Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma

Abstract

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 upregulation 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 5 0.002), microscopic vascular invasion (P 5 0.034), early recurrence (P 5 0.003), and worse prognosis (P 5 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) F requent intrahepatic metastasis is a unique feature of hepatocellular carcinoma (HCC) and the primary cause of high rates of early recurrence after initial curative therapy. To improve the clinical outcomes of patients with HCC, there is a pressing need to elucidate the molecular mechanisms of intrahepatic metastasis and to identify markers for the detection of intrahepatic invasion and the prediction of early recurrence.

The downregulation of ErbB3 binding protein 1 (EBP1) is associated with poor prognosis and enhanced cell proliferation in hepatocellular carcinoma

“…Our evaluation indicates that the decreased expression of EBP1 is associated with higher histological grade and Ki67 expression in HCC specimens, and accelerated cell growth in liver cells, suggesting that EBP1 mainly exerts its function via modulating proliferation-related pathways. However, Neuregulin/ ErbB3 signaling has been recently identified to confer invasion and early recurrence in HCC, but did not have significant impact on HCC proliferation and tumor growth [33]. Notably, AR signaling may inhibit HCC progression via suppressing HCC metastasis [34].…”

Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma

“…UM frequently metastasizes to the liver, a tissue in which both NRG1 and HGF are readily detected (44, 45), highlighting the possibility that these growth factors mediate resistance to MEK inhibitors via paracrine action. To this end, we tested the effect of stromal-produced growth factors on UM cell resistance to MEK inhibitors.…”

Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells

“…Indeed, the expression and the activation of EGFR and of its main dimerization partner HER-3 (ErbB-3) are frequently deregulated in HCC [14,15] and recent studies indicate that EGFR and HER-3 may provide compensatory signals for cancer cells to escape targeted therapies [16][17][18]. Synergistic or at least additive antitumoral effects of sorafenib combined with EGFR TKI are expected on the basis of recent preclinical data obtained in colon and lung cancer cell lines [19].…”