Hung M-H, Chen Y-L, Chu P-Y, Shih C-T, Yu H-C, Tai W-T, Shiau C-W, Chen K-F
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Oncogene. 2016 Sep 15;35(37):4891-902. doi: 10.1038/onc.2016.21. Epub 2016 Feb 15.
The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma (HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort (P=0.045). Furthermore, SET was significantly associated with cell growth and hepatosphere formation. To elucidate the anti-HCC potential of targeting SET, we generated a novel SET antagonist, EMQA (N(4)-(3-ethynylphenyl)-6,7-dimethoxy-N(2)-(4-phenoxyphenyl) quinazoline-2,4-diamine). EMQA enhanced PP2A activity via disrupting SET-PP2Ac (catalytic domain of PP2A) binding in HCC cells, which restored PP2A-mediated p-Akt downregulation and promoted HCC cell death. In HCC cells or recombinant proteins expressing the N- and C- truncated forms of SET, only the C-terminal SET was required for EMQA targeting. Furthermore, combining sorafenib and EMQA showed good synergism in inhibiting HCC survival. Our findings suggested the oncogenic role of SET and the adverse prognostic value of SET overexpression in HCC. This alteration defines a subgroup of HCC patients who could benefit from SET antagonists, such as EMQA.
SET蛋白是蛋白磷酸酶2A（PP2A）的强效抑制剂。在此，我们报告了SET在肝癌发生、临床侵袭性及抗肝细胞癌（HCC）治疗中的致癌作用。通过分析147例HCC患者的样本，我们发现SET过表达在30.6%的HCC肿瘤样本中被特异性检测到，且与HCC肿瘤更差的临床特征及高p-Akt表达显著相关。SET与Akt的共表达预示着该队列患者术后无复发生存期更短（P = 0.045）。此外，SET与细胞生长及肝球形成显著相关。为阐明靶向SET的抗HCC潜力，我们生成了一种新型SET拮抗剂EMQA（N(4)-(3-乙炔基苯基)-6,7-二甲氧基-N(2)-(4-苯氧基苯基)喹唑啉-2,4-二胺）。EMQA通过破坏HCC细胞中SET与PP2Ac（PP2A的催化结构域）的结合来增强PP2A活性，这恢复了PP2A介导的p-Akt下调并促进HCC细胞死亡。在表达SET N端和C端截短形式的HCC细胞或重组蛋白中，EMQA靶向仅需要C端SET。此外，索拉非尼与EMQA联合使用在抑制HCC存活方面显示出良好协同作用。我们的研究结果提示了SET的致癌作用以及SET过表达在HCC中的不良预后价值。这种改变定义了一组可能从SET拮抗剂（如EMQA）中获益的HCC患者亚组。
