sFRP1 exerts effects on gastric cancer cells through GSK3β/Rac1-mediated restraint of TGFβ/Smad3 signaling

Secreted frizzled-related protein 1 (sFRP1) is an inhibitor of canonical Wnt signaling; however, previous studies have determined a tumor-promoting function of sFRP1 in a number of different cancer types. A previous study demonstrated that sFRP1 overexpression was associated with an aggressive phenotype and the activation of transforming growth factor β (TGFβ) signaling. sFRP1 overexpression and sFRP1 knockdown cell models were established. Immunoblotting was conducted to examine the protein levels of the associated molecules. Immunofluorescence staining followed by confocal microscopy was performed to visualize the cytoskeleton alterations and subcellular localization of key proteins. sFRP1 overexpression restored glycogen synthase kinase 3β (GSK3β) activity, which activated Rac family small GTPase 1 (Rac1). GSK3β and Rac1 mediated the effect of sFRP1 on the positive regulation of cell growth and migration/invasion. Inhibition of GSK3β or Rac1 abolished the regulation of sFRP1 on TGFβ/SMAD family member 3 (Smad3) signaling and the aggressive phenotype; however, GSK3β or Rac1 overexpression increased cell migration/invasion and restrained Smad3 activity by preventing its nuclear translocation and limiting its transcriptional activity. The present study demonstrated a tumor-promoting function of sFRP1-overexpression by selectively activating TGFβ signaling in gastric cancer cells. GSK3β and Rac1 serve an important function in mediating the sFRP1-induced malignant alterations and signaling changes.