Activation of the TLR4/MyD88 signaling pathway contributes to the development of human hepatocellular carcinoma via upregulation of IL-23 and IL-17A.

Abstract

Toll-like receptor 4 (TLR4) and the interleukin (IL)-23/IL-17A axis serve an important role in tumor immunology. In the present study, the activation of the TLR4/myeloid differentiation primary response 88 (MyD88)-mediated signal transduction pathway in human hepatocellular carcinoma (HCC) cells was examined using immunohistochemistry, and the association between TLR4 expression and the IL-23/IL-17A axis was detected by ELISA, reverse transcription-quantitative polymerase chain reaction and western blot analysis in order to determine whether TLR4 and IL-23/IL-17A serve a role in HCC. It was observed that TLR4 expression was upregulated in HCC tissues compared with that in adjacent normal tissues. In addition, the TLR4 expression level was correlated with the degree of tumor differentiation and TNM stage. The expression levels of IL-17A and IL-23, which are key mediators of inflammation that contribute to carcinogenesis, are correlated with TLR4 expression in HCC. Cell line studies further revealed that activation of TLR4/MyD88 upregulated the expression of IL-17A and IL-23 at the mRNA and protein levels. Furthermore, activation of TLR4/MyD88 enhanced the expression of TLR4. IL-17A and IL-23 expression levels in HCC also appeared to be correlated with the TNM stage and tumor metastasis. In conclusion, the current results suggested that the TLR4/MyD88 signaling pathway is involved in HCC cell proliferation and metastasis via regulation of the IL-23/IL-17A axis; thus, the TLR4/IL-23/IL-17A pathway may represent a novel therapeutic target in HCC.