CD200 Promotes Gastric Cancer Progression and Metastasis by Inducing the β-catenin Signaling Pathway

Abstract

Gastric cancer is the fifth most common malignancy and the fourth leading cause of cancer-related mortalities worldwide. Understanding the mechanisms driving tumor growth and metastasis in gastric cancer is essential for the development of effective therapeutic strategies. In this regard, it is well-established that CD200, a glycoprotein that binds to the CD200 receptor, has notable immunosuppressive effects. The extracellular domain of CD200 is secreted into the tumor microenvironment (TME), wherein it promotes cancer progression. However, although CD200 is highly expressed in several types of cancers, the details of its intracellular roles in tumor progression remain poorly understood. In this study, we investigated the biological function and mechanism of action of CD200 in gastric cancer. Public datasets from GSE and TCGA revealed that CD200 is overexpressed in gastric cancer and that its expression is correlated with cancer stage and metastasis. Functionally, we found that CD200 enhances cell proliferation, migration, and invasion, and also promotes the expression of epithelial-mesenchymal transition (EMT)-related genes. Mechanistically, CD200 was demonstrated activate the WNT/β-catenin signaling pathway by inducing β-catenin activation. Notably, we established that the cytoplasmic domain of CD200 binds directly to β-catenin, thereby facilitating its nuclear translocation. The CD200/β-catenin/TCF4 complex subsequently promotes the transcription of β-catenin target and EMT-related genes. Collectively, our findings in this study revealed that the cytoplasmic domain of CD200 interacts with β-catenin, thereby promoting the transcriptional activation of β-catenin target genes and inducing tumor growth and metastasis in gastric cancer. These findings accordingly indicate that CD200 may serve as a potential therapeutic target for the treatment of gastric cancer.