Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma†
Article first published online: 18 JAN 2011
Copyright © 2010 American Association for the Study of Liver Diseases
Volume 53, Issue 2, pages 504–516, February 2011
How to Cite
Hsieh, S.-Y., He, J.-R., Hsu, C.-Y., Chen, W.-J., Bera, R., Lin, K.-Y., Shih, T.-C., Yu, M.-C., Lin, Y.-J., Chang, C.-J., Weng, W.-H. and Huang, S.-F. (2011), Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. Hepatology, 53: 504–516. doi: 10.1002/hep.24083
Potential conflict of interest: Nothing to report.
- Issue published online: 27 JAN 2011
- Article first published online: 18 JAN 2011
- Accepted manuscript online: 19 NOV 2010 12:06PM EST
- Manuscript Accepted: 9 NOV 2010
- Manuscript Received: 18 SEP 2010
- The National Research Program on Genomic Medicine, the National Science Council. Grant Number: 96HC006
- Department of Health, Taiwan. Grant Number: TD-C-111-006
Intrahepatic metastasis is the primary cause of the high recurrence and poor prognosis of human hepatocellular carcinoma (HCC). However, neither its molecular mechanisms nor markers for its prediction before hepatectomy have been identified. We recently revealed up-regulation of erythroblastic leukemia viral oncogene homolog 3 (ERBB3) in human HCC. Here we examined the clinical and biological significance of ERBB3 in HCC. Up-regulation of ERBB3 in HCC was strongly associated with male gender (P< 0.001), chronic hepatitis B (P = 0.002), microscopic vascular invasion (P = 0.034), early recurrence (P = 0.003), and worse prognosis (P = 0.004). Phosphorylated ERBB3 and its ligands [neuregulins (NRGs)] were detected in both HCC tissues and cells. Phosphorylation of ERBB3 could be induced by conditioned media of HCC cells and abolished by the pretreatment of conditioned media with anti-NRG antibodies or by the silencing of the endogenous NRG expression of the donor HCC cells. Human epidermal growth factor receptor 2 was required for ERBB3 phosphorylation. The downstream phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene homolog pathways were primarily elicited by NRG1/ERBB3 signaling, whereas the mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were elicited by both epidermal growth factor/epidermal growth factor receptor and NRG1/ERBB3 signaling. The activation and silencing of ERBB3-dependent signaling had potent effects on both the migration and invasion of HCC cells, but neither had significant effects on the proliferation of HCC cells, tumor formation, or tumor growth in vitro and in vivo. Conclusion: The constitutive activation of ERBB3-dependent signaling via the NRG1/ERBB3 autocrine loop plays a crucial role in the regulation of cell motility and invasion, which contribute to intrahepatic metastasis and early recurrence of HCC. ERBB3 is a marker for the prediction of intrahepatic metastasis and early recurrence. ERBB3-dependent signaling is a candidate target for the treatment of microscopic vascular invasion and for the prevention of HCC recurrence. (HEPATOLOGY 2011;53:504-516) (This article firstt published online on January 18, 2011; the title has since changed; the correct version appears in print.