Upregulation of the oncoprotein SET determines poor clinical outcomes in hepatocellular carcinoma and shows therapeutic potential
Upregulation of the oncoprotein SET determines poor clinical outcomes in hepatocellular carcinoma and shows therapeutic potential
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DOI：
10.1038/onc.2016.21
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发表时间：
2016-09-15
期刊：
影响因子：
8
通讯作者：
Chen, K-F
中科院分区：
文献类型：
--
作者：
Hung, M-H;Chen, Y-L;Chen, K-F
SET 蛋白是蛋白磷酸酶 2A (PP2A) 的有效抑制剂。在这里，我们报告了 SET 在肝癌发生、临床侵袭性和抗肝细胞癌 (HCC) 治疗中的致癌作用。通过分析 147 名 HCC 患者的样本，我们发现 SET 过表达在 30.6% HCC 肿瘤样本中被特异性检测到，并且与 HCC 肿瘤中较差的临床特征和高 p-Akt 表达显着相关。 SET 和 Akt 的共表达预测该队列的术后无复发生存期较短 (P = 0.045)。此外，SET与细胞生长和肝球形成显着相关。为了阐明 SET 的抗 HCC 潜力，我们产生了一种新型 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-PP2Ac（PP2A 催化结构域）的结合来增强 PP2A 活性，从而恢复 PP2A 介导的 p-Akt 下调并促进 HCC 细胞死亡。在表达 SET N 和 C 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，索拉非尼和 EMQA 联合使用在抑制 HCC 存活方面显示出良好的协同作用。我们的研究结果表明 SET 的致癌作用以及 SET 过表达在 HCC 中的不良预后价值。这一改变定义了可以从 EMQA 等 SET 拮抗剂中获益的 HCC 患者亚组。
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.