Institute of Pathology, Universitätsmedizin Greifswald, Friedrich-Loeffler-Straße 23e, 17475, Greifswald, Germany.
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Virchows Arch. 2021 Feb;478(2):309-318. doi: 10.1007/s00428-020-02871-z. Epub 2020 Jun 26.
ErbB2 is a prominent representative of the epidermal growth factor receptors that mainly attract attention as oncogenic drivers and therapeutic targets in cancer. Besides transmembrane signaling, ErbB2 may also translocate into the nucleus and mediate distinct nuclear signaling effects including DNA repair and cell cycle arrest. Unexpectedly, we found nuclear ErbB2 expression in human hepatocytes in various liver diseases so we aimed to investigate the characteristics of liver disease leading to nuclear ErbB2 translocation. The immunohistochemical pattern of ErbB2 staining was analyzed in 1125 liver biopsy samples from patients with hepatic dysfunction. Further signaling and metabolic markers were analyzed by immunohistochemistry in selected liver biopsy samples. We found a cytoplasmic and nuclear ErbB2 expression in hepatocytes from different disease conditions with the strongest expression detected in alcoholic steatohepatitis. Nuclear ErbB2 positivity significantly correlated with histologic parameters of hepatocellular damage including inflammatory activity in steatohepatitis, hepatocellular ballooning, and cholestasis. ErbB2 overexpressing hepatocytes revealed an increase of phospho-STAT3, a downstream effector of nuclear ErbB2 signaling. Notably, we observed in nuclear ErbB2-positive hepatocytes a downregulation of estrogen receptor expression. In alcoholic steatohepatitis and other toxic liver diseases, hepatocytes revealed a nuclear ErbB2 expression implying a so far unknown mechanism in hepatocytes upon cellular stress that might lead to resistance to cell death. Nuclear ErbB2-positive hepatocytes showed downregulation of estrogen receptor expression and increased levels of pSTAT3, which are signs of functionality of nuclear ErbB2 signaling. Furthermore, analysis of hepatocellular ErbB2 expression could serve as helpful tool for diagnosis of liver disease.
erbB2 是表皮生长因子受体的一个重要代表，主要作为致癌驱动因子和癌症治疗靶点引起关注。除了跨膜信号转导，erbB2 还可能易位到细胞核内，并介导包括 DNA 修复和细胞周期停滞在内的独特的核信号效应。出乎意料的是，我们在各种肝脏疾病的人类肝细胞中发现了核 erbB2 表达，因此我们旨在研究导致 erbB2 核易位的肝病特征。我们分析了 1125 例肝功能障碍患者肝活检样本中 erbB2 染色的免疫组化模式。在选定的肝活检样本中，进一步通过免疫组化分析了信号和代谢标志物。我们发现不同疾病状态的肝细胞中存在细胞质和核 erbB2 表达，在酒精性脂肪性肝炎中检测到最强的表达。核 erbB2 阳性与包括脂肪性肝炎中的炎症活动、肝细胞气球样变和胆汁淤积在内的肝细胞损伤的组织学参数显著相关。erbB2 过表达的肝细胞显示核 erbB2 信号的下游效应物磷酸化 STAT3 增加。值得注意的是，我们在核 erbB2 阳性的肝细胞中观察到雌激素受体表达下调。在酒精性脂肪性肝炎和其他毒性肝病中，肝细胞显示出核 erbB2 表达，这暗示了细胞应激下肝细胞中一种未知的机制，可能导致对细胞死亡的抵抗。核 erbB2 阳性的肝细胞显示雌激素受体表达下调和 pSTAT3 水平增加，这是核 erbB2 信号功能的标志。此外，肝细胞 erbB2 表达分析可以作为诊断肝病的有用工具。
