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 7

STK4 protects mice from DEN- and LPS-induced HCC in vivo.

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STK4 protects mice from DEN- and LPS-induced HCC in vivo. (A) Scheme of ...
(A) Scheme of the DEN-, CCl4-, and LPS-induced HCC model. Mice carrying macrophage-specific Stk4 deletion (Stk4ΔM/ΔM) and their littermate control (Stk4+/+) were i.p. injected with DEN (100 mg/kg). Four weeks later, these mice received weekly i.p. injections of CCl4 (0.5 ml/kg), plus daily subcutaneous injection of LPS (300 μg/kg, starting 1 week before the first CCl4 injection) for 12 weeks. Mice were sacrificed 28 weeks after DEN treatment. (B) Stk4+/+ (n ≥ 4) and Stk4ΔM/ΔM (n > 5) mice were treated with DEN for 48 hours, plus 2 weekly injections of CCl4 and daily injection of LPS. Serum IL-6 levels and mRNA levels of Il6, Il1b, Ccl2, and Ifnb in livers were determined. (C and D) Stk4+/+ (n = 5) and Stk4ΔM/ΔM (n = 8) mice were treated with DEN, plus 2 weekly injections of CCl4 and daily injection of LPS. HE staining (scale bars: 50 μm) and TUNEL assays (scale bar: 100 μm) of liver sections (C) or serum ALT and AST levels (D) were assessed. (E and F) Stk4+/+ (n = 4) and Stk4ΔM/ΔM mice (n = 8) were treated as described in (A) and sacrificed 28 weeks after DEN treatment. Sirius Red staining (E) or HE staining (F) of liver sections were performed (scale bars: 100 μm). Data represent mean ± SD. *P < 0.05 and ***P < 0.001 using 2-tailed, unpaired Student’s t test.