A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

Abstract

Keloid disease is a fibroproliferative tumour characterised 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 oncogene in keloid margin dermis, leading to the hypothesis that NRG1 contributed to keloid margin migration through ErbB2-mediated signalling. The aim of this study was to probe this hypothesis through functional in vitro studies. Exogenous NRG1 addition to keloid and normal skin fibroblasts altered cytokine expression 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 potential new therapeutic target.

Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts

“…Our finding that ErbB receptor signaling occurs in human cardiac ventricular fibroblasts builds upon our previous work demonstrating ErbB receptor expression in rat and mouse cardiac stromal cells [27], as well as that by other investigators showing that ErbB receptor expression in fibroblasts from other tissues [28], most recently in skin fibroblasts [29,30]. …”

The Keloid Disorder: Heterogeneity, Histopathology, Mechanisms and Models

“…The normal skin directly adjacent to and surrounding keloid scars is also rarely included in keloid research. Although similarity to normal skin has been reported (Jumper et al, 2017), the majority of reported results suggest that the surrounding normal skin behaves more like keloid tissue than normal skin. For example, the surrounding normal skin often itches like the keloid periphery and shows increased blood flow compared with unaffected normal skin (Liu et al, 2016).…”

“…In line with their invasive nature, keloid fibroblasts also show increased migration (Fujiwara et al, 2005a;Lim et al, 2006;Witt et al, 2008;Wen et al, 2011;Syed and Bayat, 2012;Wang et al, 2013;Fang et al, 2016;Jumper et al, 2017;Hsu et al, 2018) and capacity for invasion in 3D invasion assays (Dienus et al, 2010;He et al, 2012;Syed and Bayat, 2012;Wang et al, 2018). Furthermore, increased metabolic activity (Meenakshi et al, 2005;Vincent et al, 2008), increased ECM synthesis (McCoy et al, 1982;Abergel et al, 1987;Ala-Kokko et al, 1987;Babu et al, 1989;Berman and Duncan, 1989;Suzawa et al, 1992;Fujiwara et al, 2005a;Ong et al, 2007a;He et al, 2012) and deposition (Abergel et al, 1985;Uzawa et al, 2003;Fang et al, 2016) combined with reduced ECM degradation (Abergel et al, 1985;Berman and Duncan, 1989;Uchida et al, 2003;Yeh et al, 2006Yeh et al, , 2009Seifert et al, 2008;Russell et al, 2010;McFarland et al, 2011;Suarez et al, 2013), all contribute to the ECM overexpression and the resulting dermal protuberance that defines these scars (see Supplementary Table S3B).…”

AMF siRNA treatment of keloid through inhibition signaling pathway of RhoA/ROCK1

“…The growth of KD without self-limitation is a process of the migration of fibroblasts from the original growth site to normal skin 26 . The main features of KFs are excessive proliferation, antiapoptosis ability, and excessive synthesis and deposition of collagen 27, 28, 29. KDs have a rich blood supply and are associated with tumor-related genes and cytokines such as TGF-β, VEGF, and CTGF, and its pathogenesis has gene regulation similar to that of tumor; therefore, KD has biological characteristics of malignant tumor 25 .…”