1. Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma.
- Author
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Kivisaari, A. K., Kallajoki, M., Ala-aho, R., McGrath, J. A., Bauer, J. W., Königov, R., Medvecz, M., Beckert, W., Grénman, R., and Kähäri, V.-M.
- Subjects
METALLOPROTEINASES ,SQUAMOUS cell carcinoma ,EPIDERMOLYSIS bullosa ,EPIDERMAL growth factor ,CANCER cells ,SKIN cancer ,GENETIC disorders ,PATIENTS - Abstract
Background Tumour-specific expression of matrix metalloproteinase (MMP)-7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). Objectives To examine the potential role of MMP-7 in shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in RDEB-associated and sporadic SCCs. Methods Tissue microarrays of RDEB-associated SCC ( n = 20), non-EB SCC ( n = 60) and Bowen disease ( n = 28) were immunostained for MMP-7, CD44 variant 3 (CD44v3) and HB-EGF. Shedding of HB-EGF was studied in vitro using two cutaneous SCC cell lines. Results Immunohistochemical analysis showed that HB-EGF was absent in tumour cells when MMP-7 and CD44v3 colocalized, and that the absence of HB-EGF was more pronounced in RDEB-associated SCCs than in non-EB SCCs. The loss of HB-EGF in MMP-7-CD44v3 double-positive areas was interpreted to indicate shedding and activation of HB-EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP-7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB-EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. Conclusions These findings provide evidence for the role of MMP-7 in promoting the growth of cutaneous SCCs by shedding HB-EGF, and identify EGFR signalling as a potential therapeutic target in RDEB-associated SCC and unresectable sporadic cutaneous SCC. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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