Astrocyte elevated gene-1 regulates macrophage activation in hepatocellular carcinogenesis

Chadia L. Robertson, Rachel G. Mendoza, Nidhi Jariwala, Mikhail Dozmorov, Nitai D. Mukhopadhyay, Mark A. Subler, Jolene J. Windle, Zhao Lai, Paul B. Fisher, Shobha Ghosh, Devanand Sarkar

Research output: Contribution to journalArticle

3 Scopus citations

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 NFkB 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-1DHEP and AEG-1DMAC, respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1DHEP mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1DMAC 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.

Original languageEnglish (US)
Pages (from-to)6436-6446
Number of pages11
JournalCancer Research
Volume78
Issue number22
DOIs
StatePublished - Nov 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Robertson, C. L., Mendoza, R. G., Jariwala, N., Dozmorov, M., Mukhopadhyay, N. D., Subler, M. A., Windle, J. J., Lai, Z., Fisher, P. B., Ghosh, S., & Sarkar, D. (2018). Astrocyte elevated gene-1 regulates macrophage activation in hepatocellular carcinogenesis. Cancer Research, 78(22), 6436-6446. https://doi.org/10.1158/0008-5472.CAN-18-0659