| Autor: |
Klucky B; Division of Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum, Heidelberg, Germany., Mueller R, Vogt I, Teurich S, Hartenstein B, Breuhahn K, Flechtenmacher C, Angel P, Hess J |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer research [Cancer Res] 2007 Sep 01; Vol. 67 (17), pp. 8198-206. |
| DOI: |
10.1158/0008-5472.CAN-07-0607 |
| Abstrakt: |
Recently, we described phorbol ester-induced expression of the brain and skin serine proteinase Bssp/kallikrein 6 (Klk6), the mouse orthologue of human KLK6, in mouse back skin and in advanced tumor stages of a well-established multistage tumor model. Here, we show KLK6 up-regulation in squamous skin tumors of human patients and in tumors of other epithelial tissues. Ectopic Klk6 expression in mouse keratinocyte cell lines induces a spindle-like morphology associated with accelerated proliferation, migration, and invasion capacity. We found reduced E-cadherin protein levels in the cell membrane and nuclear translocation of beta-catenin in Klk6-expressing mouse keratinocytes and human HEK293 cells transfected with a KLK6 expression plasmid. Additionally, HEK293 cells exhibited induced T-cell factor-dependent transcription and impaired cell-cell adhesion in the presence of KLK6, which was accompanied by induced E-cadherin ectodomain shedding. Interestingly, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 interfere with KLK6-induced E-cadherin ectodomain shedding and rescue the cell-cell adhesion defect in vitro, suggesting the involvement of matrix metalloproteinase and/or a disintegrin and metalloproteinase (ADAM) proteolytic activity. In line with this assumption, we found increased levels of the mature 62-kDa ADAM10 proteinase in cells expressing ectopic KLK6 compared with mock controls. Finally, enhanced epidermal keratinocyte proliferation and migration in concert with decreased E-cadherin protein levels are confirmed in an in vivo Klk6 transgenic mouse model. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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