Role of aquaporin-4 in the regulation of migration and invasion of human glioma cells

Abstract

Abstract. glioblastoma is the most aggressive form of primary brain tumor with a tendency to invade surrounding healthy brain tissues, rendering tumors of this type largely incurable. aquaporin-4 (aQP4) is a key molecule involved in maintaining water and ion homeostasis in the central nervous system and has been recently reported to play a role in cell migration in addition to its well-known function in brain edema. increased aQP4 expression has been demonstrated in glioblastoma multiforme (gBM), suggesting that it is also involved in malignant brain tumors. Here, we identify a novel role for aquaporin-4 in glioblastoma cell migration and invasion. in the present study, we used small-interference rna technology and a pharmacological inhibitor to knock down the expression of AQP4, which resulted in specific and massive impairment of glioblastoma cell migration and invasion in vitro and in vivo. in addition, we demonstrated the possible mechanisms by which aQP4 functions in the process of glioblastoma cell invasion. the downregulation of matrix metalloprotease-2 (MMP-2) expression in ln229 cells with aQP4 reduction coincided with decreased cell invasive ability. furthermore, our study showed that aQP4 may also be involved in the regulation of glioblastoma cell adhesion. The expression of β-catenin and connexin 43 were increased in aQP4-downregulated ln229 cells consistent with their enhanced cell-cell adhesion ability. in summary, our results indicate that aQP4 is involved in the control of glioblastoma cell migration and invasion and may be a potential therapeutic target for glioblastoma cell infiltration. Introductionglioblastomas are the most common malignant tumors of the adult central nervous system. these are highly invasive and infiltrative tumors which are associated with a poor prognosis and median patient survival of only one year (1,2). a major barrier to available malignant glioma treatment is the invasion of these cells into brain parenchyma. Because of this, local therapies such as surgery or radiation therapy are ineffective (3). glioma cells invade through the ecM of the brain by activating a number of coordinated cellular processes, which include those necessary for migration and invasion. therefore, a detailed understanding of the mechanisms underlying this invasive behavior is essential for the development of novel effective therapies. aQPs (aquaporins) are a family of water channel proteins that provide a major pathway for osmotically driven water transport through cell membranes. to date, 13 aquaporin isoforms (AQP0-AQP12) have been identified in mammalian species (4). Both aQP1 and aQP4 have been clearly identified in brain, and AQP4 is known to participate mainly in brain edema after injury or other brain diseases (5). aQP4 is primarily expressed at the border between brain parenchyma and major fluid compartments, including astrocyte foot processes and glia limitans, as well as ependymal cells and subependymal astrocytes (6). this distribution suggests that aQP4 controls water fluxes into an...

Neuroimmunological Implications of AQP4 in Astrocytes

“…AQP4-deficient mice showed an improved neurological outcome after acute water intoxication and ischemic stroke [73]. In human glioma cells, AQP4 regulates migration and invasion and might be useful as a therapeutic target for cell infiltration [74]. …”

A role for ion channels in perivascular glioma invasion

“…While there appears to be a loss of AQP4 expression in the astrocytic endfoot during blood vessel co-option, invading glioma cells have been shown to display an upregulation of AQPs, including AQP1, 4, and 9 (Saadoun et al 2002a, b, Warth et al 2007; McCoy and Sontheimer 2007). Furthermore, several studies have found that when AQP expression is knocked down via siRNA, glioma cell migration is slowed (McCoy and Sontheimer 2007; Ding et al 2011). This solidifies the role that AQPs play in the hydrodynamic model of glioma cell migration.…”

Knockdown a Water Channel Protein, Aquaporin-4, Induced Glioblastoma Cell Apoptosis

“…Kong et al have indicated that AQP4 deficiency inhibited the proliferation, survival, migration and neuronal differentiation of adult neural stem cells derived from the subventricular zone of adult mice [9]. Our previous study also showed that reduction of AQP4 induced impaired migration and invasion of human glioma cells [10]. Although AQP4 has been implicated in AVD, the exact mechanisms that trigger the changes in the cellular volume remain to be elucidated [11].…”