STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinoma
Weiyun Li, … , Bin Wei, Hongyan Wang
Weiyun Li, … , Bin Wei, Hongyan Wang
Published October 12, 2015
Citation Information: J Clin Invest. 2015;125(11):4239-4254. https://doi.org/10.1172/JCI81203.
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Research Article Oncology

STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is frequently associated with pathogen infection–induced chronic inflammation. Large numbers of innate immune cells are present in HCCs and can influence disease outcome. Here, we demonstrated that the tumor suppressor serine/threonine-protein kinase 4 (STK4) differentially regulates TLR3/4/9-mediated inflammatory responses in macrophages and thereby is protective against chronic inflammation–associated HCC. STK4 dampened TLR4/9-induced proinflammatory cytokine secretion but enhanced TLR3/4-triggered IFN-β production via binding to and phosphorylating IL-1 receptor–associated kinase 1 (IRAK1), leading to IRAK1 degradation. Notably, macrophage-specific Stk4 deletion resulted in chronic inflammation, liver fibrosis, and HCC in mice treated with a combination of diethylnitrosamine (DEN) and CCl4, along with either LPS or E. coli infection. STK4 expression was markedly reduced in macrophages isolated from human HCC patients and was inversely associated with the levels of IRAK1, IL-6, and phospho-p65 or phospho-STAT3. Moreover, serum STK4 levels were specifically decreased in HCC patients with high levels of IL-6. In STK4-deficient mice, treatment with an IRAK1/4 inhibitor after DEN administration reduced serum IL-6 levels and liver tumor numbers to levels similar to those observed in the control mice. Together, our results suggest that STK4 has potential as a diagnostic biomarker and therapeutic target for inflammation-induced HCC.

Authors

Weiyun Li, Jun Xiao, Xin Zhou, Ming Xu, Chaobo Hu, Xiaoyan Xu, Yao Lu, Chang Liu, Shengjie Xue, Lei Nie, Haibin Zhang, Zhiqi Li, Yanbo Zhang, Fu Ji, Lijian Hui, Wufan Tao, Bin Wei, Hongyan Wang

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Figure 3

STK4 kinase activity is critical to inhibit TLR4/NF-κB activation.

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STK4 kinase activity is critical to inhibit TLR4/NF-κB activation. (A) T...
(A) The levels of phosphorylated IKKα/β in LPS-stimulated WT and Stk4–/– BMMs were detected by immunoblotting analysis. Samples were run on the same gel but not contiguous, as indicated by the black line. (B) Primary MEF cells overexpressing GFP or STK4 were treated with or without LPS, followed by immunostaining with Hoechst and anti–p65-RelA (scale bar: 20 μm, representative images). The number of p65-RelA+ nuclei was counted from >50 cells (mean ± SD using 2-tailed, unpaired Student’s t test). (C) Primary MEFs overexpressing GFP, STK4, or the K59R mutant were stimulated with LPS to detect mRNA levels of Il6, Il1b, and Tnfa. Values were normalized for β-actin mRNA levels (mean ± SD, n = 4, 2-way ANOVA with Holm-Sidak’s multiple comparisons test). *P < 0.05, **P < 0.01, and ***P < 0.0001.