INVESTIGATIVE REPORT
A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration
via ErbB2-mediated Signaling
Natalie JUMPER 1 , Tom HODGKINSON 1,2 , Ralf PAUS 3,4 and Ardeshir BAYAT 1,3
1
Plastic and Reconstructive Surgery Research, Stopford Building, Manchester, 2 Centre for Tissue Injury and Repair, Institute of Inflammation
and Repair, 3 Centre for Dermatology Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK, and
4
Department of Dermatology, University of Münster, Münster, Germany
Keloid disease is a fibroproliferative tumour charac-
terised by aggressive local invasion, evident from a
clinically and histologically active migrating margin.
During combined laser capture microdissection and
microarray analysis-based in situ gene expression
profiling, we identified upregulation of the polypeptide
growth factor neuregulin-1 (NRG1) and ErbB2 onco-
gene in keloid margin dermis, leading to the hypothe-
sis that NRG1 contributed to keloid margin migration
through ErbB2-mediated signalling. The aim of this
study was to probe this hypothesis through functio-
nal in vitro studies. Exogenous NRG1 addition to keloid
and normal skin fibroblasts altered cytokine expres-
sion profiles, significantly increased in vitro migration
and keloid fibroblast Src and protein tyrosine kinase 2
(PTK2/FAK) gene expression. ErbB2 siRNA knockdown
attenuated both keloid fibroblast migration and Src/
PTK2 expression, which were not recovered following
NRG1 administration, suggesting the NRG1/ErbB2/
Src/PTK2 signaling pathway may be a novel regulator
of keloid fibroblast migration, and representing a po-
tential new therapeutic target.
Key words: keloid disease; laser capture microdissection; neu-
regulin-1; ErbB2; migration.
Accepted Nov 23, 2016; Epub ahead of print Nov 24, 2016
Acta Derm Venereol 2017; 97: 675–684.
Corr: Dr Ardeshir Bayat, Plastic & Reconstructive Surgery Research, In-
stitute of Inflammation & Repair, University of Manchester, Stopford Buil-
ding, Manchester M13 9PT, UK. E-mail: [email protected]
R
epresenting the extreme end of the cutaneous scar-
ring spectrum, keloid disease is a fibroproliferative
tumour characterised by excess extracellular matrix
(ECM) deposition, increased inflammatory cytokine
expression and aggressive local invasion (1). Although
keloid is often referred to as benign, in that it does not me-
tastasize, it behaves in a tumorigenic fashion by actively
invading adjacent normal skin and spreading beyond the
boundaries of the original wound (2, 3). To date, although
significant progress has been made, the mechanisms
underlying the migration required for keloid invasion
have not been fully elucidated. The invasion and spread
of keloid scars represent a significant clinical challenge
not currently controlled with available therapies (4, 5).
To embrace this challenge and address the concept
of keloid migration, we p