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

Sami Ventelä,Juho-Antti Mäkelä,Eleonora Sittig,Leni Mannermaa,Eliisa Löyttyniemi,Jukka Westermarck,Reidar Grénman,Jarmo Kulmala,Jorma Toppari,Leena Strauss,Olli Cárpen

doi:10.18632/oncotarget.2670

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.

Highlights

Head and neck cancer is the 6th most common cancer worldwide and 90% of these cancers are diagnosed as head and neck squamous cell carcinoma (HNSCC)
Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is expressed in testicular stem cell/ progenitor population (Fig. 1A) and our recent results suggest that CIP2A promotes self-renewal of normal testicular spermatogonia expressing Octamer-binding transcription factor 4 (Oct4) and Plzf [29]
These results indicate that expression of both CIP2A and Oct4 is linked to cellular radioresistance in vivo

Summary

Introduction

Head and neck cancer is the 6th most common cancer worldwide and 90% of these cancers are diagnosed as HNSCCs (head and neck squamous cell carcinoma, [1]). Many different approaches have been introduced to clarify the cause of HNSCC aggressiveness and poor patient survival These include mutation analyses [3,4,5], locoregional diversity of HNSCC cancers [6] and mechanisms of radio/chemosensitivity [7, 8]. Features linked to cancer stem cells, such as self-renewal and pluripotency www.impactjournals.com/oncotarget have been hypothesized to be one explanation for the aggressiveness and therapy resistancy of HNSCCs [9, 10]. Despite these activities, the mechanisms behind recurrency of HNSCC cancers after adjuvant therapies are still poorly understood. Identification of mechanisms behind radioresistancy of HNSCC cells might provide novel opportunities for radiosensitation of HNSCC cells

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