Abstract
BackgroundAquaporin (AQP) 1 expression has been linked with tumor malignancy but its role in glioblastoma (GBM), a lethal glioma, remains to be clarified.MethodsAQP1 expression was examined in 33 human GBM specimens by immunohistochemistry. GBM cells (U251 and U87) that stably express AQP1 were established and used for cellular proliferation, migration, invasion, and vascular tube formation assays. The GeneChip assay was used to identify differentially expressed genes in AQP1‐expressing cells.ResultsAQP1 was expressed only in tumor cells. AQP1 dose‐dependently accelerated cell migration and invasion, but not proliferation, in GBM cell lines. AQP1 also upregulated cathepsin B, focal adhesion kinase and activities of matrix metalloproteinase 9. AQP1 in GBM cells induced wall thickness of ECV304, vascular endothelial cells, in a contact‐dependent manner. Downregulation of thrombospondin type 1 domain containing 7A (THSD7A) was identified in AQP1‐expressing GBM cells in vitro, and was negatively correlated with AQP1 expression in human GBM specimens.ConclusionAQP1 is involved in tumor malignancy by facilitating the migration and invasion of GBM cells, and promoting the formation of vascular beds that are characteristic of GBM by downregulating THSD7A.
Highlights
Gliomas are the most common primary brain tumors
Consistent with the qualitative real-time (qRT)-polymerase chain reaction (PCR) and western blotting results, we found that the U251-c18 and U87-c15 clones had the highest AQP1 expression levels (Figure 2E,F respectively)
To characterize the potential mechanisms by which AQP1 enhances the migration and invasion of GBM cells in vitro, we evaluated the expression of cathepsin B and focal adhesion kinase (FAK), proteins that regulate cell migration and invasion, in the AQP1-expressing U251 and U87 cells and control cells by western blot analysis.[22,23]
Summary
Gliomas are the most common primary brain tumors. Astrocytoma, a type of glioma, can be categorized into grades I-IV, from the lowest to the highest degree of malignancy, according to the World Health Organization Classification of Tumors. Aquaporins (AQPs) are small channel-forming transmembrane proteins that facilitate rapid transport of water and small solutes across biological membranes.[2] Thirteen AQPs have been identified in humans.[3] AQP1 was the first AQP discovered in mammals.[4] AQP1 expression has been reported in the choroid plexus, kidney, corneal endothelium, and vascular endothelial cells.[5,6] In addition, AQP1 is overexpressed in various human cancers, including biliary duct, bladder, breast, cervix, lung, prostate, nasopharynx, and brain cancers.[7] Previous studies have shown that the expression of AQP1 is positively associated with invasion, angiogenesis, cell migration, and the formation of edema in malignant tumors,[7,8,9,10,11] and high-grade astrocytomas express higher levels of AQP1 than low-grade astrocytomas.[12] Upregulation of AQP1 occurs predominantly in the perivascular space that is distant from the necrotic tumor core and has high tumor infiltration.[8] In addition, tumor microvessel proliferation is impaired in AQP1-deficient mice.[11] This evidence suggests that AQP1 upregulation causes an increase in blood vessel formation. The results of this study may enhance our understanding of the mechanisms underlying the involvement of AQP1 in GBM malignancy
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