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- Title
Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma.
- Authors
Kivisaari, A. K.; Kallajoki, M.; Ala-aho, R.; McGrath, J. A.; Bauer, J. W.; Königov, R.; Medvecz, M.; Beckert, W.; Grénman, R.; Kähäri, V.-M.
- 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.
- Subjects
METALLOPROTEINASES; SQUAMOUS cell carcinoma; EPIDERMOLYSIS bullosa; EPIDERMAL growth factor; CANCER cells; SKIN cancer; GENETIC disorders; PATIENTS
- Publication
British Journal of Dermatology, 2010, Vol 163, Issue 4, p726
- ISSN
0007-0963
- Publication type
Article
- DOI
10.1111/j.1365-2133.2010.09924.x