STK4 regulates TLR pathways and protects against chronic inflammation-related hepatocellular carcinoma
STK4 regulates TLR pathways and protects against chronic inflammation-related hepatocellular carcinoma
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STK4 调节 TLR 通路并预防慢性炎症相关的肝细胞癌。
DOI：
10.1172/jci81203
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发表时间：
2015-11-01
影响因子：
15.9
通讯作者：
Wang, Hongyan
中科院分区：
文献类型：
--
作者：
Li, Weiyun;Xiao, Jun;Wang, Hongyan
肝细胞癌（HCC）通常与病原体感染诱导的慢性炎症有关。大量的先天免疫细胞存在于HCC中，并且可以影响疾病的结果。在这里，我们证明，肿瘤抑制丝氨酸/苏氨酸蛋白激酶4（STK 4）差异调节TLR 3/4/9介导的巨噬细胞的炎症反应，从而对慢性炎症相关的HCC的保护。STK 4抑制TLR 4/9诱导的促炎细胞因子分泌，但通过结合并磷酸化IL-1受体相关激酶1（IRAK 1），导致IRAK 1降解，增强TLR 3/4触发的IFN-β产生。值得注意的是，巨噬细胞特异性Stk 4缺失导致二乙基亚硝胺（DEN）和四氯化碳（CCl 4）联合治疗的小鼠出现慢性炎症、肝纤维化和HCC，沿着LPS或E.大肠杆菌感染。从人HCC患者分离的巨噬细胞中STK 4表达显著降低，并且与IRAK 1、IL-6和磷酸化p65或磷酸化STAT 3的水平负相关。此外，血清STK 4水平在具有高水平IL-6的HCC患者中特异性降低。在STK 4缺陷小鼠中，DEN给药后用IRAK 1/4抑制剂治疗可将血清IL-6水平和肝肿瘤数量降低至与对照小鼠中观察到的水平相似的水平。总之，我们的研究结果表明，STK 4有潜力作为炎症诱导的HCC的诊断生物标志物和治疗靶点。
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.