Recognition of HER2 expression in hepatocellular carcinoma and its significance in postoperative tumor recurrence.

Abstract

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.

• Authors: Ji-Hua Shi, Wen-Zhi Guo, Yang Jin, Hua-Peng Zhang, Chun Pang, Jie Li, Pål-Dag Line, Shui-Jun Zhang
• Journal: Cancer medicine (Cancer Med) Vol. 8 Issue 3 Pg. 1269-1278 (03 2019) ISSN: 2045-7634 [Electronic] United States
• PMID: 30714677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• RNA, Messenger
• SMAD3 protein, human
• Smad3 Protein
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Animals
• Carcinoma, Hepatocellular (genetics, mortality, pathology, surgery)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation
• Disease Models, Animal
• Gene Expression
• Humans
• Immunohistochemistry
• Liver Neoplasms (genetics, mortality, pathology, surgery)
• Male
• Neoplasm Grading
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Postoperative Period
• Prognosis
• RNA, Messenger (genetics)
• Rats
• Receptor, ErbB-2 (genetics, metabolism)
• Smad3 Protein (metabolism)