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

Li Weiyun  Xiao Jun  Zhou Xin  Xu Ming  Hu Chaobo  Xu Xiaoyan  Lu Yao  Liu Chang  Xue Shengjie  Nie Lei  Zhang Haibin  Li Zhiqi  Zhang Yanbo  Ji Fu  Hui Lijian  Tao Wufan  Wei Bin  Wang Hongyan  
【摘要】: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.Many tumor suppressor genes(TSGs) have been identified in HCC.However,it remains largely unknown which TSGs are critical to preventingchronic inflammation–associated HCC at the early stages.we used 2 murine liver tumor models(DEN-and LPS-induced HCC),as well as human HCC patient samples to check whether and how STK4,a TSG,in macrophages suppresses inflammation and thereby inhibits 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.Moreover,macrophage-specific Stk4 deletion resulted in chronic inflammation,liver fibrosis,and HCC in mice treated with a combination of DEN-and LPS-induced HCC model.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.

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