Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis.
Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis.
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DOI：
10.1158/0008-5472.can-18-0659
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发表时间：
2018-11-15
期刊：
影响因子：
11.2
通讯作者：
Sarkar D
中科院分区：
文献类型：
--
作者：
Robertson CL;Mendoza RG;Jariwala N;Dozmorov M;Mukhopadhyay ND;Subler MA;Windle JJ;Lai Z;Fisher PB;Ghosh S;Sarkar D
慢性炎症是已知的癌症标志，并且是肝细胞癌（HCC）的发作和进展的中心。肝巨噬细胞在导致HCC的炎症过程中起关键作用。致癌基因星形胶质细胞升高基因-1（AEG-1）调节NF-κB活化，小鼠中AEG-1的种系敲除（AEG-1−/−）导致对炎症和实验性HCC的抵抗。在这项研究中，我们开发了条件性肝细胞和骨髓细胞特异性AEG-1−/−小鼠（分别为AEG-1ΔHEP和AEG-1ΔMAC），并通过N-亚硝基二乙胺和苯巴比妥治疗诱导HCC。AEG-1ΔHEP小鼠与对照同窝小鼠相比，疾病严重程度显著降低，而AEG-1ΔMAC小鼠具有极强的耐药性。在体外，AEG-1−/−肝细胞表现出对应激和衰老的敏感性增加。值得注意的是，AEG-1−/−巨噬细胞对M1或M2分化具有抵抗性，在迁移、内皮粘附和巨噬细胞活性方面具有显著抑制作用，表明AEG-1消融使巨噬细胞功能性无能。这些结果揭示了AEG-1在调节巨噬细胞活化中的核心作用，并表明AEG-1在肿瘤细胞和肿瘤微环境中都是刺激肝癌发生所必需的。
Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 (AEG-1) regulates NF-κB activation, and germline knockout of AEG-1 in mice (AEG-1−/−) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell-specific AEG-1−/− mice (AEG-1ΔHEP and AEG-1ΔMAC, respectively) and induced HCC by treatment with N-nitrosodiethylamine and phenobarbital. AEG-1ΔHEP mice exhibited a significant reduction in disease severity compared to control littermates, while AEG-1ΔMAC mice were profoundly resistant. In vitro, AEG-1−/− hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1−/− macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis.