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Br J Dermatol. 2019 Jan 28. doi: 10.1111/bjd.17698. [Epub ahead of print]

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.

Author information

1
Department of Bioengineering, Universidad Carlos III de Madrid, Madrid, Spain.
2
Regenerative Medicine and Tissue Engineering Group, Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
3
Bioinformatics and Biostatistics Unit, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
4
Epithelial Biomedicine Division, CIEMAT-CIBERER (U714), Madrid, Spain.
5
Tissue Engineering Unit, Centro Comunitario Sangre y Tejidos (CCST), Oviedo, Spain.
6
Department of Computational Genomics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
7
Melanoma Unit, Hospital Clinic & IDIBAPS (Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer), CIBERER (U726), Universitat de Barcelona, Barcelona, Spain.
8
Department of Pediatric Dermatology, La Paz Hospital, Madrid, Spain.
9
Department of Pediatric Dermatology, Santa Creu I Sant Pau Hospital, Barcelona, Spain.
10
Clinical Bioinformatics Area, Fundación Progreso y Salud, CDCA, Hospital Virgen del Rocío, Sevilla, Spain.
11
Functional Genomics Node, INB-ELIXIR-es, FPS, Hospital Virgen del Rocío, Sevilla, Spain.
12
Bioinformatics in Rare Diseases (BiER-U715), CIBERER, FPS, Hospital Virgen del Rocío, Sevilla, Spain.

Abstract

BACKGROUND:

Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES:

To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS:

We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS:

Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS:

Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS.

PMID:
30693469
DOI:
10.1111/bjd.17698

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