Identification of estrogen response element in the aquaporin-2 gene that mediates estrogen-induced cell migration and invasion in human endometrial carcinoma

BACKGROUND: Accumulating evidence suggests that aquaporins (AQP) can facilitate cell migration, invasion, and proliferation in tumor development in addition to water transport. OBJECTIVE: The aim of this study was to examine AQP2 expression in the endometrial tissues from patients with endometrial carcinoma (EC) and determine the roles and mechanisms of AQP2 in estrogen-related cell migration, invasion, adhesion, and proliferation of Ishikawa (IK) cells. APPROACH: AQP2 expression levels were measured in human endometrial cells and estradiol (E(2))-treated IK cells, and the estrogen-response element was identified. After blocking down and up-regulating the endogenous expression of AQP2 in IK cells, cell morphology, capacity for invasion, migration and adhesion, and expression markers of membrane/cytoskeleton were analyzed. RESULTS: AQP2 was expressed in endometrial tissues from patients with EC and endometriosis, both of which are estrogen-dependent diseases. In IK cells, E(2) dose-dependently increased AQP2 expression, which was blocked by the estrogen receptor inhibitor ICI182780. An estrogen-response element was identified in the AQP2 promoter. E(2) significantly increased the migration, invasion, adhesion, and proliferation of IK cells. AQP2 knockdown attenuated E(2)-enhanced migration, invasion, and adhesion. AQP2 knockdown reduced not only the E(2)-enhanced expression of F-actin and annexin-2 but also the E(2)-induced alteration of cell morphology. Moreover, higher expression levels of F-actin and annexin-2 were detected in the endometrial tissues from patients with EC. CONCLUSIONS: AQP2 mediates E(2)-enhanced migration, invasion, and adhesion through alteration of F-actin and annexin-2 expression and reorganization of F-actin, and inhibition of AQP may be a potential method for antitumor therapy.