δ-Catenin promotes E-cadherin processing and activates ß-catenin-mediated signaling: implications on human prostate cancer progression.

δ-Catenin binds the juxtamembrane domain of E-cadherin and is known to be overexpressed in some human tumors. However, the functions of δ-catenin in epithelial cells and carcinomas remain elusive. We found that prostate cancer cells overexpressing δ-catenin show an increase in multi-layer growth in culture. In these cells, δ-catenin colocalizes with E-cadherin at the plasma membrane, and the E-cadherin processing is noticeably elevated. E-Cadherin processing induced by δ-catenin is serum-dependent and requires MMP- and PS-1/γ-secretase-mediated activities. A deletion mutant of δ-catenin that deprives the ability of δ-catenin to bind E-cadherin or to recruit PS-1 to E-cadherin totally abolishes the δ-catenin-induced E-cadherin processing and the multi-layer growth of the cells. In addition, prostate cancer cells overexpressing δ-catenin display an elevated total ß-catenin level and increase its nuclear distribution, resulting in the activation of ß-catenin/LEF-1-mediated transcription and their downstream target genes as well as androgen receptor-mediated transcription. Indeed, human prostate tumor xenograft in nude mice, which is derived from cells overexpressing δ-catenin, shows increased ß-catenin nuclear localization and more rapid growth rates. Moreover, the metastatic xenograft tumor weights positively correlate with the level of 29kD E-cadherin fragment, and primary human prostate tumor tissues also show elevated levels of δ-catenin expression and the E-cadherin processing. Taken together, these results suggest that δ-catenin plays an important role in prostate cancer progression through inducing E-cadherin processing and thereby activating ß-catenin-mediated oncogenic signals.

Gene therapy for head and neck squamous cell carcinoma using KITENIN (KAI1 COOH-Terminal Interacting Tetraspanin)-antisense therapy.

PURPOSE: KAI1 COOH-terminal interacting tetraspanin (KITENIN) has been found to act as a promoter of metastasis in murine models of colon cancer and squamous cell carcinoma (SCC). The suppression of tumor progression and metastasis of established colon cancer in mice was observed after intravenous delivery of small interfering RNA (siRNA) targeting KITENIN. The purpose of this study was to investigate the efficacy of gene therapy targeting KITENIN in human head and neck SCC. MATERIALS AND METHODS: SNU-1041, a well-established human hypopharyngeal SCC cell line, was used. KITENIN expression in SNU-1041 was measured by Western blot analysis. The cells were prepared, maintained in culture dishes with media, and divided into two groups: the si-KITENIN group and the scrambled group (control). The siRNA targeting KITENIN (si-KITENIN) and scrambled DNA were transfected into the SNU-1041 cells in each group. The effect of gene therapy was compared by in vitro experiments to evaluate invasion, migration, and proliferation. RESULTS: KITENIN was strongly expressed in the SNU-1041 cells, and the number of invaded cells was reduced more in the si-KITENIN group than in the scrambled group (p<0.001). The speed for the narrowing gap, made through adherent cells, was lower in the si-KITENIN group (p<0.001), and the number of viable proliferating cells was reduced in the si-KITENIN group compared to the scrambled group (p<0.001, the third day). KITENIN protein expression was no longer identified in the si-KITENIN group. CONCLUSION: Gene therapy using an anti-KITENIN strategy might be effective for head and neck squamous carcinoma.