Potential conflict of interest: Nothing to report.
Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice
Article first published online: 23 JAN 2015
© 2014 by the American Association for the Study of Liver Diseases
Volume 61, Issue 3, pages 915–929, March 2015
How to Cite
Srivastava, J., Siddiq, A., Gredler, R., Shen, X.-N., Rajasekaran, D., Robertson, C. L., Subler, M. A., Windle, J. J., Dumur, C. I., Mukhopadhyay, N. D., Garcia, D., Lai, Z., Chen, Y., Balaji, U., Fisher, P. B. and Sarkar, D. (2015), Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice. Hepatology, 61: 915–929. doi: 10.1002/hep.27339
The present study was supported, in part, by grants from the James S. McDonnell Foundation and National Cancer Institute (NCI; grant nos.: R01 CA138540 [to D.S.] and R01 CA134721 [to P.B.F.]). The VCU Massey Cancer Center Transgenic/Knockout Mouse Facility, supported, in part, with funding from the National Institutes of Health/NCI Cancer Center (Support Grant P30 CA 016059), provided services in support of this project. P.B.F. holds the Thelma Newmeyer Corman Chair in Cancer Research. D.S. is the Harrison Endowed Scholar in Cancer Research and a Blick scholar.
See Editorial on Page 757
- Issue published online: 23 FEB 2015
- Article first published online: 23 JAN 2015
- Accepted manuscript online: 28 JUL 2014 03:50AM EST
- Manuscript Accepted: 20 JUL 2014
- Manuscript Received: 10 APR 2014
Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc, and AEG-1 itself induces c-Myc by activating the Wnt/β-catenin–signaling pathway. We now document the cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (albumin [Alb]/AEG-1), c-Myc (Alb/c-Myc), or both (Alb/AEG-1/c-Myc). Wild-type and Alb/AEG-1 mice did not develop spontaneous HCC. Alb/c-Myc mice developed spontaneous HCC without distant metastasis, whereas Alb/AEG-1/c-Myc mice developed highly aggressive HCC with frank metastasis to the lungs. Induction of carcinogenesis by N-nitrosodiethylamine significantly accelerated the kinetics of tumor formation in all groups. However, in Alb/AEG-1/c-Myc, the effect was markedly pronounced with lung metastasis. In vitro analysis showed that Alb/AEG-1/c-Myc hepatocytes acquired increased proliferation and transformative potential with sustained activation of prosurvival and epithelial-mesenchymal transition–signaling pathways. RNA-sequencing analysis identified a unique gene signature in livers of Alb/AEG-1/c-Myc mice that was not observed when either AEG-1 or c-Myc was overexpressed. Specifically, Alb/AEG-1/c-Myc mice overexpressed maternally imprinted noncoding RNAs (ncRNAs), such as Rian, Meg-3, and Mirg, which are implicated in hepatocarcinogenesis. Knocking down these ncRNAs significantly inhibited proliferation and invasion by Alb/AEG-1/c-Myc hepatocytes. Conclusion: Our studies reveal a novel cooperative oncogenic effect of AEG-1 and c-Myc that might explain the mechanism of aggressive HCC. Alb/AEG-1/c-Myc mice provide a useful model to understand the molecular mechanism of cooperation between these two oncogenes and other molecules involved in hepatocarcinogenesis. This model might also be of use for evaluating novel therapeutic strategies targeting HCC. (Hepatology 2015;61:915–929)