title: Porphyromonas gingivalis initiates a mesenchymal-like transition through ZEB1 in gingival epithelial cells.
abstract: The oral anaerobe Porphyromonas gingivalis is associated with the development of cancers including oral squamous cell carcinoma (OSCC). Here, we show that infection of gingival epithelial cells with P. gingivalis induces expression and nuclear localization of the ZEB1 transcription factor, which controls epithelial-mesenchymal transition. P. gingivalis also caused an increase in ZEB1 expression as a dual species community with Fusobacterium nucleatum or Streptococcus gordonii. Increased ZEB1 expression was associated with elevated ZEB1 promoter activity and did not require suppression of the miR-200 family of microRNAs. P. gingivalis strains lacking the FimA fimbrial protein were attenuated in their ability to induce ZEB1 expression. ZEB1 levels correlated with an increase in expression of mesenchymal markers, including vimentin and MMP-9, and with enhanced migration of epithelial cells into matrigel. Knockdown of ZEB1 with siRNA prevented the P. gingivalis-induced increase in mesenchymal markers and epithelial cell migration. Oral infection of mice by P. gingivalis increased ZEB1 levels in gingival tissues, and intracellular P. gingivalis were detected by antibody staining in biopsy samples from OSCC. These findings indicate that FimA-driven ZEB1 expression could provide a mechanistic basis for a P. gingivalis contribution to OSCC.
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Maryta N
authors.initials: MN
authors.lastname: Sztukowska
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Akintunde
authors.initials: A
authors.lastname: Ojo
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Saira
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Carenbauer
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Surgical and Hospital Dentistry, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Brain
authors.initials: B
authors.lastname: Shumway
authors.affiliation: School of Oral and Dental Sciences, University of Bristol, Bristol, UK.
authors.forename: Howard F
authors.initials: HF
authors.lastname: Jenkinson
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Darling
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
mesh_terms: D000818:Animals; D016866:Bacteroidaceae Infections / Q000378:metabolism / Q000382:microbiology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000382:microbiology; D002465:Cell Movement; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D010861:Fimbriae, Bacterial / Q000378:metabolism; D005786:Gene Expression Regulation; D005881:Gingiva / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D015603:Keratinocytes / Q000382:microbiology / Q000473:pathology; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics; D009062:Mouth Neoplasms / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000235:genetics / Q000472:pathogenicity*; D011401:Promoter Regions, Genetic; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1