title: Oxidative stress activation of miR-125b is part of the molecular switch for Hailey-Hailey disease manifestation.
abstract: Hailey-Hailey disease (HHD) is an autosomal dominant disorder characterized by suprabasal cutaneous cell separation (acantholysis) leading to the development of erosive and oozing skin lesion. Micro RNAs (miRNAs) are endogenous post-transcriptional modulators of gene expression with critical functions in health and disease. Here, we evaluated whether the expression of specific miRNAs may play a role in the pathogenesis of HHD. Here, we report that miRNAs are expressed in a non-random manner in Hailey-Hailey patients. miR-125b appeared a promising candidate for playing a role in HHD manifestation. Both Notch1 and p63 are part of a regulatory signalling whose function is essential for the control of keratinocyte proliferation and differentiation and of note, the expression of both Notch1 and p63 is downregulated in HHD-derived keratinocytes. We found that both Notch1 and p63 expression is strongly suppressed by miR-125b expression. Additionally, we found that miR-125b expression is increased by an oxidative stress-dependent mechanism. Our data suggest that oxidative stress-mediated induction of miR-125b plays a specific role in the pathogenesis of HHD by regulating the expression of factors playing an important role in keratinocyte proliferation and differentiation.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy National Centre for Rare Diseases Istituto Superiore di Sanità, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Manca
authors.forename: Armando
authors.initials: A
authors.lastname: Magrelli
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.forename: Karine
authors.initials: K
authors.lastname: Lefort
authors.forename: Roberto
authors.initials: R
authors.lastname: Ambra
authors.forename: Maurizio
authors.initials: M
authors.lastname: Alimandi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Biolcati
authors.forename: Daniela
authors.initials: D
authors.lastname: Uccelletti
authors.forename: Claudio
authors.initials: C
authors.lastname: Palleschi
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Eleonora
authors.initials: E
authors.lastname: Candi
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Marco
authors.initials: M
authors.lastname: Salvatore
authors.forename: Domenica
authors.initials: D
authors.lastname: Taruscio
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress; D016506:Pemphigus, Benign Familial / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D017931:DNA Primers; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins