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.
View: Text | PDF | Corrigendum
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

×

Figure 4

STK4 increases TLR3/4-induced IFN-β production in macrophages.

Options: View larger image (or click on image) Download as PowerPoint
STK4 increases TLR3/4-induced IFN-β production in macrophages. (A) WT an...
(A) WT and Stk4–/– BMMs were stimulated with LPS for 3 hours to evaluate mRNA levels of Ifnb by qRT-PCR. (B) WT and Stk4–/– BMMs (left), or PEMs transfected with Stk4 siRNA or scramble siRNA (right) were exposed to poly(I:C) for 3 hours to assess Ifnb mRNA levels. (C) TRIF, TBK1, IRF3, or IRF7 were overexpressed with STK4 and the IFN-β luciferase reporter plasmid in HEK293T cells to measure IFN-β luciferase activity. The cotransfected Renilla was used as an internal control. (D) IRF-3 phosphorylation levels in poly(I:C)-treated WT or Stk4–/– BMMs were checked by immunoblotting analysis. (E) Primary MEF cells overexpressing GFP, STK4, or the K59R mutant were stimulated with poly(I:C) to determine Ifnb mRNA levels. (F) TRIF, TBK1, and IRF3 were transfected with STK4 or K59R and the IFN-β luciferase reporter plasmid into HEK293T cells to measure IFN-β luciferase activity. Data represent mean ± SD (n ≥ 3). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 using 2-tailed, unpaired Student’s t test (A–C), 2-way ANOVA (E), or 1-way (F) with Holm-Sidak’s multiple comparisons test.