title: Epithelial to mesenchymal transition in gingival overgrowth.
abstract: Epithelial to mesenchymal transition (EMT) occurs normally in development. In pathology, EMT drives cancer and fibrosis. Medication with phenytoin, nifedipine, and cyclosporine-A often causes gingival overgrowth. Based partly on the histopathology of gingival overgrowth, the present study investigates the hypothesis that EMT could contribute to its development. We found that phenytoin-induced human gingival overgrowth tissues, the most fibrotic drug-induced variety, contain diminished epithelial E-cadherin expression, whereas fibroblast-specific protein-1 (FSP-1) and alphavbeta6 integrin levels are up-regulated. In connective tissue stroma, fibronectin and alternatively spliced fibronectin extra type III domain A (FN-ED-A) levels are increased in overgrowth lesions. Transforming growth factor (TGF)-beta1 treatment of primary human gingival epithelial cells cultured in transwell plates resulted in inhibited barrier function as determined by reduced electrical resistance, paracellular permeability assays, and cell surface E-cadherin expression. Moreover, TGF-beta1 altered the expression of other markers of EMT determined at the mRNA and protein levels: E-cadherin decreased, whereas SLUG, fibronectin, matrix metalloproteinase (MMP)2, MMP9, and MMP13 increased. Nifedipine- and cyclosporine A-induced gingival overgrowth tissues similarly contain diminished E-cadherin and elevated levels of FSP-1 and fibronectin, but normal levels of alphavbeta6 integrin. In summary, data in vitro support that human gingival epithelial cells undergo functional and gene expression changes consistent with EMT in response to TGF-beta1, and in vivo studies show that important EMT markers occur in clinical gingival overgrowth tissues. These findings support the hypothesis that EMT likely occurs in drug-induced gingival overgrowth.
authors.affiliation: Department of Periodontology and Oral Biology, Boston University, Henry M. Goldman School of Dental Medicine, 700 Albany Street W-201, Boston, MA 02118, USA.
authors.forename: Siddika Selva
authors.initials: SS
authors.lastname: Sume
authors.forename: Alpdogan
authors.initials: A
authors.lastname: Kantarci
authors.forename: Alan
authors.initials: A
authors.lastname: Lee
authors.forename: Hatice
authors.initials: H
authors.lastname: Hasturk
authors.forename: Philip C
authors.initials: PC
authors.lastname: Trackman
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects; D000951:Antigens, Neoplasm / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D005881:Gingiva / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D010672:Phenytoin / Q000009:adverse effects; D000071999:S100 Calcium-Binding Protein A4; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D000951:Antigens, Neoplasm; D015820:Cadherins; D002135:Calcium-Binding Proteins; D005353:Fibronectins; D016023:Integrins; D000071999:S100 Calcium-Binding Protein A4; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; C077591:S100A4 protein, human; D010672:Phenytoin