Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis

Cancer Res. 2018 Nov 15;78(22):6436-6446. doi: 10.1158/0008-5472.CAN-18-0659. Epub 2018 Sep 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Adhesion
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Chemotaxis
  • Diethylnitrosamine
  • Gene Expression Regulation, Neoplastic*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Inflammation
  • Liver Neoplasms / metabolism*
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Phenobarbital
  • RNA, Small Interfering / metabolism
  • RNA-Binding Proteins
  • Risk Factors
  • Tumor Microenvironment


  • Membrane Proteins
  • Mtdh protein, mouse
  • NF-kappa B
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Diethylnitrosamine
  • Phenobarbital