Downregulation of toll-like receptor 4 induces suppressive effects on hepatitis B virus-related hepatocellular carcinoma via ERK1/2 signaling. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Wang, Yiting; Cai, Jing; Zeng, Xiaoli; Chen, Yajie; Yan, Wei; Ouyang, Yuming; Xiao, Dan; Zeng, Zhiming; Huang, Long; Liu, Anwen
• Is Part Of: BMC cancer. Volume 15:Issue 1(2015)
• Page Start: 1
• Page End: 9
• Publication Date: 2015-12
• Subjects: HBV infection -- HCC -- Signaling pathways -- TLR4 -- Tumor growth; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s12885-015-1866-9
• Languages: English
• ISSNs: 1471-2407

Abstract

Abstract Background Hepatitis 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. Methods The 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). Results The 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 ofERK1/2 approximately phenocopied the growth-suppressive effect of TLR4 downregulation on HepG2.2.15 cells. In addition, TLR4 showed a physical interaction withHBx . Conclusions Taken together, TLR4 plays a tumor-promoting role in HBV-related HCC cells, which is associated with regulation ofERK1/2 activation and interaction withHBx . Therefore, TLR4 may be a potential therapeutic target for HBV-related HCC.