HDAC抑制剂丙戊酸通过减少MDSCs蓄积抑制肝癌的生长

HDAC inhibitor valproic acid suppresses hepatoma growth by attenuating myeloid-derived suppressor cells accumulation

目的研究组蛋白去乙酰化酶抑制剂丙戊酸(VPA)抑制肝癌发生发展的机制。方法将16只Balb/c小鼠注射小鼠肝癌细胞H22建立肝癌原位模型,随机分成2组:对照组和VPA组。术后第2天VPA组小鼠每天腹腔注射VPA(200mg/kg),对照组每天腹腔注射等量的生理盐水。10d后将小鼠处死,观察肿瘤大小及小鼠肝脏质量,利用流式分析小鼠脾脏部位CD4、CD8、NK细胞、MDSCs水平及肿瘤部位MDSCs的比例。建立小鼠肝癌原位模型,利用小动物活体成像分析MDSCs经1mmol/L VPA处理后在体内迁移情况。结果 VPA抑制肝癌原位模型中肝癌生长,上调脾脏CD4、CD8水平,抑制肿瘤和脾脏部位MDSCs蓄积。MDSCs经VPA处理后向肿瘤和脾脏迁移的能力减弱,而MDSCs向骨髓的迁移的能力没有受影响。结论在肝癌微环境中,VPA能够抑制MDSCs向肿瘤和脾脏部位迁移、改善肝癌微环境,从而抑制肝癌生长。本研究为肝癌的治疗提供了一定的实验基础。

Valproic acid(VPA) has been reported to play an important role in anti-cancer effects during tumor progression, but its function in the regulation of myeloid-derived suppressor cells(MDSCs) during hepatoma progression still remains elusive. The aim of this study is to investigate the role of VPA in regulation of MDSCs in hepatoma. Orthotopic transplantation tumor model of mice were intraperitoneally injected with 200 mg/kg VPA or normal saline, and the mice were sacrificed at tenth day to examine the tumor and liver. Flow cytometry was used to detect the levels of CD4, CD8, NK, MDSCs in splenocyte, and the ratio of MDSCs in the tumor. To explore the effects of VPA on the migration of MDSCs, the MDSCs separated from tumor-bearing mice were treated with 1 mmol/L VPA and then transfered to orthotopic transplantation tumor model mice of hepatoma by tail vein injection. Data showed that VPA inhibited the growth of tumor, as well as the accumulation of MDSCs in tumor and splenocyte. MDSCs pretreated with VPA showed a weaken migration ability compared with control. Taken together, this study uncovers that VPA can inhibit the tumor progression through attenuating the accumulation of MDSCs, suggesting a new treatment strategy for hepatoma.