Novel chemokine-like activities of histones in tumor metastasis.
Novel chemokine-like activities of histones in tumor metastasis.
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组蛋白在肿瘤转移中的新型趋化因子样活性
DOI：
10.18632/oncotarget.11226
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发表时间：
2016-09-20
期刊：
影响因子：
--
通讯作者：
Kang R
中科院分区：
文献类型：
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作者：
Chen R;Xie Y;Zhong X;Fu Y;Huang Y;Zhen Y;Pan P;Wang H;Bartlett DL;Billiar TR;Lotze MT;Zeh HJ 3rd;Fan XG;Tang D;Kang R
组蛋白是细胞内核小体组分和细胞外损伤相关的分子模式分子，其调节染色质重塑以及免疫应答。然而，它们在细胞迁移和侵袭中的细胞外作用仍然不确定。在这里，我们证明了组蛋白是一种新的具有趋化因子样活性的肿瘤转移调节因子。事实上，外源性组蛋白通过Toll样受体（TLR）4而不是TLR 2或晚期糖基化终产物的受体促进肝细胞癌（HCC）细胞迁移和侵袭。TLR 4介导的细胞外信号调节激酶（ERK）对核因子-κB（NF-κB）的激活是组蛋白诱导的趋化因子（例如，C-C基序配体9/10）产生。TLR 4-ERK-NF-κB信号传导的药理学和遗传学抑制损害组蛋白诱导的趋化因子产生和HCC细胞迁移此外，TLR 4耗竭（通过使用TLR 4-/-小鼠和TLR 4-shRNA）或组蛋白释放/活性抑制（通过给予肝素和H3中和抗体）减弱了通过小鼠尾静脉注射的HCC细胞的肺转移。因此，组蛋白通过TLR 4-NF-κB途径促进HCC细胞的肿瘤转移，并代表治疗HCC患者的新靶点。
Histones are intracellular nucleosomal components and extracellular damage-associated molecular pattern molecules that modulate chromatin remodeling, as well as the immune response. However, their extracellular roles in cell migration and invasion remain undefined. Here, we demonstrate that histones are novel regulators of tumor metastasis with chemokine-like activities. Indeed, exogenous histones promote both hepatocellular carcinoma (HCC) cell migration and invasion through toll-like receptor (TLR)4, but not TLR2 or the receptor for advanced glycosylation end product. TLR4-mediated activation of nuclear factor-κB (NF-κB) by extracellular signal-regulated kinase (ERK) is required for histone-induced chemokine (e.g., C-C motif ligand 9/10) production. Pharmacological and genetic inhibition of TLR4-ERK-NF-κB signaling impairs histone-induced chemokine production and HCC cell migration. Additionally, TLR4 depletion (by using TLR4−/− mice and TLR4-shRNA) or inhibition of histone release/activity (by administration of heparin and H3 neutralizing antibody) attenuates lung metastasis of HCC cells injected via the tail vein of mice. Thus, histones promote tumor metastasis of HCC cells through the TLR4-NF-κB pathway and represent novel targets for treating patients with HCC.