AQP-4 in peritumoral edematous tissue is correlated with the degree of glioma and with expression of VEGF and HIF-alpha

It is recognized that expression of AQP4 protein is much greater in gliomas than in normal tissue. The relationship between AQP4 and glioma-associated brain edema is affected by osmotic pressure and hypoxia. In this study, we detected changes of AQP4 expression in tumor and peritumoral edematous tissues to analyze the relationship between AQP4 protein and the edema index (EI). We also detected expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) to investigate their relationship with AQP4 protein, and thus to uncover the molecular biological mechanisms of AQP4 expression in glioma-associated brain edema. Sixty-five patients with brain glioma were divided into tumor and peritumor groups. Fresh tumor specimens, including six cases of grade I glioma, 18 of grade II, 11 of grade III and 30 of grade IV, and peritumoral edematous tissue specimens (1 cm distant from the tumor) were resected from these patients, and AQP4 protein expression levels were detected by western blot. Different AQP4 expression in the tumor and peritumor groups were compared. The relationship between AQP4 expression levels and the degree of peritumoral edema, and expression differences in different grades, were analyzed. Immunofluorescence cytochemistry was used to detect positive expression of AQP4 protein, VEGF protein, and HIF-1α protein in tumor tissue, and differences between expression were analyzed. Western blot showed that AQP4 expression in the peritumor (0.7697 ± 0.0941) and tumor (0.6934 ± 0.0625) groups was higher than in the control group (0.6215 ± 0.0884), and was highest in the peritumor group (both P < 0.01). AQP4 expression level in the peritumor group was positively correlated with EI (r = 0.677, P < 0.001) whereas AQP4 expression level in the tumor group was not correlated with EI (r = 0.096, P > 0.05). AQP4 expression increased with higher tumor grades in the peritumor group, but differences were not significant in the tumor group. Immunofluorescence cytochemical staining revealed that AQP4 protein in normal brain tissue was mainly expressed in the cell membrane surface, and that cytoplasm and nuclear staining was shallow. In glioma cells, AQP4 was widely distributed in the cytoplasm, particularly in the edematous area around the tumor. AQP4 protein expression in the tumor was significantly positively correlated with both VEGF protein (r = 0.877, P < 0.001) and HIF-1α protein (r = 0.876, P < 0.001). AQP4 expression was higher in brain tumor, especially peritumor. The degree of peritumoral edema correlates with AQP4 protein expression only in peritumor, whereas AQP4 expression is in accordance with expression of VEGF and HIF-1α. In glioma-associated brain edema, AQP4 is coregulated by osmotic pressure and hypoxia, with predominance of osmotic regulation, and is redistributed in glioma cells, mainly in the cytoplasm, and its expression level increased with higher glioma grades.