HER2–CDH1 Interaction via Wnt/B-Catenin Is Associated with Patients’ Survival in HER2-Positive Metastatic Gastric Adenocarcinoma

Abstract

Trastuzumab is a human epidermal growth factor receptor 2 (HER2) inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between CDH1 mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two series of gastric cancer (GC): Series 1 (n = 38): HER2+ and HER2- mGC; Series 2 (n = 36) HER2- GC with and without metastasis. To confirm the results, the same expression profiles were analyzed in 354 GC from The Cancer Genome Atlas (TCGA) dataset. The difference in gene expression connected HER2 overexpression with canonical wingless-type (Wnt)/β-catenin pathway and immunohistochemical (IHC) expression loss of E-cadherin (E-CAD). CDH1 mRNA expression was simultaneously associated with the rs16260-A variant and an increase in E-CAD expression. Differences in retinoic acid receptor alfa (RARA), RPL19 (coding for the 60S ribosomal L19 protein), catenin delta 1 (CTNND1), and epidermal growth factor (EGF) mRNA levels—all included in the Wnt/β-catenin pathway—were found associated with overall survival (OS). RARA, CTNND1, and EGF resulted in independent OS prognostic factors. EGF was confirmed as an independent factor along with TNM stage in HER2-overpressed mGC from TCGA collection. Our study highlighted factors involved in the WNT/β-catenin pathway that interconnected E-CAD with HER2 overexpression and patient survival.

Association between eight hypermethylation-related genes and gastric cancer: a systematic review and meta-analysis

“…Thus, the methylation status of the p16 promoter in GC tissue could help predict the potential of malignance and progression of GC. CDH1 is essential in the maintenance of cell morphology and regulation of cell adhesion (14). CDH1 gene encodes E-cadherin (E-cad), which participates in the inhibition of migration and invasion of tumor cells (15).…”

HER2+ advanced gastric cancer: Current state and opportunities (Review)

“…Furthermore, HER2 triggers epithelial-to-mesenchymal transition by activating the Wnt/β-catenin pathway. This activation, in turn, amplifies the migratory and invasive capabilities of GC cells ( 13 , 14 ). A thorough exploration of the features and underlying mechanisms of HER2 + AGC may reveal valuable insights for its effective management ( 15 ).…”