Aquaporin 3 Overexpression Research Articles

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation.

Antigen cross presentation, whereby exogenous antigens are presented by MHC class I molecules to CD8+ T cells, is essential for generating adaptive immunity to pathogens and tumor cells. Following endocytosis, it is widely understood that protein antigens must be transferred from endosomes to the cytosol where they are subject to ubiquitination and proteasome degradation prior to being translocated into the endoplasmic reticulum (ER), or possibly endosomes, via the TAP1/TAP2 complex. Revealing how antigens egress from endocytic organelles (endosome-to-cytosol transfer, ECT), however, has proved vexing. Here, we used two independent screens to identify the hydrogen peroxide-transporting channel aquaporin-3 (AQP3) as a regulator of ECT. AQP3 overexpression increased ECT, whereas AQP3 knockout or knockdown decreased ECT. Mechanistically, AQP3 appears to be important for hydrogen peroxide entry into the endosomal lumen where it affects lipid peroxidation and subsequent antigen release. AQP3-mediated regulation of ECT was functionally significant, as AQP3 modulation had a direct impact on the efficiency of antigen cross presentation in vitro. Finally, AQP3-/- mice exhibited a reduced ability to mount an anti-viral response and cross present exogenous extended peptide. Together, these results indicate that the AQP3-mediated transport of hydrogen peroxide can regulate endosomal lipid peroxidation and suggest that compromised membrane integrity and coordinated release of endosomal cargo is a likely mechanism for ECT.

Overexpression of Aquaporin 1 in Synovium Aggravates Rat Collagen-Induced Arthritis Through Regulating β-Catenin Signaling: An in vivo and in vitro Study.

IntroductionPrevious studies have confirmed that aquaporin 1 (AQP1) is up-regulated in synovium of rheumatoid arthritis (RA), but its exact pathogenic mechanisms in RA are unclear. This study revealed the pathogenic role of AQP1 in rat collagen-induced arthritis (CIA) and the underlying mechanisms related to β-catenin signaling.Materials and MethodsSecondary paw swelling and pathological changes of ankle joints were used to evaluate the severity of rat CIA. Synovial AQP1 and β-catenin expression were measured by immunohistochemistry (IHC) and Western blot assay. AQP1 siRNA was applied to knockdown AQP1 in cultured CIA fibroblast-like synoviocyte (FLS). Assays of MTT, PCNA immunofluorescence and transwell were performed to detect cell proliferation, migration and invasion. The protein levels of β-catenin pathway members and ratio of TOP/FOP luciferase activity were also measured.ResultsIn vivo, we revealed that synovial AQP1 and β-catenin expressions in CIA rats were higher than normal rats, and synovial AQP1 expression of CIA rats increased in parallel with secondary paw swelling and total pathological score on joint damage. Correlation analysis of IHC results indicated that synovial AQP1 expression positively correlated with β-catenin expression in CIA rat. In vitro, AQP1 siRNA apparently reduced the proliferation, migration and invasion of CIA FLS by inhibiting β-catenin signaling pathway. As an activator of β-catenin signaling, lithium chloride (an inhibitor of GSK-3β) reversed the inhibitory effects of AQP1 siRNA on the cultured CIA FLS.ConclusionWe concluded that the overexpression of synovial AQP1 aggravated rat CIA by promoting the activation of FLS through β-catenin signaling pathway.

MiR-3194-3p Inhibits Breast Cancer Progression by Targeting Aquaporin1.

Increasing evidence indicates that the Aquaporin1 (AQP1) aberrant expression may be related to a wide variety of human cancers, including breast cancer (BC). In the present study, we explore the effects and possible mechanism of miR-3194-3p on the biological behaviors of BC. At first, miR-3194-3p is found to modulate AQP1 expression targeting the 3′-UTR using miRNA target prediction algorithms. MiR-3194-3p expression is markedly downregulated, and AQP1 expression is upregulated in BC tissues compared with adjacent normal breast tissues. Moreover, the differential expression of miR-3194-3p and AQP1 are observed in four BC cells with different malignancy degree. Meanwhile, a significant negative correlation between AQP1 and miR-3194-3p expressions in tumor tissues from 30 BC patients is revealed. miR-3194-3p mimic remarkably inhibits cell proliferation, migration, and invasion as well as promotes apoptosis in MDA-MB-231 cells while miR-3194-3p inhibitors exert an opposite role in MCF-7 cells. Dual-luciferase reporter system demonstrates that AQP1 is a direct target gene of miR-3194-3p. Overexpression of AQP1 by pBABE-puro-AQP1 vector partially abrogates the effect of miR-3194-3p mimic in MDA-MB-231 cells. In short, our results suggest that miR-3194-3p suppresses BC cell proliferation, migration, and invasion by targeting AQP1, providing a novel insight into BC tumorigenesis and treatment.

AQP1 modulates tendon stem/progenitor cells senescence during tendon aging

The link between tendon stem/progenitor cells (TSPCs) senescence and tendon aging has been well recognized. However, the cellular and molecular mechanisms of TSPCs senescence are still not fully understood. In present study, we investigated the role of Aquaporin 1 (AQP1) in TSPCs senescence. We showed that AQP1 expression declines with age during tendon aging. In aged TSPCs, overexpression of AQP1 significantly attenuated TSPCs senescence. In addition, AQP1 overexpression also restored the age-related dysfunction of self-renewal, migration and tenogenic differentiation. Furthermore, we demonstrated that the JAK-STAT signaling pathway is activated in aged TSPCs, and AQP1 overexpression inhibited the JAK-STAT signaling pathway activation which indicated that AQP1 attenuates senescence and age-related dysfunction of TSPCs through the repression of JAK−STAT signaling pathway. Taken together, our findings demonstrated the critical role of AQP1 in the regulation of TSPCs senescence and provided a novel target for antagonizing tendon aging.

