Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.
Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
Int J Cancer. 2018 Dec 1;143(11):2997-3007. doi: 10.1002/ijc.31827. Epub 2018 Oct 9.
Chronic liver inflammation is crucial in the pathogenesis of hepatocellular carcinoma (HCC). Activation of the inflammasome complex is a key inflammatory process that has been associated with different liver diseases, but its role in HCC development remains largely unexplored. Here we analyzed the impact of different inflammasome components, including absent in melanoma 2 (AIM2) and NOD-like receptor family pyrin domain containing 3 (NLRP3), in the development of diethylnitrosamine (DEN)-induced HCC in mice. Genetic inactivation of AIM2, but not NLRP3, reduces liver damage and HCC development in this model. AIM2 deficiency ameliorates inflammasome activation, liver inflammation and proliferative responses during HCC initiation. We also identified that AIM2 is highly expressed in Kupffer cells, and that AIM2-mediated production of IL-1β by these cells is enhanced after DEN-induced liver damage. Our data indicate that AIM2 promotes inflammation during carcinogenic liver injury and that it contributes to genotoxic HCC development in mice, thereby recognizing AIM2 as a potential therapeutic target in this disease.
慢性肝脏炎症在肝细胞癌 (HCC) 的发病机制中起着关键作用。炎性小体复合物的激活是一个关键的炎症过程，与不同的肝脏疾病有关，但它在 HCC 发展中的作用在很大程度上仍未得到探索。在这里，我们分析了不同炎性小体成分（包括黑色素瘤缺失 2 (AIM2) 和 NOD 样受体家族富含吡啶结构域蛋白 3 (NLRP3)）在二乙基亚硝胺 (DEN) 诱导的小鼠 HCC 发展中的作用。AIM2 的基因缺失而非 NLRP3 的缺失可减少该模型中的肝损伤和 HCC 发展。AIM2 缺乏可改善 HCC 起始时的炎性小体激活、肝炎症和增殖反应。我们还发现 AIM2 在库普弗细胞中高表达，并且 DEN 诱导的肝损伤后这些细胞中由 AIM2 介导的 IL-1β 的产生增强。我们的数据表明，AIM2 在致癌性肝损伤期间促进炎症，并且有助于小鼠的遗传毒性 HCC 发展，从而将 AIM2 识别为该疾病的潜在治疗靶点。
