RECK Inhibits Stemness Gene Expression and Tumorigenicity of Gastric Cancer Cells by Suppressing ADAM-Mediated Notch1 Activation

摘要: The Reversion-inducing Cysteine-rich Protein with Kazal Motifs (RECK) gene encodes a membrane-anchored glycoprotein that exhibits strong inhibitory activity against various matrix metalloproteinases (MMPs) and disintegrin metalloproteinase 10 (ADAM10). RECK functions as tumor suppressor by inhibiting migration, invasion, angiogenesis. However, whether can modulate the stem-like phenotypes of cancer cells is not known. In this study, we demonstrate down-regulated in gastric further reduced CD133-positive cells. Ectopic expression induces down-regulation stemness genes including Sox2, Oct4, Nanog stem cell marker CD133. Treatment DAPT (a γ-secretase inhibitor) or TAPI-2 hydroxamate-based inhibitor MMPs, necrosis factor α converting enzyme ADAM17) reduces Notch1 shedding activation which results attenuation Our data show ADAM10 ADAM17 are co-pulled down suggesting physical interaction between ADAMs on surface. addition, suppresses sphere formation size Overexpression Notch intracellular domain (NICD) effectively reverse effect More importantly, tumorigenic vivo. Conversely, knockdown non-tumorigenic GI2 increases CD133 forming ability. Collectively, these indicate represses properties ADAM-mediated activation. J. Cell. Physiol. 229: 191–201, 2014. © 2013 Wiley Periodicals, Inc.