Using the PCR-based subtractive messenger RNA hybridization assay described in this paper, we isolated a hitherto uncharacterized gene, transmembrane protein 207 (TMEM207), which was selectively expressed in collagen gel-invading cultured signet-ring cell carcinoma KATO-III cells. TMEM207 has a C-terminal proline-rich PPxY motif, which binds to the WW domain-containing oxidoreductase, WWOX. Enforced expression of TMEM207 significantly increased Matrigel invasion activity of KATO-III cells in vitro without affecting cell growth. In contrast, expression of TMEM207 with mutations in the PPxY motif did not significantly increase Matrigel invasion activity of KATO-III cells. Immunohistochemical staining showed that TMEM207 was strongly expressed in 7 of 30 gastric signet-ring cell carcinoma tissue specimens. Notably, TMEM207 expression was associated with the depth of cancer invasion and the presence of lymph node metastasis. The results of co-immunoprecipitation followed by western immunoblotting showed that TMEM207 is bound to WWOX in a PPxY motif-dependent manner. Small interfering RNA-mediated downregulation of WWOX also significantly increased Matrigel invasion activity of KATO-III cells. Notably, exogenous expression of TMEM207 impaired the WWOX-mediated repression of Matrigel invasion activity of another cultured signet-ring cell carcinoma cell line, NUGC-4 cells. Recent studies have highlighted the fact that WWOX acts as a tumor suppressor factor in various malignant tumors, including gastric cancer. On the basis of these findings and the results of the present study, we think that overexpression of TMEM207 may facilitate invasive activity and metastasis of gastric signet-ring cell carcinoma, which possibly occur through binding to WWOX and attenuation of its function.