Lin Min, Liu Yiming, Ding Xiaokun, Ke Qinjian, Shi Jieyao, Ma Zewei, Gu Hongqian, Wang Haixi, Zhang Chuanfeng, Yang Chenxi, Fang Zejun, Zhou Linfu, Ye Ming
Central Laboratory, Sanmen People's Hospital of Zhejiang Sanmen, China.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University Hangzhou, China.
Am J Cancer Res. 2019 Feb 1;9(2):285-299. eCollection 2019.
For decades, E2F1 has been recognized as a retinoblastoma protein (RB) binding transcription factor that regulates the cell cycle. E2F1 binds preferentially to RB and accelerates the cell cycle in most cancer cells. However, it is thought that E2F1 modulates cell proliferation in other ways as well. Herein, it has been discovered that in pathological tissues derived from hepatocellular carcinoma (HCC) patients, E2F1 correlates positively with IQGAP3 and that both of these factors are highly expressed (N = 164, R = 0.6716). In addition, a high level of E2F1 or IQGAP3 predicted poor survival in HCC patients. Further study determined that E2F1 transactivates IQGAP3, the GTPase binding protein in MHCC-97H cells. Co-immunoprecipitation analysis indicated that IQGAP3 interacts with PKCδ and competitively inhibits the interaction between PKCδ and PKCα, resulting in phosphorylation of PKCα activation and promotion of cell proliferation. This study reveals that highly expressed E2F1 not only transactivates cell-cycle-related factors but also promotes HCC proliferation by activating the phosphorylation of PKCα.
几十年来，E2F1一直被认为是一种与视网膜母细胞瘤蛋白（RB）结合的转录因子，可调节细胞周期。E2F1优先与RB结合，并在大多数癌细胞中加速细胞周期。然而，人们认为E2F1也以其他方式调节细胞增殖。在此发现，在源自肝细胞癌（HCC）患者的病理组织中，E2F1与IQGAP3呈正相关，且这两种因子均高表达（N = 164，R = 0.6716）。此外，高水平的E2F1或IQGAP3预示着HCC患者的生存预后较差。进一步研究确定，E2F1可反式激活MHCC-97H细胞中的GTP酶结合蛋白IQGAP3。免疫共沉淀分析表明，IQGAP3与PKCδ相互作用，并竞争性抑制PKCδ与PKCα之间的相互作用，导致PKCα磷酸化激活并促进细胞增殖。本研究表明，高表达的E2F1不仅可反式激活细胞周期相关因子，还可通过激活PKCα的磷酸化促进肝癌细胞增殖。
