title: TGF-β1-dependent induction and nuclear translocation of FHL2 promotes keratin expression in pilomatricoma.
abstract: Pilomatricoma is a tumour derived from hair matrix cells, which shows progressive keratin expression. Tumorigenesis is frequently associated with activating mutations in β-catenin gene inducing nuclear expression of β-catenin protein. The present study analysed the role of transforming growth factor-β1 (TGF-β1) and four-and-a-half LIM domain protein 2 (FHL2) in pilomatricoma in synopsis with their expression patterns in human anagen hair. Human anagen hair showed TGF-β1 and nuclear FHL2 expression in the outer root sheath layer separated from nuclear β-catenin staining, which was observed in cells of matrix and inner root sheath layers. Correspondingly, 41 out of 50 pilomatricomas showed co-labelling of TGF-β1 and nuclear FHL2 in tumour cells, which mostly lacked nuclear β-catenin expression. Tumoural proliferation (ki67) was associated with nuclear β-catenin staining but not with expression of nuclear FHL2. In early pilomatricomas, TGF-β1 expression was observed in few peripheral tumour cells showing absent or faint nuclear FHL2 co-staining. TGF-β1 expression extended in growing tumours going along with strong nuclear FHL2 co-labelling as well as progressive keratin 14 and keratin 1 expression. In vitro, cultured human keratinocytes showed weak to marked autocrine TGF-β1 expression; in case of enhanced TGF-β1 expression associated with keratin 10 staining. TGF-β1-treatment of cultured human keratinocytes induced nuclear and cytoplasmatic FHL2 staining as well as keratin 14 staining. Accordingly, siRNA-mediated FHL2 knockdown of TGF-β1-stimulated keratinocytes reduced keratin 14 staining. In conclusion, tumoural TGF-β1 secretion seems to induce nuclear translocation of co-factor FHL2 mediating progressive keratin expression in pilomatricoma.
authors.affiliation: Institute of Pathology, University of Cologne Medical School, Kerpener Str. 62, 50924, Cologne, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Friedrichs
authors.forename: Dennis
authors.initials: D
authors.lastname: Fink
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kindler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006201:Hair Diseases / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D007633:Keratins / Q000096:biosynthesis*; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D018296:Pilomatrixoma / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult
chemical_list: C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D007633:Keratins