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 5

STK4 binds to and phosphorylates IRAK1.

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STK4 binds to and phosphorylates IRAK1. (A) HEK293T cells overexpressing...
(A) HEK293T cells overexpressing HA-GFP, HA-IRAK1, Myc-STK4, or Myc-K59R were prepared for immunoprecipitation and immunoblotting with the indicated antibodies. (B) Immunoprecipitation was performed using anti-IRAK1 antibody from RAW264.7 cells, followed by immunoblotting with anti-IRAK1 or anti-STK4 antibodies. (C) HEK293T cells were transfected with HA-IRAK1 and Myc-STK4 or the C-terminal deletion mutant Myc-STK4-ΔC, followed by immunoprecipitation and immunoblotting with the indicated antibodies. (D) HEK293T cells were transfected with Myc-STK4 and HA-IRAK1 or its truncated mutants, including the N-terminal fragment (100-750aa), the kinase domain (199-562aa), and the C-terminal end (562-750aa). Immunoprecipitation using anti-Myc antibody was performed followed by immumoblotting. (E) Immunoprecipitation using anti-IRAK1 antibody was performed from WT and Stk4–/– BMMs, followed by anti-IRAK1 immunoblotting. Samples were run on the same gel but not contiguous, as indicated by the black line. (A–E). Data represent the representative experiments from at least 3 independent experiments.