Impaired function of extracellular matrix 1 alters the fibrogenic and carcinogenic properties: implications of underlying mechanisms for the pathogenesis of lichen sclerosus

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16334
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: University of Fukui
• Principal Investigator: Utsunomiya Natsuko 福井大学, 学術研究院医学系部門(附属病院部), 医員 (50792090)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 硬化性苔癬 / ECM1 / 自己抗体 / 基底膜

Outline of Final Research Achievements

Lichen sclerosus (LS) is an acquired inflammatory dermatosis that mainly affects anogenital area. Serum autoantibodies to extracellular matrix protein 1 (ECM1) in patients may hold clues in the underlying pathogenesis of LS. cDNA microarray comparing between ECM1-knockdown and control fibroblasts identified 3,035 differentially expressed genes, which related exclusively to protein binding for cell adhesion and proliferation, apoptosis, intracellular signaling, and extracellular matrix organization. Of these, laminin-332 and collagen-IV displayed unique immunolabeling of the basement membrane zone and dermal vessels in the LS skin by ECM1 knockdown. ECM1-knockdown fibroblasts exhibited a marked delay in cell migration and gel contraction. ECM1 gene silencing may prime selective dysregulation and disassembly of structural and extracellular matrix molecules in fibroblasts, reflecting the microstructural disorganization in LS pathology.

Free Research Field

皮膚疾患

Academic Significance and Societal Importance of the Research Achievements

本研究では、抗体を指標とした硬化性苔癬の血清診断ならびに病勢把握ツールの開発に向けた臨床応用の可能性を追求しながら、患者血清中に存在する抗ECM1抗体の病的意義の解明を目指した。ヒト線維芽細胞を用いてECM1を特異的に発現を低下させると連動する線維化と癌化に関与する遺伝子を同定した。これらの成果は、硬化性苔癬の分子特異的な病態のさらなる真相解明に直結し、本症の早期診断や患者の生命予後を改善させる知見へと繋がる可能性が高いと考えられる。