S. Nisar1,2, J. L. Roberson1,5, B. C. Carney1,3, A. Alkhalil1, L. T. Moffatt1,4, J. W. Shupp1,2,3,4 1Firefighters’ Burn and Surgical Research Laboratory, MedStar Health Research Institute,Washington, DC, USA 2The Burn Center, MedStar Washington Hospital Center,Washington DC, WASHINGTON DC, USA 3Georgetown University School of Medicine,Department Of Biochemistry,Washington DC, DISTRICT OF COLUMBIA, USA 4Georgetown University School of Medicine,Department Of Surgery,Washington DC, WASHINGTON DC, USA 5The George Washington University School of Medicine and Health Sciences,Department Of Surgery,Washington DC, WASHINGTON DC, USA
Introduction:
Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease that presents as recurrent abscesses causing fistulous tracts and scarring in areas of apocrine glands. This is painful and debilitating condition leads to poor quality of life. Etiology of HS is multifactorial. NOTCH signaling pathway, involved in embryological development, cell differentiation, and signaling, has been implicated in the pathogenesis of HS, but is poorly understood. This study evaluates dysregulation of NOTCH and related signaling pathways in HS in an effort to identify potential therapeutic targets.
Methods:
Skin biopsies of lesional HS were collected during surgical excision under an IRB-approved protocol. Normal skin was collected from otherwise to be discarded panniculectomy samples and used as control. RNA was extracted and quantified and cDNA was generated via RT-PCR from 3 normal and 4 HS skin biopsies. A PCR array, containing 84 genes involved in and related to NOTCH pathway, was used to identify genes that are dysregulated in HS. Candidate genes were identified if there was 2.5 fold change in gene expression, compared to normal skin, in at least 2 of the HS samples.
Results:
NOTCH array analysis identified 3 genes with 2.5 fold upregulation in 2 out of 4 samples. Function and average fold change of each is as follows: KRT1 maintains skin integrity, (avg=1.76), UbD is involved in proteosomal degradation (avg=0.98) and CCNE1 regulates cell cycle (avg=2.45). Nine genes with 2.5 fold down-regulation were found. CCND1 regulates G1/S transition (avg=-3.23), Hey1 is involved in somite development (avg=-11.58), MFNG demarcates boundaries during embryological development (avg=-4.67), MMP7 is involved in tissue remodeling (avg=-5.10), Notch 4 leads to cell proliferation and differentiation (avg=-6.40), DLL4 encodes for NOTCH ligand (avg=-6.16), LFNG defines boundaries during embryological development (avg=-7.43), PPAR-g promotes adipocyte differentiation (avg=-13.92), and LMO2, has a role in yolk sac erythropoiesis (avg=-8.08). Furthermore, heat map anlaysis revealed one HS sample to have different gene expression profile compared to control and other HS samples (Figure).
Conclusion:
Genes involved in embryological development, and skin and adipocyte differentiation are dysregulated in HS samples when compared to normal skin. This is a novel finding and has not been previously reported. Furthermore, gene expression profile is different in one sample, likely due to an early stage of the disease. Work is ongoing to correlate the identified candidate genes with their respective protein levels by immunohistochemical analysis of formalin-preserved HS skin biopsies with the eventual goal of identifying molecular targets for treatment of HS.
