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Type VII Collagen Is Required for Ras-Driven Human Epidermal Tumorigenesis
Susana Ortiz-Urda,1,2John Garcia,1,2Cheryl L. Green,1,2Lei Chen,1,2Qun Lin,1,2Dallas P. Veitch,1,2Lynn Y. Sakai,3Hyangkyu Lee,1,2M. Peter Marinkovich,1,2Paul A. Khavari1,2*
Type VII collagen defects cause recessive dystrophic epidermolysisbullosa (RDEB), a blistering skin disorder often accompaniedby epidermal cancers. To study the role of collagen VII in thesecancers, we examined Ras-driven tumorigenesis in RDEB keratinocytes.Cells devoid of collagen VII did not form tumors in mice, whereasthose retaining a specific collagen VII fragment (the amino-terminalnoncollagenous domain NC1) were tumorigenic. Forced NC1 expressionrestored tumorigenicity to collagen VII–null epidermisin a non–cell-autonomous fashion. Fibronectin-like sequenceswithin NC1 (FNC1) promoted tumor cell invasion in a laminin5–dependent manner and were required for tumorigenesis.Tumor-stroma interactions mediated by collagen VII thus promoteneoplasia, and retention of NC1 sequences in a subset of RDEBpatients may contribute to their increased susceptibility tosquamous cell carcinoma.
1 VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA. 2 Program in Epithelial Biology, 269 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305, USA. 3 Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97201, USA
* To whom correspondence should be addressed. E-mail: khavari{at}cmgm.stanford.edu
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