期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 122, 期 2, 页码 586-599出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI43937
关键词
-
资金
- Centre National de la Recherche Scientifique (CNRS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Ligue Nationale Contre Le Cancer (Equipe labellisee)
- Agence Nationale de Recherche (ANR) 07-Physiology
- Axe 3 of Canceropole Ile-de-France
- Association Francaise des Etudes sur le Foie
- Laboratoire ROCHE
- Grants-in-Aid for Scientific Research [23590275] Funding Source: KAKEN
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 beta-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of beta-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic beta-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by beta-catenin and activation of the NF-kappa B 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 beta-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic beta-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in beta-catenin-induced liver tumotigenesis. We provide strong evidence that, by activating pro-and antiinflammatory mediators, beta-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most beta-catenin-activated HCCs are of better prognosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据