High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increases PI3K and MAPK signalling, cell migration and invasion

C. Pourreyron, M. Chen, J. A. McGrath, J. C. Salas-Alanis, A. P. South, I. M. Leigh

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background Epidermolysis bullosa is a group of inherited skin fragility diseases varying in severity from mild scarring to infant mortality. Great efforts are being undertaken to develop therapeutic strategies to treat the more pernicious forms of this disease, particularly those associated with recessive, loss-of-function mutations. In such cases significant effort is directed toward delivering recombinant protein at levels sufficient to demonstrate clinical benefit. Recessive dystrophic epidermolysis bullosa (RDEB) predisposes patients to a high incidence of life-threatening cutaneous squamous cell carcinoma (cSCC). Mutations in the gene encoding type VII collagen, COL7A1, are the sole cause of this disease and conflicting reports concerning type VII collagen and COL7A1 in carcinogenesis exist. Objectives To investigate potential oncogenic effects of expressing recombinant type VII collagen in patient cells. Methods We used retroviral transduction to introduce type VII collagen into keratinocytes derived from patients with and without RDEB. Results Retroviral expression of type VII collagen in cSCC keratinocytes established from patients with RDEB resulted in increased cell adhesion, migration and invasion coupled with a concurrent increase in PI3K and MAPK signalling. Conclusions Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer. What's already known about this topic? Recombinant type VII collagen induces invasion of recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes transformed with oncogenic Ras and IκBαM via activation of the PI3K pathway. What does this study add? High levels of type VII collagen expression induce increased migration and invasion in RDEB cutaneous squamous cell carcinoma keratinocytes and a concurrent increase in activation of the PI3K pathway. Therapeutic efforts to restore type VII collagen expression in patients with RDEB should be mindful of increasing protein levels above endogenous levels. © 2013 British Association of Dermatologists.
Original languageEnglish
Pages (from-to)1256-1265
Number of pages10
JournalBritish Journal of Dermatology
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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Collagen Type VII
Epidermolysis Bullosa Dystrophica
Phosphatidylinositol 3-Kinases
Keratinocytes
Cell Movement
Squamous Cell Carcinoma
Skin
Epidermolysis Bullosa
Mutation
Infant Mortality
Skin Neoplasms
Recombinant Proteins
Skin Diseases
Cell Adhesion
Cicatrix
Carcinogenesis

Cite this

@article{1923b039bb8948a7b8e6178bbfb3b89b,
title = "High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increases PI3K and MAPK signalling, cell migration and invasion",
abstract = "Background Epidermolysis bullosa is a group of inherited skin fragility diseases varying in severity from mild scarring to infant mortality. Great efforts are being undertaken to develop therapeutic strategies to treat the more pernicious forms of this disease, particularly those associated with recessive, loss-of-function mutations. In such cases significant effort is directed toward delivering recombinant protein at levels sufficient to demonstrate clinical benefit. Recessive dystrophic epidermolysis bullosa (RDEB) predisposes patients to a high incidence of life-threatening cutaneous squamous cell carcinoma (cSCC). Mutations in the gene encoding type VII collagen, COL7A1, are the sole cause of this disease and conflicting reports concerning type VII collagen and COL7A1 in carcinogenesis exist. Objectives To investigate potential oncogenic effects of expressing recombinant type VII collagen in patient cells. Methods We used retroviral transduction to introduce type VII collagen into keratinocytes derived from patients with and without RDEB. Results Retroviral expression of type VII collagen in cSCC keratinocytes established from patients with RDEB resulted in increased cell adhesion, migration and invasion coupled with a concurrent increase in PI3K and MAPK signalling. Conclusions Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer. What's already known about this topic? Recombinant type VII collagen induces invasion of recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes transformed with oncogenic Ras and IκBαM via activation of the PI3K pathway. What does this study add? High levels of type VII collagen expression induce increased migration and invasion in RDEB cutaneous squamous cell carcinoma keratinocytes and a concurrent increase in activation of the PI3K pathway. Therapeutic efforts to restore type VII collagen expression in patients with RDEB should be mindful of increasing protein levels above endogenous levels. {\circledC} 2013 British Association of Dermatologists.",
author = "C. Pourreyron and M. Chen and McGrath, {J. A.} and Salas-Alanis, {J. C.} and South, {A. P.} and Leigh, {I. M.}",
year = "2014",
month = "1",
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doi = "10.1111/bjd.12715",
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pages = "1256--1265",
journal = "British Journal of Dermatology",
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High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increases PI3K and MAPK signalling, cell migration and invasion. / Pourreyron, C.; Chen, M.; McGrath, J. A.; Salas-Alanis, J. C.; South, A. P.; Leigh, I. M.

