Affiliation:
1. Department of Molecular Biology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine China
2. Department of Clinical Laboratory Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine China
Abstract
Trastuzumab is widely used in human epidermal growth factor receptor 2 (HER2)‐positive gastric cancer (GC) therapy, but ubiquitous resistance limits its clinical application. In this study, we first showed that CD44 antigen is a significant predictor of overall survival for patients with HER2‐positive GC. Next, we found that CD44 could be co‐immunoprecipitated and co‐localized with HER2 on the membrane of GC cells. By analyzing the interaction between CD44 and HER2, we identified that CD44 could upregulate HER2 protein by inhibiting its proteasome degradation. Notably, the overexpression of CD44 could decrease the sensitivity of HER2‐positive GC cells to trastuzumab. Further mechanistic study showed that CD44 upregulation could induce its ligand, hyaluronan (HA), to deposit on the cancer cell surface, resulting in covering up the binding sites of trastuzumab to HER2. Removing the HA glycocalyx restored sensitivity of the cells to trastuzumab. Collectively, our findings suggested a role for CD44 in regulating trastuzumab sensitivity and provided novel insights into HER2‐targeted therapy.
Funder
National Natural Science Foundation of China
Subject
Cell Biology,Molecular Biology,Biochemistry