Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis.
Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis.
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DOI：
10.1038/ncomms15433
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发表时间：
2017-05-16
影响因子：
16.6
通讯作者：
Ling L
中科院分区：
文献类型：
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作者：
Zhou M;Yang H;Learned RM;Tian H;Ling L
肝细胞癌（HCC）是一种原发性肝脏恶性肿瘤，是世界范围内癌症死亡的第二大原因。成纤维细胞生长因子19（FGF 19）是HCC患者中最常扩增的基因之一。此外，已显示表达FGF 19转基因的小鼠发展HCC。然而，介导FGF 19依赖性肿瘤发生的下游信号通路仍有待破译。在这里，我们表明，FGF 19触发了一个以前未被怀疑的，非细胞自主的程序，通过在肝脏微环境中产生的IL-6激活肝细胞中的STAT 3信号。我们发现，肝细胞特异性缺失Stat 3，基因消融IL-6，治疗与中和抗IL-6抗体或管理的小分子JAK抑制剂，废除FGF 19诱导的肿瘤发生，而调节功能的FGF 19在胆汁酸，葡萄糖和能量代谢保持完整。总的来说，这些数据揭示了IL-6/STAT 3轴在增强小鼠中FGF 19驱动的HCC中的关键作用，这一发现可能与HCC发病机制有关。成纤维细胞生长因子19（FGF 19）中和抗体抑制肝细胞癌（HCC）生长，但具有安全性问题。在这里，作者表明FGF 19通过IL-6的产生激活STAT 3信号传导促进HCC，并且靶向IL-6通路消除了FGF 19诱导的HCC而没有副作用。
Hepatocellular carcinoma (HCC), a primary malignancy of the liver, is the second leading cause of cancer mortality worldwide. Fibroblast Growth Factor 19 (FGF19) is one of the most frequently amplified genes in HCC patients. Moreover, mice expressing an FGF19 transgene have been shown to develop HCC. However, the downstream signalling pathways that mediate FGF19-dependent tumorigenesis remain to be deciphered. Here we show that FGF19 triggers a previously unsuspected, non-cell-autonomous program to activate STAT3 signalling in hepatocytes through IL-6 produced in the liver microenvironment. We show that the hepatocyte-specific deletion of Stat3, genetic ablation of Il6, treatment with a neutralizing anti-IL-6 antibody or administration of a small-molecule JAK inhibitor, abolishes FGF19-induced tumorigenesis, while the regulatory functions of FGF19 in bile acid, glucose and energy metabolism remain intact. Collectively, these data reveal a key role for the IL-6/STAT3 axis in potentiating FGF19-driven HCC in mice, a finding which may have translational relevance in HCC pathogenesis. Fibroblast Growth Factor 19 (FGF19) neutralizing antibodies inhibit hepatocellular carcinoma (HCC) growth but have safety issues. Here, the authors show that FGF19 promotes HCC by activating STAT3 signalling via IL-6 production and that targeting IL-6 pathway abolishes FGF19-induced HCC without side effects.