☆ 4.7 Article Proceedings Paper

Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells

RADIOTHERAPY AND ONCOLOGY (2013)

期刊

RADIOTHERAPY AND ONCOLOGY

卷 108, 期 3, 页码 500-505

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ELSEVIER IRELAND LTD

DOI: 10.1016/j.radonc.2013.06.011

关键词

HPV; Hypoxia; Radiosensitivity; Gene expression; Head and neck cancer

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Oncology Radiology, Nuclear Medicine & Medical Imaging

资金

Danish Cancer Society
Danish Medical Research Council
EC FP7 project METOXIA [222741]
CIRRO - The Lundbeck Foundation Centre for Interventional Research in Radiation Oncology

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Background and purpose: HPV associated Head and Neck Squamous Cell Carcinoma (HNSCC) represents a distinct subgroup of HNSCC characterized by a favorable prognosis and a distinct molecular biology. Previous data from the randomized DAHANCA 5 trial indicated that HPV positive tumors did not benefit from hypoxic modifications by Nimorazole during radiotherapy, whereas a significant benefit was observed in the HPV negative tumors. However, more studies have demonstrated equal frequencies of hypoxic tumors among HPV-positive and HPV-negative tumors. The aim of the present study was to determine radiosensitivity, the impact of hypoxia and the effect of Nimorazole in HPV positive and HPV negative cell lines. Materials and method: The used cell lines were: UDSCC2, UMSCC47 and UPCISCC90 (HPV positive) and FaDu(DD), UTSCC33 and UTSCC5 (HPV negative). Cells were cultured under normoxic or hypoxic conditions, and gene expression levels of previously established hypoxia induced genes were assessed by qPCR. Cells were irradiated with various doses under normoxia, hypoxia or hypoxia +1 mM Nimorazole, and the clonogenic survival was determined. Results: The HPV positive and HPV negative cell lines exhibited similar patterns of upregulation of hypoxia induced genes in response to hypoxia. The HPV positive cell lines were up to 2.4 times more radiation sensitive than HPV negative cell lines. However, all HPV positive cells displayed the same response to hypoxia in radiosensitivity, with an OER in the range 2.3-2.9, and a sensitizer effect of Nimorazole of 1.13-1.29, similar to HPV negative cells. Conclusions: Although HPV positive cells had a markedly higher radiosensitivity compared to HPV negative cells, they displayed the same relative radioresistance under hypoxia and the same relative sensitizer effect of Nimorazole. The clinical observation that HPV positive patients do not seem to benefit from Nimorazole treatment is not due to inherent differences in hypoxia sensitivity or response to Nimorazole, but can be accounted for by the overall higher radiosensitivity of HPV positive cells. (C) 2013 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 108 (2013) 500-505

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p63 Directs Subtype-Specific Gene Expression in HPV plus Head and Neck Squamous Cell Carcinoma

Alexandra Ruth Glathar, Akinsola Oyelakin, Christian Gluck, Jonathan Bard, Satrajit Sinha

Summary: The heterogeneity of head and neck squamous cell carcinoma (HNSCC) is reflected in its diverse etiology, including Human Papillomavirus-positive (HPV+) HNSCC subtypes. One aggressive subtype of HPV+ HNSCC is characterized by elevated expression of genes involved in keratinization, which is regulated by the oncogenic transcription factor Delta Np63. The TP63 gene locus is frequently targeted by HPV integration, and HPV oncoproteins drive Delta Np63 expression, suggesting a functional link between Delta Np63 and HPV+ HNSCC that has not been explored. This study demonstrates that HPV+ HNSCCs can be classified based on Delta Np63 expression levels, and an associated gene signature profile is derived. The study also identifies crucial Delta Np63-bound super-enhancers that likely mediate subtype-specific gene expression in HPV+ HNSCC, anchored by the PI3K-mTOR pathway. These findings highlight the importance of Delta Np63 as a key regulator of oncogenic pathways in a specific subtype of HPV+ HNSCC, and suggest its potential as a biomarker for patient stratification and treatment choices.

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