In: British Journal of Dermatology, 01.01.2014, p. 1256-1265.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High levels of type VII collagen expression in recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma keratinocytes increases PI3K and MAPK signalling, cell migration and invasion

AU - Pourreyron, C.

AU - Chen, M.

AU - McGrath, J. A.

AU - Salas-Alanis, J. C.

AU - South, A. P.

AU - Leigh, I. M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background Epidermolysis bullosa is a group of inherited skin fragility diseases varying in severity from mild scarring to infant mortality. Great efforts are being undertaken to develop therapeutic strategies to treat the more pernicious forms of this disease, particularly those associated with recessive, loss-of-function mutations. In such cases significant effort is directed toward delivering recombinant protein at levels sufficient to demonstrate clinical benefit. Recessive dystrophic epidermolysis bullosa (RDEB) predisposes patients to a high incidence of life-threatening cutaneous squamous cell carcinoma (cSCC). Mutations in the gene encoding type VII collagen, COL7A1, are the sole cause of this disease and conflicting reports concerning type VII collagen and COL7A1 in carcinogenesis exist. Objectives To investigate potential oncogenic effects of expressing recombinant type VII collagen in patient cells. Methods We used retroviral transduction to introduce type VII collagen into keratinocytes derived from patients with and without RDEB. Results Retroviral expression of type VII collagen in cSCC keratinocytes established from patients with RDEB resulted in increased cell adhesion, migration and invasion coupled with a concurrent increase in PI3K and MAPK signalling. Conclusions Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer. What's already known about this topic? Recombinant type VII collagen induces invasion of recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes transformed with oncogenic Ras and IκBαM via activation of the PI3K pathway. What does this study add? High levels of type VII collagen expression induce increased migration and invasion in RDEB cutaneous squamous cell carcinoma keratinocytes and a concurrent increase in activation of the PI3K pathway. Therapeutic efforts to restore type VII collagen expression in patients with RDEB should be mindful of increasing protein levels above endogenous levels. © 2013 British Association of Dermatologists.

AB - Background Epidermolysis bullosa is a group of inherited skin fragility diseases varying in severity from mild scarring to infant mortality. Great efforts are being undertaken to develop therapeutic strategies to treat the more pernicious forms of this disease, particularly those associated with recessive, loss-of-function mutations. In such cases significant effort is directed toward delivering recombinant protein at levels sufficient to demonstrate clinical benefit. Recessive dystrophic epidermolysis bullosa (RDEB) predisposes patients to a high incidence of life-threatening cutaneous squamous cell carcinoma (cSCC). Mutations in the gene encoding type VII collagen, COL7A1, are the sole cause of this disease and conflicting reports concerning type VII collagen and COL7A1 in carcinogenesis exist. Objectives To investigate potential oncogenic effects of expressing recombinant type VII collagen in patient cells. Methods We used retroviral transduction to introduce type VII collagen into keratinocytes derived from patients with and without RDEB. Results Retroviral expression of type VII collagen in cSCC keratinocytes established from patients with RDEB resulted in increased cell adhesion, migration and invasion coupled with a concurrent increase in PI3K and MAPK signalling. Conclusions Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer. What's already known about this topic? Recombinant type VII collagen induces invasion of recessive dystrophic epidermolysis bullosa (RDEB) keratinocytes transformed with oncogenic Ras and IκBαM via activation of the PI3K pathway. What does this study add? High levels of type VII collagen expression induce increased migration and invasion in RDEB cutaneous squamous cell carcinoma keratinocytes and a concurrent increase in activation of the PI3K pathway. Therapeutic efforts to restore type VII collagen expression in patients with RDEB should be mindful of increasing protein levels above endogenous levels. © 2013 British Association of Dermatologists.

U2 - 10.1111/bjd.12715

DO - 10.1111/bjd.12715

M3 - Article

SP - 1256

EP - 1265

JO - British Journal of Dermatology

JF - British Journal of Dermatology

SN - 0007-0963

ER -