Abstract
The water channel aquaporin 1 (AQP1) has been implicated in tumor progression and metastasis. It is hypothesized that AQP1 expression can facilitate the transmembrane water transport leading to changes in cell structure that promote migration. Its impact in neuroblastoma has not been addressed so far. The objectives of this study have been to determine whether AQP1 expression in neuroblastoma is dependent on hypoxia, to demonstrate whether AQP1 is functionally relevant for migration, and to further define AQP1-dependent properties of the migrating cells. This was determined by investigating the reaction of neuroblastoma cell lines, particularly SH-SY5Y, Kelly, SH-EP Tet-21/N and SK-N-BE(2)-M17 to hypoxia, quantitating the AQP1-related water permeability by stopped-flow spectroscopy, and studying the migration-related properties of the cells in a modified transwell assay. We find that AQP1 expression in neuroblastoma cells is up-regulated by hypoxic conditions, and that increased AQP1 expression enabled the cells to form a phenotype which is associated with migratory properties and increased cell agility. This suggests that the hypoxic tumor microenvironment is the trigger for some tumor cells to transition to a migratory phenotype. We demonstrate that migrating tumor cell express elevated AQP1 levels and a hypoxic biochemical phenotype. Our experiments strongly suggest that elevated AQP1 might be a key driver in transitioning stable tumor cells to migrating tumor cells in a hypoxic microenvironment.
Highlights
aquaporin 1 (AQP1) was the first molecular water channel to be described (Preston et al, 1992)
AQP1 expression of neuroblastoma cell was evaluated by immunohistochemistry, quantitative PCR and western blotting under normoxic and hypoxic conditions
Exposure of neuroblastoma cell lines Kelly, SH-SY5Y, SK-N-B(2)-M17, and SH-EP Tet-21/N to hypoxia led to an increase of AQP1 expression detected by immunohistochemistry in Kelly and to a lesser degree in SH-SY5Y cells (Figure 1A)
Summary
AQP1 was the first molecular water channel to be described (Preston et al, 1992). It is located in the plasma membrane and physiologically predominantly found in red blood cells, kidney, lung, vascular endothelium, brain and eye (King et al, 2004). AQP1 has been reported to be associated with a poor prognosis, especially in later stages of colon cancer, lung cancer and breast cancer (Otterbach et al, 2010; Machida et al, 2011; Yoshida et al, 2013) In these stages, hypoxia within the solid tumor is increasing. There is evidence that HIF-1α facilitates upregulation of other aquaporins, namely AQP4 and AQP9, in a rat model of traumatic brain injury (Ding et al, 2009). This could suggest that AQP1 is regulated by mechanisms within the hypoxic tumor microenvironment
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