title: Positive and negative regulation of podoplanin expression by TGF-β and histone deacetylase inhibitors in oral and pharyngeal squamous cell carcinoma cell lines.
abstract: OBJECTIVE
  Podoplanin, a transmembrane sialomucin-like glycoprotein, is known to express at high frequency in oral squamous cell carcinomas (OSCC) and possess metastasis-promoting activity such as increased invasion and platelet-aggregating activity. However, the regulatory mechanism of podoplanin expression in OSCC remains unknown.
  
  
  METHODS
  In the present study, we investigated the podoplanin expression in both clinical specimens from total 80 patients (50 OSCC and 30 pharyngeal SCC) and in 4 OSCC cell lines in vitro.
  
  
  RESULTS
  Immunohistochemical analysis of surgically resected specimens of OSCC revealed podoplanin expression in 70% of OSCC cases with localization primarily in the basal layer of squamous cancer nest and the expression was inversely correlated with squamous cell differentiation. In vitro analysis of OSCC cell lines revealed 36 that podoplanin expression was decreased in response to the squamous cell differentiation (Cytokeratin 10 expression as a marker) induced by treatment with histone deacetylase (HDAC) inhibitors such as sodium butyrate and trichostatin. Furthermore, transforming growth factor-β (TGF-β) significantly enhanced podoplanin expression in OSCC cell lines in line with increased phosphorylation of Smad2. A TGF-β type I receptor inhibitor (SB431542) significantly inhibited such induction of podoplanin expression by TGF-β at both the protein and mRNA level. However, in a subset of OSCC cell line, its expression was only weakly dependent on TGF-β and squamous differentiation.
  
  
  CONCLUSIONS
  These results suggest that regulation of podoplanin is not simple, but in the majority of OSCC cell lines, its expression is positively and negatively regulated by TGF-β receptor/Smad signaling pathway and epigenetic mechanism leading to squamous differentiation, respectively.
authors: The First Department of Oral and Maxillofacial Surgery, School of Dentistry, Aichi-Gakuin University, Nagoya 464-8651, Japan.
authors: Mitsuhiko
authors: M
authors: Ohta
authors: Atsushi
authors: A
authors: Abe
authors: Fumi
authors: F
authors: Ohno
authors: Yasuhisa
authors: Y
authors: Hasegawa
authors: Harunari
authors: H
authors: Tanaka
authors: Shinichiro
authors: S
authors: Maseki
authors: Eisaku
authors: E
authors: Kondo
authors: Kenichi
authors: K
authors: Kurita
authors: Hayao
authors: H
authors: Nakanishi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis; D002087:Butyrates / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000556:secondary; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D053550:Keratin-10 / Q000032:analysis; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010610:Pharyngeal Neoplasms / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000187:drug effects; D014062:Tongue Neoplasms / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000098853:Podoplanin
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D002087:Butyrates; D004149:Dioxoles; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053550:Keratin-10; D008562:Membrane Glycoproteins; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C507493:KRT10 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin; C497782:SMAD2 protein, human