Journal
CANCER RESEARCH
Volume 78, Issue 22, Pages 6436-6446Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-0659
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1R01DK107451-01A1]
- Virginia Commonwealth University Massey Cancer Center pilot project
- NIH/NCI Cancer Center Support Grant [P30 CA016059]
- NATIONAL CANCER INSTITUTE [P30CA016059] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK107451] Funding Source: NIH RePORTER
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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 kappa B 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-1(Delta HEP) and AEG-1(Delta MAC), respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1(Delta HEP) mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1(Delta MAC) 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. (C) 2018 AACR.
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