肝细胞癌中 HER2 表达的识别及其与术后肿瘤复发的关系。
Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence.
机构信息
Department of Hepatobiliary and Pancreatic Surgery, Henan Key Laboratory of Digestive Organ transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Department of Transplantation Medicine, Institute of Surgical Research, Oslo University Hospital, Oslo, Norway.
出版信息
Cancer Med. 2019 Mar;8(3):1269-1278. doi: 10.1002/cam4.2006. Epub 2019 Feb 4.
BACKGROUND
The ERBB2 oncogene hypothesis is challenged in hepatocellular carcinoma (HCC) with the conflicting evidences of human epidermal growth factor receptor 2 (HER2) overexpression. HER2 could be a new target as a treatment option for HCC as well as tumor recurrence after surgery. HER2 in HCC biology needs further explorations.
METHODS
Clinical and mRNA data of HCC patients were obtained from TCGA HCC cohort, GSE89377 and GSE115018. Western Blotting and immunohistochemistry were employed to test expression of HER2, E-cadherin, and Vimentin. In HepG2, JM1, HER2-transfected McA cells, and TGF-β cocultured JM1 cells, HCC biology, including cell survival, proliferation, and epithelial-to-mesenchymal transition (EMT) phenotypes were evaluated.
RESULTS
ERBB2 mRNA amplification was found in HCC datasets, and its expression was downregulated in high grade HCC with a worse overall survival. HER2 overexpression was identified in H4IIE, HepG2, JM1 cells, and 82% (14/17) HCC samples, and tumor stage was correlated with expression of HER2, E-cadherin, and Vimentin (P < 0.05). Trastuzumab with the high concentrations suppressed proliferation of HER2-positive hepatoma cells (P < 0.05); in the coculture model to induce EMT of JM1 cells, HER2 expression increased with downregulated E-cadherin and upregulated Vimentin. Trastuzumab intravenous injection inhibited in vivo tumor size and metastases (P < 0.05). Signal analysis revealed that HER2 functioned through upregulation of β-catenin and inhibition of SMAD3.
CONCLUSION
HER2 expression pattern is linked with tumor stage and overall survival; the transforming function of HER2 is found more relevant through β-catenin and SMAD3. HER2-targeted treatment is recommended to suppress the HER2-mediated tumor growth during postoperative liver regeneration.
背景
在肝细胞癌（HCC）中，ERBB2 癌基因假说受到挑战，因为人类表皮生长因子受体 2（HER2）过表达的证据相互矛盾。HER2 可能成为 HCC 以及手术后肿瘤复发的新治疗靶点。HER2 在 HCC 生物学中的作用需要进一步探索。
方法
从 TCGA HCC 队列、GSE89377 和 GSE115018 中获得 HCC 患者的临床和 mRNA 数据。采用 Western Blotting 和免疫组化检测 HER2、E-钙黏蛋白和波形蛋白的表达。在 HepG2、JM1、HER2 转染的 McA 细胞以及 TGF-β 共培养的 JM1 细胞中，评估 HCC 生物学，包括细胞存活、增殖和上皮-间充质转化（EMT）表型。
结果
在 HCC 数据集发现 ERBB2 mRNA 扩增，其表达在高级别 HCC 中下调，总生存率更差。在 H4IIE、HepG2、JM1 细胞和 82%（14/17）的 HCC 样本中鉴定出 HER2 过表达，肿瘤分期与 HER2、E-钙黏蛋白和波形蛋白的表达相关（P<0.05）。高浓度的曲妥珠单抗抑制 HER2 阳性肝癌细胞的增殖（P<0.05）；在共培养模型中诱导 JM1 细胞的 EMT，HER2 表达增加，E-钙黏蛋白下调，波形蛋白上调。曲妥珠单抗静脉注射抑制体内肿瘤大小和转移（P<0.05）。信号分析显示，HER2 通过上调 β-连环蛋白和抑制 SMAD3 发挥作用。
结论
HER2 的表达模式与肿瘤分期和总生存率相关；通过 β-连环蛋白和 SMAD3 发现 HER2 的转化功能更为相关。建议进行 HER2 靶向治疗，以抑制术后肝再生过程中 HER2 介导的肿瘤生长。
Zotero 插件