Abstract
Background
Aquaporin 1 (AQP1) is a membrane protein whose main function is to transfer water via cellular membranes. Recent studies have described important roles for AQP1 in epithelial carcinogenesis and tumor behavior. The objectives of the present study were to investigate the role of AQP1 in the regulation of genes involved in tumor progression and the clinicopathological significance of its expression in esophageal squamous cell carcinoma (ESCC).
Methods
Immunohistochemistry for the AQP1 protein was performed to investigate the expression of AQP1 in primary tumor tissues of 50 human ESCC samples underwent curative esophagectomy. Samples were categorized into two groups according to the expression of AQP1 in each of cytoplasm and nuclear membrane, and relationships with the clinicopathological features and prognosis of ESCC patients were investigated. Next, the location of AQP1 protein in TE5, TE15, and KYSE70 cells was investigated using immunofluorescence analysis. In addition, apoptosis assay was performed in these ESCC cells and the gene expression profiles of AQP1-depleted TE5 cells was analyzed using microarray and bioinformatic studies.
Results
In an immunohistochemical analysis, AQP1 was primarily located in the cytoplasm and/or the nuclear membrane of carcinoma cells. The 5-year survival rate of patients with the ‘cytoplasm dominant’ expression of AQP1 (46.8%) was significantly lower than other patients (77.6%). A multivariate analysis of the 5-year overall survival rate showed that the pT categories and cytoplasm dominance groups of AQP1 were independent prognostic factors (P = 0.042 and 0.036, respectively). Immunofluorescence analysis revealed that AQP1 protein mainly existed in the cytoplasm in TE5 and TE15 cells. On the other hand, the expression of AQP1 in KYSE170 cells was confirmed on the nuclear membrane. The depletion of AQP1 using siRNA induced apoptosis in TE5 and TE15 cells. The results of microarray analysis revealed that Death receptor signaling pathway-related genes were changed in AQP1-depleted TE5 cells.
Conclusion
The results of the present study suggested that the cytoplasm dominant expression of AQP1 is related to a poor prognosis in patients with ESCC, and that it regulates tumor progression by affecting Death receptor signaling pathway. These results provide insights into the role of AQP1 as a biomarker for ESCC.
Disclosure
All authors have declared no conflicts of interest.
Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice