Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basement-membrane type VII collagen.
Type VII collagen (ColVII) is the main component of anchoring fibrils, attachment structures within the lamina densa of the basement membrane that are responsible for attachment of the epidermis to the dermis in skin. Mutations in the human ColVII gene, COL7A1, cause the severe inherited blistering disorder recessive dystrophic epidermolysis bullosa (RDEB) affecting skin and mucosae, associated with a greatly increased risk of skin cancer. In this study, we examined the effect of loss of ColVII on squamous cell carcinoma (SCC) tumourigenesis using RNAi in a 3D organotypic skin model. Our findings suggest that loss of ColVII promotes SCC migration and invasion as well as regulating cell differentiation with evidence for concomitant promotion of epithelial-mesenchymal transition (EMT). Immunostaining of RDEB skin and a tissue array of sporadic cutaneous SCCs confirmed that loss of ColVII correlates with decreased involucrin expression in vivo. Gene-expression-array data and immunostaining demonstrated that loss of ColVII increases expression of the chemokine ligand-receptor CXCL10-CXCR3 and downstream-associated PLC signalling, which might contribute to the increased metastatic potential of SCCs with reduced or absent ColVII expression. Together, these findings may explain the aggressive behaviour of SCCs in RDEB patients and may also be relevant to non-RDEB skin cancer, as well as other tumours from organs where ColVII is expressed.
Centre for Cutaneous Research, Cancer Research UK Skin Tumour Laboratory, Institute of Cell and Molecular Science, William Harvey Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London E1 2AT, UK.
Vera L
VL
Martins
Jashmin J
JJ
Vyas
Mei
M
Chen
Karin
K
Purdie
Charles A
CA
Mein
Andrew P
AP
South
Alan
A
Storey
John A
JA
McGrath
Edel A
EA
O'Toole
D001485:Basement Membrane / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D024143:Collagen Type VII / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011498:Protein Precursors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D046509:Tissue Culture Techniques
D015415:Biomarkers; D015820:Cadherins; D024143:Collagen Type VII; D011498:Protein Precursors; D034741:RNA, Small Interfering; C032253:involucrin; D020778:Matrix Metalloproteinase 2