Oncotarget

Research Papers:

Nuclear p16INK4a expression predicts enhanced radiation response in head and neck cancers

Rüveyda Dok _, Layka Abbasi Asbagh, Evert Jan Van Limbergen, Anna Sablina and Sandra Nuyts

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Oncotarget. 2016; 7:38785-38795. https://doi.org/10.18632/oncotarget.9609

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Abstract

Rüveyda Dok1, Layka Abbasi Asbagh2,3, Evert Jan Van Limbergen1,4,5, Anna Sablina2,3, Sandra Nuyts1,4

1Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium

2VIB Center for the Biology of Disease, Leuven, Belgium

3Department of Human Genetics, KU Leuven, University of Leuven, Leuven, Belgium

4Department of Radiation Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium

5Current address: Maastro Clinic, Maastricht, The Netherlands

Correspondence to:

Sandra Nuyts, email: [email protected]

Keywords: nuclear p16INK4a expression, head and neck cancers, radiotherapy, DNA repair, HPV

Received: February 12, 2016    Accepted: April 29, 2016    Published: May 26, 2016

ABSTRACT

Immunohistochemistry analysis of p16INK4a in head and neck squamous cell carcinomas (HNSCC) tumor samples revealed that 28% of tumors showed nuclear/cytoplasmic p16INK4a localization, while 37% of tumors had cytoplasmic p16INK4a. Our previous study showed that p16INK4a inhibits the DNA repair response independently of its function in the cell cycle, suggesting that p16INK4a subcellular localization should be considered during stratification of HNSCC patients.

Using p16INK4a mutants with different localization signals, we found that expression of nuclear p16INK4a, but not cytoplasmic p16INK4a impaired RAD51 foci formation, indicating that nuclear localization of p16INK4a is crucial for its function in DNA repair. We next investigated the role of p16INK4a subcellular localization in radiation response in a retrospective cohort of 261 HNSCC patients treated with chemoradiation. We found that only HNSCC patients expressing nuclear p16INK4a expression showed better outcome, locoregional control and disease free survival, after chemoradiation. In concordance with the patient data, only expression of nuclear p16INK4a increased radiosensitivity of HNSCC cells. These results implicate nuclear p16INK4a expression as a potent marker to predict radiation response of HNSCC patients and should be taken into account in intensification or de-escalation studies.


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