| First Author | Robertson CL | Year | 2018 |
| Journal | Cancer Res | Volume | 78 |
| Issue | 22 | Pages | 6436-6446 |
| PubMed ID | 30181179 | Mgi Jnum | J:266850 |
| Mgi Id | MGI:6256876 | Doi | 10.1158/0008-5472.CAN-18-0659 |
| Citation | Robertson CL, et al. (2018) Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis. Cancer Res 78(22):6436-6446 |
| abstractText | 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 NFkappaB 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(DeltaHEP) and AEG-1(DeltaMAC), respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1(DeltaHEP) mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1(DeltaMAC) 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. (c)2018 AACR. |
