A positive feedback loop between CDH11 and TGF-β signaling regulates migration and invasion of gastric cancer

OBJECTIVE: To investigate the molecular functions and underlying mechanisms of cadherin 11 (CDH11) in the pathogenesis of advanced gastric cancer (GC), and to evaluate the therapeutic potential of targeting CDH11 and its associated signaling pathways. METHODS: The clinicopathological significance of CDH11 in GC was analyzed using the TCGA database. Experiments were conducted to assess the impact of genetic variations on the function of GC cell lines. The therapeutic potential of targeting CDH11 was evaluated in vitro and in vivo. The clinical relevance of CDH11 expression was further validated. RESULTS: TCGA analysis showed that CDH11 was highly expressed in GC and served as an independent prognostic biomarker. High CDH11 expression was also associated with a potentially immunosuppressive tumor microenvironment (TME) in GC. Mechanistically, CDH11 promoted epithelial-mesenchymal transition (EMT) and GC progression by upregulating TGF-β1 and activating TGF-β signaling. Activated TGF-β signaling enhanced CDH11 transcription via the binding of the downstream transcription factor Snail2 to the CDH11 promoter, thereby forming a positive regulatory loop. The targeting of CDH11/TGF-β signaling significantly suppressed migration and invasion of GC in vitro and lung metastasis of GC in vivo. Clinically, CDH11 and Vimentin were highly expressed in GC, especially in the diffuse-type cases, and a positive correlation between them was also identified. In the clinical samples, CDH11 was positively correlated with M2 macrophage marker CD163 and immune checkpoint PD-L1. CONCLUSION: The present study identifies a novel positive feedback loop between CDH11 and TGF-β signaling, which critically regulates EMT, migration, invasion and metastasis of GC cells. The targeting of this axis may represent a promising therapeutic strategy for GC.