Bufalin Suppresses Migration and Invasion of Hepatocellular Carcinoma Cells Elicited by Poly (I:C) Therapy.
Bufalin Suppresses Migration and Invasion of Hepatocellular Carcinoma Cells Elicited by Poly (I:C) Therapy.
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DOI：
10.1080/2162402x.2018.1426434
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Wang C
中科院分区：
文献类型：
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作者：
Feng Y;Chen Y;Meng Y;Cao Q;Liu Q;Ling C;Wang C
Toll样受体3（TLR 3）激动剂作为多聚核糖肌苷酸-多聚核糖胞苷酸（poly（I：C））已被认为是癌症的潜在免疫治疗佐剂，而TLR 3激动剂在肝细胞癌（HCC）治疗中的确切作用尚未明确评估。与以前的报道一致，我们发现poly（I：C）触发TLR 3抑制肝癌细胞的细胞增殖并诱导凋亡。然而，当使用低浓度的poly（I：C）时，其不能显著抑制HCC细胞的增殖和诱导凋亡，从而促进体外迁移和侵袭以及体内转移。更重要的是，我们发现蟾毒灵，一个突出的组成部分，可以抑制聚（I：C）激发的迁移，侵袭和转移的肝癌细胞，尽管蟾毒灵不能加强聚（I：C）诱导的增殖抑制和诱导凋亡。蟾毒灵可抑制poly（I：C）诱导的MHCC 97 H细胞Tank结合激酶1（TBK 1）、干扰素调节因子3（IRF 3）和NF-κB通路的激活。TBK 1抑制剂而非NF-κB抑制剂抑制了poly（I：C）诱导的迁移和侵袭，这进一步得到了TBK 1缺陷（Tbk 1-/-）细胞的支持。在另一个使用poly（I：C）转染的模型中，蟾蜍灵也可以抑制HCC细胞的迁移和侵袭，而在Tbk 1-/-MHCC 97 H细胞中没有观察到。我们的数据表明，蟾蜍灵可以抑制肝癌细胞的转移，在聚（I：C）治疗通过削弱TBK 1的激活，表明蟾蜍灵可以用于与多聚（I：C）治疗肝癌的联合治疗，以逆转多聚（I：C）触发的肝癌细胞的转移。
The Toll-like receptor 3 (TLR3) agonists as polyriboinosinic–polyribocytidylic acid (poly (I:C)) have been implicated as potential immunotherapy adjuvant for cancer whereas the exact roles of TLR3 agonists in hepatocellular carcinoma (HCC) treatment have not been clearly evaluated. In consistent with previous reports, we found that poly (I:C) triggering of TLR3 inhibited cell proliferation and induced apoptosis in HCC cells. However, poly (I:C), when used at lower concentration that cannot remarkably inhibit proliferation and induce apoptosis in HCC cells, enhanced the migration and invasion in vitro and the metastasis in vivo. More importantly, we found that bufalin, a prominent component of toad venom, could suppress poly (I:C)-inspired migration, invasion and metastasis of HCC cells despite that bufalin could not potentiate poly (I:C)-induced inhibition of proliferation and induction of apoptosis. In MHCC97 H cells, bufalin impaired poly (I:C)-induced activation of Tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway and NF-κB pathway. Inhibitor for TBK1 but not NF-κB suppressed poly (I:C)-inspired migration and invasion, which was further supported by using TBK1 deficient (Tbk1–/–) cells. In another model using poly (I:C) transfection, bufalin could also suppress the migration and invasion of HCC cells, which was not observed in Tbk1–/– MHCC97 H cells. Our data suggest that bufalin can suppress the metastasis of HCC cells in poly (I:C) therapy by impairing TBK1 activation, indicating that bufalin may be used in combination with poly (I:C) therapy in HCC treatment for the sake of reversing poly (I:C)-triggered metastasis of HCC cells.