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ß-Catenin/Wnt Signaling Regulates Expression of the Membrane Type 3 Matrix Metalloproteinase in Gastric Cancer

¹ Department of Surgery, Division of Surgical Oncology; ² Department of Pathology and Laboratory Medicine; ³ Cincinnati Children's Hospital Medical Center; and ⁴ Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, Ohio

Requests for reprints: Andrew M. Lowy, Division of Surgical Oncology, Barrett Cancer Center, University of Cincinnati, Cincinnati, OH 45219. Phone: 513-584-8900; Fax: 513-584-0459; E-mail: andrew.lowy{at}uc.edu.

Activation of Wnt signaling through ß-catenin dysregulation occurs in numerous human tumors, including gastric cancer. The specific consequences of Wnt signaling in gastric cancer, however, are not well characterized. This study shows that the introduction of mutant ß-catenin into gastric cancer cell lines by adenoviral infection enhances invasiveness and proliferation and up-regulates the expression of the gene encoding the matrix metalloproteinase (MMP) family member membrane type 3 MMP (MT3-MMP). Up-regulation of MT3-MMP is critical to the invasive phenotype as shown by small interfering RNA (siRNA) studies. Immunohistochemical staining also showed that MT3-MMP was highly expressed in gastric cancers with activating ß-catenin mutations. These observations suggest that Wnt activation may contribute to gastric cancer progression by increasing the invasiveness of neoplastic cells in the stomach via up-regulation of MT3-MMP expression. (Cancer Res 2006; 66(9): 4734-41)