Transforming Growth Factor Beta2 Promotes Migration and Inhibits the Proliferation of Gastric Cancer Cells by Regulating the pSmad2/3-NDRG1 Signaling Pathway

Abstract

Transforming growth factor beta2 (TGFβ2) is upregulated in gastric cancer (GC), playing a crucial role in driving its progression. However, the biological effects of TGFβ2 in GC metastasis and proliferation remain not fully understood. Our study reveals that TGFβ2 enhances N-myc downstream-regulated gene 1 (NDRG1) protein expression by activating the TGFβR/Smad2/3-dependent pathway, accelerating GC progression. TGFβ2 knockdown downregulates NDRG1 by inhibiting the TGFβR/Smad2/3 signaling pathway, which in turn inhibits GC cell migration and epithelial–mesenchymal transition (EMT) but stimulates proliferation. Both TGFβ2 upregulation and NDRG1 upregulation enhance GC cell migration in vitro and promote lung metastasis in mouse models. Interfering with NDRG1 reverses TGFβ2-induced migration, and inhibiting Smad2/3 or TGFβR reverses TGFβ2-induced NDRG1 upregulation and GC cell migration. Clinical sample analysis shows high TGFβ2 and NDRG1 expression in GC, associated with poor prognosis. Our study reveals that TGFβ2 upregulates NDRG1 via the TGFβR/Smad2/3 pathway, driving GC progression and highlighting the potential role of the TGFβ2NDRG1 axis in GC-targeted therapies.