Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma.
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).


OBJECTIVE
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.
Kivisaari
A K
AK
Department of Dermatology, University of Turku and Turku University Hospital, PO Box 52, 20521 Turku, Finland.
Kallajoki
M
M
Ala-aho
R
R
McGrath
J A
JA
Bauer
J W
JW
Königová
R
R
Medvecz
M
M
Beckert
W
W
Grénman
R
R
Kähäri
V-M
VM
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D055815:Young Adult
C121450:CD44V3,8-10; D004151:Dipeptides; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7