Toll-like receptor 4 signaling promotes invasion of hepatocellular carcinoma cells through MKK4/JNK pathway
Toll-like receptor 4 signaling promotes invasion of hepatocellular carcinoma cells through MKK4/JNK pathway
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Toll样受体4信号通过MKK4/JNK通路促进肝癌细胞侵袭
DOI：
10.1016/j.molimm.2015.10.015
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发表时间：
2015-01-01
影响因子：
3.6
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Dong, Yu-Qing;Lu, Chuan-Wei;Chen, Wei
toll样受体（TLR） 4介导的信号传导在多种癌症的细胞存活、侵袭和转移中起重要作用。本研究旨在探讨TLR4信号在肝细胞癌（HCC）细胞系侵袭中的作用及其下游通路。我们发现，TLR4的激动剂LPS显著增强了HCC细胞的侵袭性和MMP2和MMP9的表达，以及11l -6和TNF α的产生。LPS处理显著增加了HCC细胞表面TLR4的表达和MKK4/JNK的激活，而TLR4的敲低抑制了LPS诱导的侵袭和MKK4和JNK的磷酸化。此外，沉默MKK4或抑制JNK活性导致hcc侵袭性受损，MMPs和TLR4的表达水平降低，以及细胞因子的产生受限。然而，LPS刺激仅引发NF-kappa B的适度活化，NF-kappa B或NF-kappa B抑制剂的沉默对hcc的侵袭能力和TLR4表达无明显影响，但抑制IL-6和TNF - α的产生。这些发现表明，LPS-TLR4信号主要通过MKK4/JNK途径增强hcc的侵袭性。(C) 2015 Elsevier Ltd.版权所有。
Toll-like receptor (TLR) 4-mediated signaling has been shown to be important to cell survival, invasion and metastasis in a variety of cancers. The present study aimed to explore the role and downstream pathways of TLR4 signaling in the invasion of hepatocellular carcinoma (HCC) cell lines. We found that LPS, the agonist of TLR4, notably enhanced the invasiveness of HCC cells and the expression of MMP2 and MMP9, as well as the production of 1L-6 and TNF alpha. LPS treatment dramatically increased the TLR4 expression on HCC cells surface and MKK4/JNK activation, while knockdown of TLR4 inhibited the LPS-induced invasion and the phosphorylation of MKK4 and JNK. Furthermore, silencing of MKK4 or inhibition of JNK activity led to impaired invasiveness of HCCs, low expression level of MMPs and TLR4, as well as limited production of cytokines. However, LPS stimulation only triggered moderate activation of NF-kappa B. Silencing of NF-kappa B or NF-kappa B inhibitor had no obvious effect on the invasive ability of HCCs and TLR4 expression, but suppressed IL-6 and TNF alpha production. These findings suggested that LPS-TLR4 signaling enhanced the invasiveness of HCCs mainly through MKK4/JNK pathway. (C) 2015 Elsevier Ltd. All rights reserved.