Implication of myeloid differentiation factor 88 inhibitor TJ-M2010-5 for therapeutic intervention of hepatocellular carcinoma
Implication of myeloid differentiation factor 88 inhibitor TJ-M2010-5 for therapeutic intervention of hepatocellular carcinoma
复制标题
髓样分化因子88抑制剂TJ-M2010-5对肝细胞癌治疗干预的意义
DOI：
10.1111/hepr.13359
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发表时间：
2019-10-01
影响因子：
4.2
通讯作者：
Zhou, Ping
中科院分区：
文献类型：
--
作者：
Liu, Jing;Zhang, Xue;Zhou, Ping
目的髓系分化因子88(MyD88)在肿瘤的增殖和转移中起关键作用。靶向MyD88是肿瘤治疗中的一种有效策略。TJ-M2010-5是氨基噻唑的小分子衍生物，能抑制MyD88二聚体的形成。为了探索TJ-M2010-5在肿瘤治疗中的潜力，我们检测了TJ-M2010-5对肝细胞癌的抗肿瘤作用及其相关机制。方法观察TJ-M2010-5瘤内注射对H22荷瘤BALB/c小鼠的抗肿瘤作用。监测肿瘤生长情况。免疫荧光法检测MyD88和Ki-67的表达。体外观察TJ-M2010-5对H22细胞增殖、细胞周期、坏死和凋亡的影响。用流式细胞仪检测TJ-M2010-5对巨噬细胞的直接和间接作用。结果TJ-M2010-5诱导肝癌细胞发生G(0)/G(1)和G(1)/S期阻滞。机制上，TJ-M2010-5通过细胞外调节蛋白激酶-1/2/P90核糖体S6激酶/糖原合成酶-3β信号通路抑制MyD88的下游激活。细胞周期蛋白依赖性激酶(CDK)6/细胞周期蛋白D1和细胞周期蛋白2/细胞周期蛋白E复合体表达下调。更重要的是，TJ-M2010-5显著抑制了小鼠肿瘤的生长。此外，经TJ-M2010-5治疗后，肿瘤微环境中抗肿瘤M1巨噬细胞(F4/80(+)CD11c(+))的比例增加。综上所述，这些数据表明TJ-M2010-5是一种很有前途的治疗肝癌的药物。结论MyD88是一种可行的抗肿瘤治疗靶点，TJ-M2010-5是一种合格的肝癌治疗候选细胞。
Aim Myeloid differentiation factor 88 (MyD88) plays a key role in tumor proliferation and metastasis. Targeting MyD88 is a potent strategy in tumor therapy. TJ-M2010-5 is a small molecule derivative of aminothiazole and could inhibit dimer formation of MyD88. To explore the potential of TJ-M2010-5 in tumor therapy, we determined its antitumor effect and correlate mechanisms of TJ-M2010-5 in hepatocellular carcinoma (HCC). Methods The antitumor effect of intratumoral injection of TJ-M2010-5 to H22 tumor-bearing BALB/c mice was observed. Tumor growth was monitored. The expression of MyD88 and Ki-67 were detected by immunofluorescence. In vitro, the impacts of TJ-M2010-5 on proliferation, cell cycle, necrosis, and apoptosis of H22 cells were evaluated. The direct and indirect effects of TJ-M2010-5 on macrophages were evaluated using flow cytometry. Results TJ-M2010-5 induced both G(0)/G(1) and G(1)/S phase arrests in HCC cells. Mechanically, downstream activation of MyD88 was suppressed by TJ-M2010-5 through the extracellular regulated protein kinase-1/2/p90 ribosomal S6 kinase/glycogen synthase kinase-3 beta signaling pathway. In turn, cyclin-dependent kinase (CDK)6/cyclin D1 and CDK2/cyclin E complexes were downregulated. More importantly, TJ-M2010-5 significantly inhibited tumor growth in mice. Additionally, the portion of antitumor M1 macrophages (F4/80(+)CD11c(+)) in the tumor microenvironment were increased after TJ-M2010-5 treatment. Together, these data indicate that TJ-M2010-5 is a promising therapeutic drug for HCC. Conclusions These results indicate that MyD88 is a feasible target for antitumor treatment and TJ-M2010-5 is a qualified candidate for HCC therapy.