH3) 通过激活 NF-κB 通路促进肝细胞癌细胞侵袭性
DOI：
10.1002/path.4479
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发表时间：
2015-02-01
影响因子：
7.3
通讯作者：
Song, Libing
中科院分区：
文献类型：
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作者：
Dai, Ting;Zhang, Dongsheng;Song, Libing
肝细胞癌（HCC）是最致命的恶性肿瘤之一，NF-B通路在其中起着重要作用，并被组成性激活。需要更好地了解HCC的分子发病机制和NF-B途径，以改善患者的预后。在这里，我们发现了一个未被发现的蛋白参与nf - b诱导的激活，高尔基磷酸化蛋白3 （GOLPH3）。在HCC中，GOLPH3的mRNA和蛋白表达水平经常上调，并且在测试和验证队列中，GOLPH3的表达与临床分期和生存密切相关。GOLPH3在PLC/PRF/5 （PLC）和Huh7肝癌细胞中异位过表达，可保护顺铂诱导的肝癌细胞凋亡，促进血管生成和增殖，提高肝癌细胞在体外和体内的侵袭性，而抑制GOLPH3导致侵袭性降低。通过分析两份已发表的HCC患者资料，GOLPH3的表达与NF-B信号传导显著相关。此外，我们证明GOLPH3促进k63相关的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-B必需调节剂（NEMO）的多泛素化，并在HCC细胞中基本维持NF-B的激活。综上所述，我们的研究结果提供了证据，证明GOLPH3是HCC患者的预后和/或潜在的治疗性生物标志物，并在HCC进展过程中激活NF-B通路中发挥重要作用。版权所有(c) 2014大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, in which the NF-B pathway plays an important role and is constitutively activated. Better understanding of the molecular pathogenesis of HCC and the NF-B pathway are needed to improve patient outcomes. Herein, we identified an unappreciated protein involved in NF-B-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-B 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-B essential modulator (NEMO) and substantially sustained the activation of NF-B 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-B pathway during HCC progression. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.