Tunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD44s and the ERK1/2 pathway.
Tunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD44s and the ERK1/2 pathway.
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衣霉素通过抑制 CD44 和 ERK1/2 通路抑制肝细胞癌的细胞增殖和迁移
DOI：
10.1111/cas.13518
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发表时间：
2018-04
期刊：
影响因子：
5.7
通讯作者：
Tian H
中科院分区：
文献类型：
--
作者：
Hou H;Ge C;Sun H;Li H;Li J;Tian H
衣霉素（TM）是一种N-连接糖基化（NLG）抑制剂，具有很强的抗肿瘤活性，其确切的潜在分子机制仍有待阐明。在我们以前的研究中，我们发现TM逆转了耐药性，提高了肝细胞癌（HCC）联合治疗的疗效。本文研究了TM对肝癌细胞增殖和迁移的影响及其作用机制。结果表明，TM能抑制肝癌细胞的增殖和迁移，并诱导肝癌细胞凋亡。TM通过诱导细胞凋亡和细胞周期阻滞在G2/M期抑制肝癌细胞增殖。同时，TM通过抑制CD 44介导的上皮间质转化（EMT）来抑制HCC细胞的迁移。TM通过降低CD 44表达和改变其糖基化而抑制HCC细胞的迁移和侵袭。此外，CD 44 s参与促进EMT，并与HCC患者的不良预后相关。CD 44 s过表达促进肝癌细胞的肿瘤迁移和ERK 1/2的活化磷酸化，而TM抑制CD 44 s过表达相关的细胞迁移。TM抑制细胞迁移和侵袭的能力在CD 44 s敲低细胞和CD 44 s过表达细胞中分别增强或逆转。MEK/ERK抑制剂U 0126和TM抑制HCC细胞中透明质酸诱导的细胞迁移。此外，TM通过ERK 1/2依赖性机制抑制外源性转化生长因子β（TGF-β）介导的EMT，并恢复TGF-β介导的E-钙粘蛋白丢失。总之，我们的研究提供了TM通过抑制CD 44 s和ERK 1/2信号通路抑制HCC细胞增殖和迁移的证据。
Tunicamycin (TM) is an N‐linked glycosylation (NLG) inhibitor with strong antitumor activity, the exact underlying molecular mechanism of which remains to be elucidated. In our previous studies, we found that TM reversed drug resistance and improved the efficacy of combination treatments for hepatocellular carcinomas (HCC). Here, we investigated the effects of TM on HCC cell proliferation and migration as well as the mechanism of those effects. Our results showed that TM inhibited cell proliferation and migration as well as induced apoptosis of hepatocellular carcinoma cells. TM inhibited proliferation of HCC cells by inducing cell apoptosis and cell cycle arrest at the G2/M phase. Meanwhile, TM inhibited migration of HCC cells by suppressing CD44s‐mediated epithelial‐mesenchymal transition (EMT). TM inhibited migration and invasion of HCC cells by decreasing CD44 expression and altering its glycosylation. In addition, CD44s is involved in promoting EMT and is associated with a poor prognosis in HCC patients. Overexpression of CD44s promoted tumor migration and activated phosphorylation of ERK1/2 in HCC cells, whereas TM inhibited CD44s overexpression‐associated cell migration. The ability of TM to inhibit cell migration and invasion was enhanced or reversed in CD44s knockdown cells and cells overexpressing CD44s, respectively. The MEK/ERK inhibitor U0126 and TM inhibited hyaluronic acid‐induced cell migration in HCC cells. Furthermore, TM inhibited exogenous transforming growth factor beta (TGF‐β)‐mediated EMT by an ERK1/2‐dependent mechanism and restored the TGF‐β‐mediated loss of E‐cadherin. In summary, our study provides evidence that TM inhibits proliferation and migration of HCC cells through inhibition of CD44s and the ERK1/2 signaling pathway.
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