Abstract
BackgroundThe 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.MethodsIn 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.ResultsIn 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.ConclusionsWe 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.
Highlights
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 associated with metastasis formation in HNSCC
Besides being mainly expressed in eye lens and muscle tissues [16], αB-crystallin can be found in several types of cancer, among which head and neck squamous cell carcinoma (HNSCC) [17,18,19] and breast carcinomas [20,21,22]. αB-crystallin expression is associated with metastasis formation in HNSCC and in breast carcinomas [19,23] and in other types of cancer, expression is often correlated with poor prognosis as well [12,13]
Results αB-crystallin protein is increased in the hypoxic areas of HNSCC biopsies The expression of αB-crystallin protein was analyzed in the hypoxic and normoxic regions present in sections of HNSCC biopsies of 38 different patients
Summary
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 associated with metastasis formation in HNSCC. ΑB-crystallin (HspB5) is a small heat shock protein, which is associated with metastasis formation in HNSCC. Hypoxia might be intermittent when the blood flow is restored after temporary vascular shutdown, which can αB-crystallin is a small heat shock protein, which can bind to partially unfolded proteins, thereby keeping them in a soluble state to prevent their aggregation [12,13]. It may protect cells from death induced by van de Schootbrugge et al BMC Cancer 2014, 14:252 http://www.biomedcentral.com/1471-2407/14/252 accumulation of unfolded proteins [14]. We analyzed whether the expression of αB-crystallin protein is affected in hypoxic regions of HNSCC’s and whether αB-crystallin knockdown influences cell survival under hypoxic stress
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