title: Heparin-binding EGF-like growth factor promotes epithelial-mesenchymal transition in human keratinocytes.
abstract: We have shown that autocrine proliferation of human keratinocytes (KCs) is strongly dependent upon amphiregulin (AREG), whereas blockade of heparin-binding EGF-like growth factor (HB-EGF) inhibits KC migration in scratch wound assays. Here we demonstrate that expression of soluble HB-EGF (sHB-EGF) or full-length transmembrane HB-EGF (proHB-EGF), but not proAREG, results in profound increases in KC migration and invasiveness in monolayer culture. Coincident with these changes, HB-EGF significantly decreases mRNA expression of several epithelial markers including keratins 1, 5, 10, and 14 while increasing expression of markers of cellular motility including SNAI1, ZEB1, COX-2, and MMP1. Immunostaining revealed HB-EGF-induced expression of the mesenchymal protein vimentin and decreased expression of E-cadherin, as well as nuclear translocation of β-catenin. Suggestive of a trade-off between KC motility and proliferation, overexpression of HB-EGF also reduced KC growth by >90%. We also show that HB-EGF is strongly induced in regenerating epidermis after partial-thickness wounding of human skin. Taken together, our data suggest that expression of HB-EGF in human KCs triggers a migratory and invasive phenotype with many features of epithelial-mesenchymal transition (EMT), which may be beneficial in the context of cutaneous wound healing.
authors.affiliation: Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5675, USA. sstoll@umich.edu
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Stoll
authors.forename: Laure
authors.initials: L
authors.lastname: Rittié
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Johnson
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
mesh_terms: D066258:Amphiregulin; D015820:Cadherins / Q000096:biosynthesis; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D058750:Epithelial-Mesenchymal Transition; D006023:Glycoproteins / Q000096:biosynthesis; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology*; D007633:Keratins / Q000096:biosynthesis; D021381:Protein Transport; D014746:Vimentin / Q000096:biosynthesis; D014945:Wound Healing; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C495270:CTNNB1 protein, human; D015820:Cadherins; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D014746:Vimentin; D051176:beta Catenin; D007633:Keratins