Liu Yao, Song Liming, Ni Hengli, Sun Lina, Jiao Weijuan, Chen Lin, Zhou Qun, Shen Tong, Cui Hongxia, Gao Tianming, Li Jianming
Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
Carcinogenesis. 2017 Apr 1;38(4):465-473. doi: 10.1093/carcin/bgx017.
ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.
ERBB4是表皮生长因子受体（EGFR）家族的成员之一，在生理和病理过程中起关键作用。最近，我们发现ERBB4对慢性乙型肝炎病毒感染具有保护作用。然而，ERBB4在肝细胞癌（HCC）中的作用仍不清楚。在此，我们使用体外模型、体内动物模型和HCC临床样本，探讨ERBB4在HCC发生发展中的作用。本研究使用了肝脏特异性ERBB4敲除等位基因和除心脏外的全ERBB4敲除小鼠。分别通过给予四氯化碳（CCl4）和二乙基亚硝胺（DEN）建立小鼠肝脏炎症和肿瘤模型。使用90例HCC患者及其配对对照的商业组织芯片来评估ERBB4的表达及其预后价值。通过微阵列分析研究在ERBB4缺失情况下发生改变的基因，并通过实时PCR进一步验证。我们发现，小鼠体内ERBB4的缺失会导致更严重的损伤和肝肿瘤形成，并且ERBB4的缺失有助于肝细胞肿瘤的发生发展。在HCC临床样本中，ERBB4表达下调，并对HCC患者具有预后价值。机制上，ERBB4的缺失通过抑制肿瘤抑制因子tp53inp1的表达来抑制p53表达。我们的研究揭示了ERBB4是HCC发生发展中的一种抑制因子，并提示了HCC中存在ERBB4-TP53INP1-P53轴。
