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HER2 Regulates Cancer Stem Cell Activities via the Wnt Signaling Pathway in Gastric Cancer Cells

 Da Hyun Jung  ;  Yoo Jin Bae  ;  Jie-Hyun Kim  ;  You Keun Shin  ;  Hei-Cheul Jeung 
 ONCOLOGY, Vol.97(5) : 311-318, 2019 
Journal Title
Issue Date
Antigens, CD/analysis ; Cadherins/analysis ; Cell Line, Tumor ; Humans ; Neoplasm Invasiveness ; Neoplastic Stem Cells/physiology* ; Octamer Transcription Factor-3/analysis ; Polycomb Repressive Complex 1/analysis ; Receptor, ErbB-2/analysis ; Receptor, ErbB-2/physiology* ; Stomach Neoplasms/chemistry ; Stomach Neoplasms/pathology* ; Wnt Signaling Pathway/physiology* ; beta Catenin/analysis
Cancer stem cell ; Epithelial-to-mesenchymal transition ; Gastric cancer ; HER2 ; Wnt
INTRODUCTION: Human epidermal growth factor 2 (HER2) gene overexpression in breast carcinoma cell lines has been shown to drive mammary carcinogenesis and tumor growth and invasion through its effects on mammary stem cells. OBJECTIVE: Therefore, we investigated the mechanism by which HER2 regulates cancer stem cell (CSC) activity in gastric cancer cells. METHODS: HER2 was transfected into MKN28 gastric cancer cells, and its role in regulating CSC activity was determined by characterizing the HER2-overexpressing cells. RESULTS: The sphere formation assay revealed that the sphere sizes and frequency of sphere formation were significantly greater for the HER2-overexpressing cells than for the MKN28 control cells. The CSC markers Oct-4 and BMI1 were more highly expressed in the HER2-overexpressing cells, as were the EMT markers. This was accompanied by a significant enhancement in cellular invasion of the Matrigel and migration. The E-cadherin level was significantly downregulated, and the mesenchymal marker Snail upregulated, in the HER2-transfected cells. HER2 overexpression activated the well-characterized CSC-associated Wnt/β-catenin signaling pathway, as shown by the luciferase assay. After treatment of these cells with the Wnt signal inhibitor PRI-724, the BMI1 and Oct-4 levels were decreased for 24 h and Snail was also downregulated. Immunofluorescence staining revealed the significant restoration of E-cadherin levels in the HER2-transfected cells after PRI-724 treatment. CONCLUSIONS: These results established a role for HER2 in regulating gastric CSC activity, with Wnt/β-catenin signaling being mediated via a HER2-dependent pathway. In summary, HER2-overexpressing gastric cancer cells exhibited increased stemness and invasiveness and were regulated by Wnt/β-catenin signaling.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jie-Hyun(김지현) ORCID logo https://orcid.org/0000-0002-9198-3326
Jung, Da Hyun(정다현) ORCID logo https://orcid.org/0000-0001-6668-3113
Jeung, Hei Cheul(정희철) ORCID logo https://orcid.org/0000-0003-0952-3679
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