title: Anti-apoptotic role of the sonic hedgehog signaling pathway in the proliferation of ameloblastoma.
abstract: Sonic hedgehog (SHH) signaling pathway is crucial to growth and patterning during organogenesis. Aberrant activation of the SHH signaling pathway can result in tumor formation. We examined the expression of SHH signaling molecules and investigated the involvement of the SHH pathway in the proliferation of ameloblastoma, the most common benign tumor of the jaws. We used immunohistochemistry on ameloblastoma specimens and immunocytochemistry and reverse transcription-PCR on the ameloblastoma cell line AM-1. We also used the inhibitors of SHH signaling, SHH neutralizing antibody and cyclopamine, to assess the effects of SHH on the proliferation of AM-1 cells. We detected expression of SHH, patched, GLI1, GLI2 and GLI3 in the ameloblastoma specimens and AM-1 cells. The proliferation of these cells was significantly inhibited in the presence of SHH neutralizing antibody or cyclopamine; this was confirmed by BrdU incorporation assays. Furthermore, in the presence of SHH neutralizing antibody, nuclear translocation of GLI1 and GLI2 was abolished, apoptosis was induced, BCL-2 expression decreased and BAX expression increased. Our results suggest that the SHH signaling pathway is constitutively active in ameloblastoma and plays an anti-apoptotic role in the proliferation of ameloblastoma cells through autocrine loop stimulation.
authors.affiliation: Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Kanda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mitsuyasu
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakao
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kawano
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Ryota
authors.initials: R
authors.lastname: Matsubara
authors.forename: Seiji
authors.initials: S
authors.lastname: Nakamura
mesh_terms: D000564:Ameloblastoma / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007573:Jaw Neoplasms / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C509239:SHH protein, human; D051028:bcl-2-Associated X Protein