Journal
BRITISH JOURNAL OF DERMATOLOGY
Volume 163, Issue 4, Pages 726-735Publisher
WILEY
DOI: 10.1111/j.1365-2133.2010.09924.x
Keywords
epidermolysis bullosa; heparin-binding epidermal growth factor-like growth factor; matrix metalloproteinase; squamous cell carcinoma; tissue microarray
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Funding
- Dystrophic Epidermolysis Bullosa Research Association (DebRA, U.K.)
- Academy of Finland [203421, 114405]
- Sigrid Juselius Foundation
- Cancer Research Foundation of Finland
- Southwestern Finland Cancer Societies
- Turku University Hospital [13336, 13010]
- Finnish Dermatological Society
- Finnish Society of Dermatopathology
- K. Albin Johansson Foundation
- Cancer Foundation Finland sr [100104] Funding Source: researchfish
- Academy of Finland (AKA) [203421, 203421] Funding Source: Academy of Finland (AKA)
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P>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.
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