Downregulation of toll-like receptor 4 induces suppressive effects on hepatitis B virus-related hepatocellular carcinoma via ERK1/2 signaling

BMC Cancer

Research Article

Yajie Chen¹  Xiaoli Zeng¹  Dan Xiao¹  Jing Cai¹  Anwen Liu¹  Wei Yan¹  Yiting Wang¹  Yuming Ouyang¹  Zhiming Zeng¹  Long Huang¹ 

[1] Department of Oncology, the Second Affiliated Hospital of Nanchang University, 330006, Nanchang, Jiangxi Province, China;

关键词: HBV infection;    HCC;    Signaling pathways;    TLR4;    Tumor growth;   

DOI  :  10.1186/s12885-015-1866-9

 received in 2015-01-28, accepted in 2015-10-27,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundHepatitis B virus (HBV) infection is a major risk factor which can lead to development of hepatocellular carcinoma (HCC). In this study, we aimed to explore the effects of toll-like receptor 4 (TLR4) downregulation on the growth and survival of HBV-related HCC cells and to examine the molecular mechanisms been involved.MethodsThe expression levels of TLR4 were examined in a panel of HCC cell lines (HepG2, SMMC7721, Huh7, HepG2.2.15 and Hep3B). The effects of TLR4 downregulation on the proliferation, apoptosis, and tumorigenicity of HBV-related HepG2.2.15 cells were determined. The effects of TLR4 downregulation on multiple signaling pathways were also measured. Co-immunoprecipitation and immunofluoresence staining assays were performed to investigate the interaction between TLR4 and HBV X protein (HBx).ResultsThe mRNA and protein levels of TLR4 were significantly increased in HepG2.2.15 cells than those in the other cells which have been studied. Downregulation of TLR4 significantly decreased the proliferation and induced G2/M cell cycle arrest and apoptosis in HepG2.2.15 cells. TLR4 depletion inhibited HepG2.2.15 cell colony formation and tumor growth in nude mice. TLR4 silencing decreased the phosphorylation of ERK1/2 but not JNK1/2, p38, or NF-κB. Chemical inhibition of ERK1/2 approximately phenocopied the growth-suppressive effect of TLR4 downregulation on HepG2.2.15 cells. In addition, TLR4 showed a physical interaction with HBx.ConclusionsTaken together, TLR4 plays a tumor-promoting role in HBV-related HCC cells, which is associated with regulation of ERK1/2 activation and interaction with HBx. Therefore, TLR4 may be a potential therapeutic target for HBV-related HCC.

【 授权许可】

CC BY   
© Wang et al. 2015