Matrix metalloproteinase‐7 activates heparin‐binding epidermal growth factor‐like growth factor in cutaneous squamous cell carcinoma |
| |
Authors: | AK Kivisaari M Kallajoki R Ala‐aho JA McGrath JW Bauer R Königová M Medvecz W Beckert R Grénman V‐M Kähäri |
| |
Institution: | 1. Department of Dermatology, University of Turku and Turku University Hospital, PO Box 52, 20521 Turku, Finland;2. Medicity Research Laboratory, University of Turku, Turku, Finland;3. Department of Pathology, Turku University Hospital, Turku, Finland;4. St John’s Institute of Dermatology, King’s College London (Guy’s Campus), London, U.K.;5. Department of Dermatology, General Hospital, Salzburg, Austria;6. Burn Centre, Charles University, Prague, Czech Republic;7. Department of Dermatology, Venereology and Dermato‐oncology, Semmelweis University Budapest, Budapest, Hungary;8. Laboratory for Histology and Cytology, Nürtingen, Germany;9. Department of Otorhinolaryngology – Head and Neck Surgery, University of Turku, Turku, Finland |
| |
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. |
| |
Keywords: | epidermolysis bullosa heparin‐binding epidermal growth factor‐like growth factor matrix metalloproteinase squamous cell carcinoma tissue microarray |
|
|