Type VII collagen is required for Ras-driven human epidermal tumorigenesis.
Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers. To study the role of collagen VII in these cancers, we examined Ras-driven tumorigenesis in RDEB keratinocytes. Cells devoid of collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal noncollagenous domain NC1) were tumorigenic. Forced NC1 expression restored tumorigenicity to collagen VII-null epidermis in a non-cell-autonomous fashion. Fibronectin-like sequences within NC1 (FNC1) promoted tumor cell invasion in a laminin 5-dependent manner and were required for tumorigenesis. Tumor-stroma interactions mediated by collagen VII thus promote neoplasia, and retention of NC1 sequences in a subset of RDEB patients may contribute to their increased susceptibility to squamous cell carcinoma.
Ortiz-Urda
Susana
S
VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA.
Garcia
John
J
Green
Cheryl L
CL
Chen
Lei
L
Lin
Qun
Q
Veitch
Dallas P
DP
Sakai
Lynn Y
LY
Lee
Hyangkyu
H
Marinkovich
M Peter
MP
Khavari
Paul A
PA
D000293:Adolescent; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002648:Child; D024143:Collagen Type VII / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D004198:Disease Susceptibility; D016108:Epidermolysis Bullosa Dystrophica / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D011905:Genes, ras; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D009361:Neoplasm Invasiveness; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D000097794:Kalinin
D000906:Antibodies; D015815:Cell Adhesion Molecules; D024143:Collagen Type VII; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D000097794:Kalinin; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse