title: Potential role for inhibition of protein phosphatase 2A tumor suppressor in salivary gland malignancies.
abstract: The aetiology and pathogenesis of salivary gland malignancies remain unknown. To reveal novel molecular factors behind the development of salivary gland cancer, we performed gene expression analyses from Smgb-Tag mouse salivary gland samples. The overall purpose was to apply these results for clinical use to find new approaches for both possible therapeutic targets and more accurate diagnostic tools. Smgb-Tag mouse strain, in which salivary neoplasms arise through a dysplastic phase in submandibular glands, was investigated using genome-wide microarray expression analysis, ingenuity pathway analysis, RT-PCR, and immunohistochemistry. Thirty-eight human salivary gland adenoid cystic carcinoma samples were investigated using immunohistochemistry for validation purposes. Our genome-wide study showed that Ppp2r1b, a PP2A subunit encoding tumor suppressor gene, is underexpressed in submandibular gland tumors of Smgb-Tag mice. mTOR signaling pathway was significantly enriched and mTOR linked PP2A subunit gene B55 gamma was significantly underexpressed in the analyses. Furthermore, parallel immunohistochemical analysis of three PP2A inhibitors demonstrated that two PP2A inhibitors, CIP2A and SET, are highly expressed in both dysplastic and adenocarcinomatous tumors of the Smgb-Tag mice. In addition, all 38 investigated human salivary adenoid cystic carcinoma samples stained positively for CIP2A and most for SET. Finally, p-S6 staining showed activation of mTOR pathway in human adenoid cystic carcinoma samples. Our results suggest that PP2A inhibition either via PP2A subunit underexpression or PP2A inhibitor overexpression play an important role in the formation of salivary gland malignancy, potentially due to mTOR signaling activation.
authors.affiliation: The Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu, BioCity, Turku, FI-20521, Finland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Routila
authors.affiliation: Department of Physiology, University of Turku, Kiinamyllynkatu 10, Turku, FI-20520, Finland.
authors.forename: Juho-Antti
authors.initials: JA
authors.lastname: Mäkelä
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, FI-20521, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Luukkaa
authors.affiliation: Department of Pathology, University of Turku, Kiinamyllynkatu 10, Turku, FI-20520, Finland.
authors.forename: Ilmo
authors.initials: I
authors.lastname: Leivo
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, FI-20521, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Irjala
authors.affiliation: The Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu, BioCity, Turku, FI-20521, Finland.|Department of Pathology, University of Turku, Kiinamyllynkatu 10, Turku, FI-20520, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Central Hospital and University of Helsinki, HUCH, Helsinki, FI-00029, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Mäkitie
authors.affiliation: The Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu, BioCity, Turku, FI-20521, Finland.|Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, FI-20521, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Ventelä
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D051381:Rats; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D012471:Salivary Proteins and Peptides / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056488:Histone Chaperones; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C513473:SET protein, human; D012471:Salivary Proteins and Peptides; D014157:Transcription Factors; C072564:Smgb Protein, rat; D054648:Protein Phosphatase 2