title: TGF-β1, Smad-2/-3, Smad-1/-5/-8, and Smad-4 signaling factors are expressed in ameloblastomas, adenomatoid odontogenic tumors, and calcifying cystic odontogenic tumors: an immunohistochemical study.
abstract: OBJECTIVE
  The TGF-β/Smad signaling pathway regulates diverse cellular functions, including tooth development, and is involved in numerous pathological processes such as tumorigenesis. The aim of this study was to investigate the immunoexpression of the TGF-β/Smad signaling pathway members in ameloblastoma (AM), calcifying cystic odontogenic tumor (CCOT), and adenomatoid odontogenic tumor (AOT).
  
  
  METHODS
  This retrospective cross-sectional study included 65 tissue specimens: 34 AMs, 13 CCOTs, and 18 AOTs. Serial sections were immunohistochemically stained with TGF-β1, Smad-4, Smad-1/-5/-8, and Smad-2/-3 antibodies, and a semiquantitative measurement of the positive cells was carried out by two oral pathologists using a 0-3 scale (0: no immunoreactivity, 1: <20% positive cells, 2: 20-50% positive cells, 3: >50% positive cells).
  
  
  RESULTS
  All biomarkers studied were found significantly decreased in AM compared to CCOT and AOT. AOT and CCOT expressed Smad-1/-5/-8 more strongly compared to AM (OR = 11.66, P < 0.001 and OR = 5.34, P = 0.013, respectively), and Smad-2/-3 immunostaining was found significantly increased in CCOT (OR = 10.42, P = 0.001) and AOT (OR = 5.16, P < 0.004) compared to AM. Similarly, Smad-4 was expressed more strongly in AOT and CCOT compared to AM (P = 0.001), while AOT demonstrated a fivefold higher chance to express TGF-β1 compared to AM (P = 0.011).
  
  
  CONCLUSIONS
  TGF-β/Smad signaling pathway is activated in AM, AOT, and CCOT. The statistically significant reduced TGF-β1/Smad immunoexpression in AM compared to AOT/CCOT could be associated with the more aggressive biological behavior of AM including increased cell proliferation and reduced apoptosis and differentiation. Thus, the biomarkers TGF-β, Smad-4, Smad-1/-5/-8, and Smad-2/-3 could serve as supplementary diagnostic indices between odontogenic tumors of high and low neoplastic dynamics.
authors.affiliation: Department of Oral Pathology and Medicine, Dental School, University of Athens, Athens, Greece. vasia1996@yahoo.com
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Karathanasi
authors.forename: Konstantinos I
authors.initials: KI
authors.lastname: Tosios
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Nikitakis
authors.forename: Evangelia
authors.initials: E
authors.lastname: Piperi
authors.forename: Ioannis
authors.initials: I
authors.lastname: Koutlas
authors.forename: George
authors.initials: G
authors.lastname: Trimis
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sklavounou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000564:Ameloblastoma / Q000473:pathology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D018333:Odontogenic Cyst, Calcifying / Q000473:pathology*; D009808:Odontogenic Tumors / Q000473:pathology*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000032:analysis*; D051898:Smad1 Protein / Q000032:analysis; D051899:Smad2 Protein / Q000032:analysis; D051900:Smad3 Protein / Q000032:analysis; D051901:Smad4 Protein / Q000032:analysis; D051902:Smad5 Protein / Q000032:analysis; D051904:Smad8 Protein / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000032:analysis*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D053773:Transforming Growth Factor beta1