CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance

// Sami Ventelä 1, 2, 6 , Eleonora Sittig 1 , Leni Mannermaa 1 , Juho-Antti Mäkelä 2 , Jarmo Kulmala 8 , Eliisa Löyttyniemi 5 , Leena Strauss 3 , Olli Cárpen 4 , Jorma Toppari 2, 7 , Reidar Grénman 6 , Jukka Westermarck 1, 4 1 Turku Centre for Biotechnology, University of Turku and Åbo Akademi, Turku, Finland 2 Department of Physiology, University of Turku, Finland 3 Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, Finland 4 Department of Pathology, University of Turku, Finland 5 Department of Biostatistics, University of Turku, Finland 6 Department of Otorhinolaryngology – Head and Neck Surgery, Turku University Hospital, Turku, Finland 7 Department of Pediatrics, Turku University Hospital, Turku, Finland 8 Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland Correspondence to: Jukka Westermarck, e-mail: jukwes@utu.fi Keywords: Serine 62 phosphorylated MYC, PLZF, Nanog, spermatogonia, PP2A, tissue microarray, CD44+, CD24+ Received: April 24, 2014 Accepted: November 02, 2014 Published: December 01, 2014 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.