Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion,Tnfr1deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

中文翻译：

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由于慢性线粒体功能障碍和ROS，来自枯否细胞的Tnf通过JNK触发胆管细胞肿瘤发生

肝内胆管癌（ICC）是高度恶性的异质性癌症，治疗选择不佳。我们发现线粒体功能障碍和氧化应激触发利基胆管细胞过度生长和肿瘤发生。来自Kupffer细胞的肝损伤，活性氧（ROS）和旁分泌肿瘤坏死因子（Tnf）导致JNK介导的胆管细胞增殖和致癌转化。抗氧化剂治疗，枯否细胞枯竭，Tnfr1缺失或JNK抑制可减少胆管细胞肿瘤前病变。在Akt / Notch或p53 / Kras诱导的ICC模型中，肝脏特异性JNK1 / 2缺失导致肿瘤减少和存活率提高。在人ICC中，存在ICC病变附近的高Tnf表达，胆管细胞JNK磷酸化和周围肝细胞中的ROS积累。因此，枯否细胞衍生的Tnf促进胆管细胞的增殖/分化和致癌作用。靶向ROS / Tnf / JNK轴可能为ICC治疗提供机会。