Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Hepatology. 2011 Feb;53(2):504-16. doi: 10.1002/hep.24083. Epub 2011 Jan 18.
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.
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.
肝内转移是人类肝细胞癌（HCC）高复发和预后不良的主要原因。然而，其分子机制或肝切除前预测的标志物尚未确定。我们最近发现红细胞生成性白血病病毒癌基因同系物 3（ERBB3）在人 HCC 中上调。在此，我们研究了 ERBB3 在 HCC 中的临床和生物学意义。HCC 中 ERBB3 的上调与男性（P < 0.001）、慢性乙型肝炎（P = 0.002）、微血管侵犯（P = 0.034）、早期复发（P = 0.003）和预后不良（P = 0.004）密切相关。在 HCC 组织和细胞中均检测到磷酸化 ERBB3 及其配体[神经调节蛋白（NRGs）]。HCC 细胞的条件培养基可诱导 ERBB3 磷酸化，并用抗 NRG 抗体预处理条件培养基或沉默供体 HCC 细胞的内源性 NRG 表达可消除磷酸化。人表皮生长因子受体 2（HER2）是 ERBB3 磷酸化所必需的。下游磷酸肌醇 3-激酶/v-akt 鼠胸腺瘤病毒癌基因同系物途径主要由 NRG1/ERBB3 信号引发，而丝裂原激活蛋白激酶/细胞外信号调节激酶途径则由表皮生长因子/表皮生长因子受体和 NRG1/ERBB3 信号共同引发。ERBB3 依赖性信号的激活和沉默对 HCC 细胞的迁移和侵袭均有强烈影响，但对 HCC 细胞的增殖、肿瘤形成或体外和体内肿瘤生长均无显著影响。
通过 NRG1/ERBB3 自分泌环的组成性激活 ERBB3 依赖性信号在调节细胞运动性和侵袭性方面起着至关重要的作用，这有助于 HCC 的肝内转移和早期复发。ERBB3 是预测肝内转移和早期复发的标志物。ERBB3 依赖性信号是治疗微血管侵犯和预防 HCC 复发的候选靶点。
