Abstract
PurposeThe aquaporin (AQP) family consists of a number of small integral membrane proteins that transport water and glycerol. AQPs are critical for trans-epithelial fluid transport. Recent reports demonstrated that AQPs, particularly AQP1 and AQP5, are expressed in high grade tumor cells of a variety of tissue origins, and that AQPs are involved in cell migration and metastasis. Based on this background, we examined whether AQP3, another important member of the AQP family, could facilitate cell migration in human breast cancers.MethodsPotential role of AQP3 was examined using two representative breast cancer cell lines (MDA-MB-231 and Bcap-37). Briefly, AQP3 expression was inhibited with a lentivirus construct that stably expressed shRNA against the AQP3 mRNA. AQP3 expression inhibition was verified with Western blot. Cell migration was examined using a wound scratch assay in the presence of fibroblast growth factor-2 (FGF-2). In additional experiments, AQP3 was inhibited by CuSO4. Fibroblast growth factor receptor (FGFR) kinase inhibitor PD173074, PI3K inhibitor LY294002, and MEK1/2 inhibitor PD98059 were used to dissect the molecular mechanism of FGF-2 induced AQP3 expression.ResultsFGF-2 treatment increased AQP3 expression and induced cell migration in a dose dependent manner. Silencing AQP3 expression by a lentiviral shRNA inhibited FGF-2 induced cell migration. CuSO4, a water transport inhibitor selective for AQP3, also suppressed FGF-2-induced cell migration. The FGFR kinase inhibitor PD173074, significantly inhibited FGF-2-induced AQP3 expression and cell migration. The PI3K inhibitor LY294002 and MEK1/2 inhibitor PD98059 inhibited, but not fully blocked, FGF-2-induced AQP3 expression and cell migration.ConclusionsAQP3 is required for FGF-2-induced cell migration in cultured human breast cancer cells. Our findings also suggest the importance of FGFR-PI3K and FGFR-ERK signaling in FGF-2-induced AQP3 expression. In summary, our findings suggest a novel function of AQP3 in cell migration and metastasis of breast cancers.
Highlights
Breast cancer is the most prevalent malignancy and the second leading cause of cancer death in women
AQP3 is required for fibroblast growth factor-2 (FGF-2)-induced cell migration in cultured human breast cancer cells
Our findings suggest the importance of Fibroblast growth factor receptor (FGFR)-PI3K and FGFR-ERK signaling in FGF-2-induced AQP3 expression
Summary
Breast cancer is the most prevalent malignancy and the second leading cause of cancer death in women. Significant progress has been made in tumor detection and treatment. Metastasis remains a significant cause of morbidity and mortality of this disease [1]. Growth factors control tumor cell invasion and migration, and metastasis. FGF-2 is one of those growth factors that are associated with cancer development, and has been demonstrated to be an essential regulator of epithelial cell proliferation, migration and angiogenesis [2]. The biological activities of FGF-2 are meditated by a dual receptor system consisting of high-affinity tyrosine kinase receptor and low affinity binding sites corresponding to heparan sulfate proteoglycans (HSPN) [3]. The formation of active FGF-FGFR complex is the prerequisite for effective intracellular signaling
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