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Open Access Research article

Effect of hypoxia on the expression of αB-crystallin in head and neck squamous cell carcinoma

Chantal van de Schootbrugge1, Elisabeth MJ Schults1, Johan Bussink2, Paul N Span2, Reidar Grénman3, Ger JM Pruijn1, Johannes HAM Kaanders2 and Wilbert C Boelens1*

Author Affiliations

1 Department of Biomolecular Chemistry, Institute for Molecules and Materials and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 271, RIMLS, PO Box 9101, 6500 HB Nijmegen, The Netherlands

2 Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands

3 Department of Otorhinolaryngology–Head and Neck Surgery, Turku University Hospital, University of Turku, PO Box 52, FI-20521 Turku, Finland

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BMC Cancer 2014, 14:252  doi:10.1186/1471-2407-14-252

Published: 11 April 2014

Abstract

Background

The presence of hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with therapeutic resistance and increased risk of metastasis formation. αB-crystallin (HspB5) is a small heat shock protein, which is also associated with metastasis formation in HNSCC. In this study, we investigated whether αB-crystallin protein expression is increased in hypoxic areas of HNSCC biopsies and analyzed whether hypoxia induces αB-crystallin expression in vitro and in this way may confer hypoxic cell survival.

Methods

In 38 HNSCC biopsies, the overlap between immunohistochemically stained αB-crystallin and pimonidazole-adducts (hypoxiamarker) was determined. Moreover, expression levels of αB-crystallin were analyzed in HNSCC cell lines under hypoxia and reoxygenation conditions and after exposure to reactive oxygen species (ROS) and the ROS scavenger N-acetylcysteine (NAC). siRNA-mediated knockdown was used to determine the influence of αB-crystallin on cell survival under hypoxic conditions.

Results

In all biopsies αB-crystallin was more abundantly present in hypoxic areas than in normoxic areas. Remarkably, hypoxia decreased αB-crystallin mRNA expression in the HNSCC cell lines. Only after reoxygenation, a condition that stimulates ROS formation, αB-crystallin expression was increased. αB-crystallin mRNA levels were also increased by extracellular ROS, and NAC abolished the reoxygenation-induced αB-crystallin upregulation. Moreover, it was found that decreased αB-crystallin levels reduced cell survival under hypoxic conditions.

Conclusions

We provide the first evidence that hypoxia stimulates upregulation of αB-crystallin in HNSCC. This upregulation was not caused by the low oxygen pressure, but more likely by ROS formation. The higher expression of αB-crystallin may lead to prolonged survival of these cells under hypoxic conditions.

Keywords:
CRYAB protein; HspB5; Carcinoma; Squamous cell of head and neck; Hypoxia; Reactive oxygen species; Hypoxic cell survival