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 9

The inverse correlation of STK4 expression with IRAK1 levels in macrophages from human HCC samples.

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The inverse correlation of STK4 expression with IRAK1 levels in macropha...
(A) HE staining (scale bar: 100 μm) and IHC staining (scale bar: 50 μm) with anti-CD68, anti-STK4, and anti-IRAK1 of human liver sections from paracarcinoma tissue and tumors of HCC patients. (B) The adjacent sections from human HCC tumors or healthy livers were stained with anti-CD68, anti-STK4, or anti-IRAK1 (scale bars: 50 μm). (C) IRAK1 and STK4 expression in liver-infiltrated macrophages from HCC patients was examined by FACS (n = 9), and their correlation was assessed with Pearson’s test. (D) Mice were i.p. injected the IRAK1/4 inhibitor (3 mg/kg, twice a week), starting 1 week before the first CCl4 injection. Serum IL-6 levels (WT [n = 7], Stk4–/– [n = 5], WT+IRAK1 Inh [n = 7], and Stk4–/– +IRAK1 Inh [n = 7]) were checked 6 weeks after DEN treatment (left panel), and liver tumor formation (n = 3) was detected by micro-CT imaging 18 weeks after DEN treatment (right panel). One-way ANOVA with Newman-Keuls or Holm-Sidak’s multiple comparisons test was used. Data represent mean ± SD. *P < 0.05.