title: Toll-like receptor 4 signaling promotes invasion of hepatocellular carcinoma cells through MKK4/JNK pathway.
abstract: 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 IL-6 and TNFα. 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-кB. Silencing of NF-кB or NF-кB inhibitor had no obvious effect on the invasive ability of HCCs and TLR4 expression, but suppressed IL-6 and TNFα production. These findings suggested that LPS-TLR4 signaling enhanced the invasiveness of HCCs mainly through MKK4/JNK pathway.
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China; Department of Clinical Laboratory, the Chinese Medicine Hospital of Hangzhou, Hangzhou 310007, China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Dong
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Chuan-Wei
authors.initials: CW
authors.lastname: Lu
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Waqaar
authors.initials: W
authors.lastname: Hameed
authors.affiliation: Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: chenwei566@zju.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human
keywords: Hepatocellular carcinoma; Invasion; Jun N-terminal kinase; Lipopolysaccharide; Toll-like receptor 4