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2017 ; 12
(3
): e0172955
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Site-specific gene expression profiling as a novel strategy for unravelling
keloid disease pathobiology
#MMPMID28257480
Jumper N
; Hodgkinson T
; Paus R
; Bayat A
PLoS One
2017[]; 12
(3
): e0172955
PMID28257480
show ga
Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by
heterogeneity, excess collagen deposition and aggressive local invasion. Lack of
a validated animal model and resistance to a multitude of current therapies has
resulted in unsatisfactory clinical outcomes of KD management. In order to
address KD from a new perspective, we applied for the first time a site-specific
in situ microdissection and gene expression profiling approach, through combined
laser capture microdissection and transcriptomic array. The aim here was to
analyse the utility of this approach compared with established methods of
investigation, including whole tissue biopsy and monolayer cell culture
techniques. This study was designed to approach KD from a hypothesis-free and
compartment-specific angle, using state-of-the-art microdissection and gene
expression profiling technology. We sought to characterise expression differences
between specific keloid lesional sites and elucidate potential contributions of
significantly dysregulated genes to mechanisms underlying keloid pathobiology,
thus informing future explorative research into KD. Here, we highlight the
advantages of our in situ microdissection strategy in generating expression data
with improved sensitivity and accuracy over traditional methods. This
methodological approach supports an active role for the epidermis in the
pathogenesis of KD through identification of genes and upstream regulators
implicated in epithelial-mesenchymal transition, inflammation and immune
modulation. We describe dermal expression patterns crucial to collagen deposition
that are associated with TGF?-mediated signalling, which have not previously been
examined in KD. Additionally, this study supports the previously proposed
presence of a cancer-like stem cell population in KD and explores the possible
contribution of gene dysregulation to the resistance of KD to conventional
therapy. Through this innovative in situ microdissection gene profiling approach,
we provide better-defined gene signatures of distinct KD regions, thereby
addressing KD heterogeneity, facilitating differential diagnosis with other
cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas
for future KD research.