Abstract
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 NFκB 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 (DEN) and phenobarbital (PB). AEG-1ΔHEP mice exhibited a significant reduction in disease severity compared with 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.Significance: These findings distinguish a novel role of macrophage-derived oncogene AEG-1 from hepatocellular AEG-1 in promoting inflammation and driving tumorigenesis. Cancer Res; 78(22); 6436-46. ©2018 AACR.
Highlights
The risk factors for hepatocellular carcinoma (HCC) include viral hepatitis, alcoholism, and nonalcoholic fatty liver disease, all of which lead to chronic inflammation [1]
Inflammation is an integral component of DEN-induced HCC and we documented that activation of NFkB, a key regulator of inflammation, was markedly abrogated in AEG-1À/À hepatocytes and macrophages compared with AEG-1þ/þ [20]
Migration of AEG-1þ/þ Bone marrow–derived macrophages (BMDM) toward Dihxy-sgAEG-1 cells was significantly lower than that toward Dihxy-sgCon cells, an effect further decreased in AEG-1À/À BMDMs (Fig. 6D). These observations were confirmed in an in vivo system in which AEG-1þ/þ and total AEG-1À/À mice were injected with DEN at 2 weeks and transformed hepatocytes and BMDMs were isolated at 12 weeks
Summary
The risk factors for hepatocellular carcinoma (HCC) include viral hepatitis, alcoholism, and nonalcoholic fatty liver disease, all of which lead to chronic inflammation [1]. There is infiltration of monocytederived macrophages into the liver further contributing to the inflammatory process. During initial tumorigenesis, damaged hepatocytes release cytokines, such as IL1b, which stimulate Kupffer cells to activate NFkB, resulting in the release of IL6 that. Activates the oncogenic STAT3 signaling in the hepatocytes thereby promoting proliferation of transformed cells [3,4,5,6,7,8,9,10]. Tumor-associated macrophages (resident and infiltrating) secrete various cytokines and chemokines, including IL1b, TNFa, IL6, CCL2, and CXCL10, which increase HCC cell proliferation and NFkB-mediated protection from
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