title: CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance.
abstract: Radiotherapy is a mainstay for treatment of many human cancer types, including head and neck squamous cell carcinoma (HNSCC). Thereby, it is clinically very relevant to understand the mechanisms determining radioresistance. Here, we identify CIP2A as an Oct4 target gene and provide evidence that they co-operate in radioresistance. Oct4 positively regulates CIP2A expression both in testicular cancer cell lines as well as in embryonic stem cells. To expand the relevance of these findings we show that Oct4 and CIP2A are co-expressed in CD24 positive side-population of patient-derived HNSCC cell lines. Most importantly, all Oct4 positive HNSCC patient samples were CIP2A positive and this double positivity was linked to poor differentiation level, and predicted for decreased patient survival among radiotherapy treated HNSCC patients. Oct4 and CIP2A expression was also linked with increased aggressiveness and radioresistancy in HNSCC cell lines. Together we demonstrate that CIP2A is a novel Oct4 target gene in stem cells and in human cancer cell lines. Clinically these results suggest that diagnostic evaluation of HNSCC tumors for Oct4 or Oct4/CIP2A positivity might help to predict HNSCC tumor radioresistancy. These results also identify both Oct4 and CIP2A as potential targets for radiosensitation.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland. Department of Physiology, University of Turku, Finland. Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital, Turku, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Ventelä
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Sittig
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland.
authors.forename: Leni
authors.initials: L
authors.lastname: Mannermaa
authors.affiliation: Department of Physiology, University of Turku, Finland.
authors.forename: Juho-Antti
authors.initials: JA
authors.lastname: Mäkelä
authors.affiliation: Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.
authors.forename: Jarmo
authors.initials: J
authors.lastname: Kulmala
authors.affiliation: Department of Biostatistics, University of Turku, Finland.
authors.forename: Eliisa
authors.initials: E
authors.lastname: Löyttyniemi
authors.affiliation: Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Strauss
authors.affiliation: Department of Pathology, University of Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Cárpen
authors.affiliation: Department of Physiology, University of Turku, Finland. Department of Pediatrics, Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital, Turku, Finland.
authors.forename: Reidar
authors.initials: R
authors.lastname: Grénman
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland. Department of Pathology, University of Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D001755:Blastocyst / Q000166:cytology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009373:Neoplasms, Germ Cell and Embryonal / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011836:Radiation Tolerance; D000077195:Squamous Cell Carcinoma of Head and Neck; D013736:Testicular Neoplasms / Q000378:metabolism; D013737:Testis / Q000378:metabolism*
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human