title: Bone destruction by invading oral squamous carcinoma cells mediated by the transforming growth factor-beta signalling pathway.
abstract: BACKGROUND
  Gingival squamous cell carcinoma (SCC) cells frequently invade mandibular bone, and this destruction is associated with a worse prognosis. However, the relationship between bone destruction and associated factors is unclear. In this study, the role and diagnostic utility of transforming growth factor-beta (TGF-beta) type I receptor (TbetaRI) in bone destruction of the mandible was investigated.
  
  
  METHODS
  The expression of TbetaRI was explored by using an immunohistochemical method on paraffin-embedded tissues from 21 cases of mandibular SCC. An inhibitor of the kinase activity of the TbetaRI (TbetaRI-I) was used to assess the role of TbetaRI in bone destruction by a human oral SCC cell line (HSC-2) that highly expresses TbetaRI.
  
  
  RESULTS
  TbetaRI-positive signals were closely associated with destructive invasion of the mandible by oral SCC cells. Consistent with these results, TbetaRI-I greatly reduced HSC-2 cell-induced bone destruction and osteoclast formation in vivo and in vitro. TbetaRI-I treatment reduced the expression of TNF-alpha, RANKL and connective tissue growth factor (CTGF/CCN2), all of which were up-regulated by TGF-beta in HSC-2 cells.
  
  
  CONCLUSIONS
  These data demonstrated an important role for TGF-beta signalling in bone invasion by oral SCC cells, and suggest that the bone destruction is mediated by RANKL, TNF-alpha and CCN2.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikatacho, Okayama 700-8525, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Goda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimo
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Yoshihama
authors.forename: Nur Mohammad Monsur
authors.initials: NM
authors.lastname: Hassan
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ibaragi
authors.forename: Naito
authors.initials: N
authors.lastname: Kurio
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Okui
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Honami
authors.forename: Koji
authors.initials: K
authors.lastname: Kishimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sasaki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005887:Gingival Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: C526317:CCN2 protein, human; D053245:RANK Ligand; D018125:Receptors, Transforming Growth Factor beta; C505688:TNFSF11 protein, human; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I