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致癌β-catenin 触发炎症反应,决定了小鼠肝癌的侵袭性。

Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.

机构信息

INSERM, U1016, Institut Cochin, Paris, France. 2CNRS, UMR8104, Paris, France.

出版信息

J Clin Invest. 2012 Feb;122(2):586-99. doi: 10.1172/JCI43937. Epub 2012 Jan 17.

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by β-catenin and activation of the NF-κB pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver β-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic β-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in β-catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro- and antiinflammatory mediators, β-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most β-catenin-activated HCCs are of better prognosis.

摘要

肝细胞癌(HCC)是全球癌症相关死亡的第三大原因。其发病机制常与肝炎症有关。β-连环蛋白基因编码的功能获得性突变是在人类 HCC 中经常发现的遗传修饰。因此,我们使用遗传修饰的小鼠模型研究了炎症是否是β-连环蛋白诱导肿瘤发生的一个组成部分,这些模型重现了这个肿瘤过程的起始和进展阶段。致癌β-连环蛋白信号被发现会在肝细胞中诱导一个炎症程序,涉及β-连环蛋白的直接转录控制和 NF-κB 途径的激活。这导致了一种特定的炎症反应,其强度决定了肿瘤侵袭性的程度。趋化因子样趋化因子白细胞衍生趋化因子 2(LECT2)和不变自然杀伤 T(iNKT)细胞被鉴定为肝脏β-连环蛋白诱导炎症的关键相互作用效应物。在缺乏编码 LECT2 或 iNKT 细胞的基因的遗传缺失模型中,肝脏β-连环蛋白信号触发了具有肺转移的高度恶性 HCC 的形成。因此,我们的结果表明炎症是β-连环蛋白诱导的肝肿瘤发生的关键因素。我们提供了强有力的证据表明,通过激活促炎和抗炎介质,β-连环蛋白信号产生了一种炎症微环境,对肿瘤的发展有影响。我们的数据与大多数β-连环蛋白激活的 HCC 具有更好的预后这一事实是一致的。

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