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


CONCLUSIONS
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.
Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan. siming@adm.cgmh.org.tw
Sen-Yung
SY
Hsieh
Jung-Ru
JR
He
Chih-Yun
CY
Hsu
Wan-Ju
WJ
Chen
Rabindranath
R
Bera
Kuo-Yang
KY
Lin
Tsung-Chieh
TC
Shih
Ming-Chin
MC
Yu
Yu-Jr
YJ
Lin
Chee-Jen
CJ
Chang
Wen-Hui
WH
Weng
Shiu-Fen
SF
Huang
D019898:Autocrine Communication / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology
D020890:Neuregulin-1; D034741:RNA, Small Interfering; D020893:Receptor, ErbB-3