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.

中文翻译：

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透明质酸糖萼与 CD44 的锚定降低了 HER2 阳性胃癌细胞对曲妥珠单抗的敏感性

曲妥珠单抗广泛用于人表皮生长因子受体2（HER2）阳性胃癌（GC）治疗，但普遍存在的耐药性限制了其临床应用。在这项研究中，我们首先证明 CD44 抗原是 HER2 阳性 GC 患者总生存期的重要预测因子。接下来，我们发现CD44可以与HER2免疫共沉淀并共定位在GC细胞膜上。通过分析CD44和HER2之间的相互作用，我们发现CD44可以通过抑制其蛋白酶体降解来上调HER2蛋白。值得注意的是， CD44的过度表达可以降低 HER2 阳性 GC 细胞对曲妥珠单抗的敏感性。进一步的机制研究表明，CD44上调可以诱导其配体透明质酸（HA）沉积在癌细胞表面，从而覆盖曲妥珠单抗与HER2的结合位点。去除 HA 糖萼可恢复细胞对曲妥珠单抗的敏感性。总的来说，我们的研究结果表明 CD44 在调节曲妥珠单抗敏感性中发挥作用，并为 HER2 靶向治疗提供了新的见解。