Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study.
Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study.
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DOI：
10.1038/srep38407
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发表时间：
2016-12-02
影响因子：
4.6
通讯作者：
Kato N
中科院分区：
文献类型：
--
作者：
Goto K;Annan DA;Morita T;Li W;Muroyama R;Matsubara Y;Ito S;Nakagawa R;Tanoue Y;Jinushi M;Kato N
肝细胞癌 (HCC) 的药物治疗选择有限。最近，我们在全基因组关联研究（GWAS）中鉴定出抗肿瘤配体MHC I类多肽相关序列A（MICA）基因是丙型肝炎病毒诱导的肝癌的易感基因。为了根据GWAS的结果证明HCC免疫治疗的概念，在本研究中，我们寻找可以恢复MICA表达的药物。 FDA 批准的药物库筛选发现抗癌药物伏立诺他是最热门的药物，表明组蛋白脱乙酰酶抑制剂 (HDACis) 是有效的候选药物。事实上，HDACi 诱导的 HCC 细胞特异性 MICA 表达增强了共培养中自然杀伤 (NK) 细胞介导的细胞毒性，通过 MICA 脱落酶抑制剂处理进一步增强了这种毒性。在体内观察到 NK 2D 组同样增强了 NK 细胞的抗肿瘤活性。代谢组学分析揭示了 HDACi 介导的 MICA 诱导和 HCC 抑制的能量供应和应激变化，为化学免疫治疗作用提供了机制。这些数据表明选择性 HCC 先天免疫治疗的有前途的策略。
Pharmacotherapeutic options are limited for hepatocellular carcinoma (HCC). Recently, we identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) gene as a susceptibility gene for hepatitis C virus-induced HCC in a genome-wide association study (GWAS). To prove the concept of HCC immunotherapy based on the results of a GWAS, in the present study, we searched for drugs that could restore MICA expression. A screen of the FDA-approved drug library identified the anti-cancer agent vorinostat as the strongest hit, suggesting histone deacetylase inhibitors (HDACis) as potent candidates. Indeed, the HDACi-induced expression of MICA specific to HCC cells enhanced natural killer (NK) cell-mediated cytotoxicity in co-culture, which was further reinforced by treatment with an inhibitor of MICA sheddase. Similarly augmented anti-tumor activity of NK cells via NK group 2D was observed in vivo. Metabolomics analysis revealed HDACi-mediated alterations in energy supply and stresses for MICA induction and HCC inhibition, providing a mechanism for the chemoimmunotherapeutic actions. These data are indicative of promising strategies for selective HCC innate immunotherapy.
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影响因子：
4.6
作者：
Iwao C;Shidoji Y
通讯作者：
Shidoji Y
影响因子：
3.7
作者：
Drozdov I;Bornschein J;Wex T;Valeyev NV;Tsoka S;Malfertheiner P
通讯作者：
Malfertheiner P
影响因子：
7.3
作者：
Krieg S;Ullrich E
通讯作者：
Ullrich E
影响因子：
5.6
作者：
Kakuni M;Yamasaki C;Tachibana A;Yoshizane Y;Ishida Y;Tateno C
通讯作者：
Tateno C
影响因子：
4.1
作者：
Cuperlovic-Culf M;Touaibia M;St-Coeur PD;Poitras J;Morin P;Culf AS
通讯作者：
Culf AS