Effect of low temperature on the regulation of cell volume after hypotonic shock in gastric cancer cells.

Although peritoneal lavage with distilled water performed after surgery prevents peritoneal seeding, cancer cells may avoid rupture under mild hypotonicity through regulatory volume decrease(RVD), which is the homeostatic regulation of ion and water transport. The aim of the present study was to investigate the effect of low temperature on cell volume and cell death under hypoosmolal conditions and determine the underlying molecular mechanisms in gastric cancer (GC). Three human GC cell lines (NUGC4, KATO‑III and MKN45) were exposed to hypotonic solutions, and the effects of low temperature on cell volume and viability were examined. Low temperature‑induced changes in membrane transporters were evaluated, and knockdown and overexpression experiments were conducted to determine their effects on cell volume during hypotonic stimulation. Low temperature (24˚C) during hypotonic stimulation inhibited RVD and enhanced the cytocidal effects on GC cells. The expression of leucine‑rich repeat containing proteinA (LRRC8A), a component of a Cl‑ channel, was decreased, and aquaporin5 (AQP5) expression was increased at low temperatures. LRRC8A knockdown markedly slowed the decrease in cell volume following cell swelling by hypotonic shock. AQP5 overexpression enhanced initial cell swelling after hypotonic shock and increased the final cell volume. These results suggest that a hypotonic solution at low temperature increased initial water influx via activation of AQP5 and decreased Cl‑ efflux via inhibition of LRRC8A. Therefore, low temperature enhanced the hypotonicity‑induced cytocidal effects on GC cells, and these results may contribute to the development of a novel lavage method effective in reducing peritoneal recurrence in GC.

AQP1 Overexpression in the CSF of Obstructive Hydrocephalus and Inversion of Its Polarity in the Choroid Plexus of a Chiari Malformation Type II Case.

The choroid plexus (ChP) is involved in the production of cerebrospinal fluid (CSF) and is intimately related to CSF physiopathology. Aquaporin-1 (AQP1) is the water channel directly implicated in CSF production and a potential therapeutic target in the management of CSF circulation disorders. Pathologies that present ventriculomegaly are associated with defective CSF turnover and AQPs are involved in both the production and reabsorption of CSF. This work examines the levels of AQP1 and its dynamics in ventriculomegaly conditions such as congenital hydrocephalus (communicating and obstructive) or type II lissencephaly versus control. We specifically address the expression of AQP1 in the CSF of 16 term-pregnancy infants where it was found to be significantly increased in obstructive cases when compared with communicating hydrocephalus or control patients. We also defined histologically the expression of AQP1 in the ChP from 6 nonsurvival preterm-pregnancy infants ranging ages between 20 and 25 gestational weeks in which AQP1 was mainly expressed at the apical pole of the ChP epithelium (ChPE) in control and lissencephalic patients. AQP1 expression from the Chiari malformation case showed an inverted polarity being expressed in the basal pole of the ChPE colocalizing with the glucose transporter 1 where this transporter is naturally located.

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability.

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZpatients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase incaspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

Cytoprotective effect of aquaporin 1 against lipopolysaccharide-induced apoptosis and inflammation of renal epithelial HK-2 cells.

Sepsis is the most common underlying disease of disseminated intravascular coagulation. Acute kidney injury is a common and serious complications of sepsis. In the present study, a lipopolysaccharide (LPS)-induced human proximal tubule cell line (HK-2 cells) was selected as an in vitro model of septic acute kidney injury. The aim of the present study was to investigate whether aquaporin 1 (AQP-1) has a cytoprotective role in LPS-induced HK-2 cells. HK-2 cells were treated with 0–16 µg/ml LPS for 0–24 h to establish the in vitro model of sepsis. The results demonstrated that AQP-1 levels were the lowest of the eight AQP genes expressed in LPS-induced HK-2 cells. Prior to LPS treatment, HK-2 cells were transfected with pcDNA-AQP-1 or small interfering-AQP-1 and cell counting kint-8 and flow cytometry assays were performed to assess cell viability and apoptosis rate, respectively. Changes in the expression of proinflammatory cytokines and chemokines, as well as important factors in the p38, extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) pathways, were assessed using reverse transcription-quantitative polymerase chain reaction, western blotting and ELISA, respectively. LPS treatment reduced viability, increased apoptosis and upregulated the expression of proinflammatory cytokines and chemokines in HK-2 cells. AQP-1 overexpression significantly reversed the effects of LPS and downregulated the expression of tumor necrosis factor-α, interleukin (IL)-8, IL-1β and monocyte chemoattractant protein-1. The p38, ERK1/2 and JNK pathways were activated by LPS; however, the p38 and ERK1/2 pathways were blocked in AQP-1-overexpressing cells. AQP-1 overexpression was demonstrated to confer a survival advantage to LPS-injured HK-2 cells by controlling cell viability, apoptosis and inflammation, possibly via modulation of the p38 and ERK1/2 pathways. The results of the present study suggest that AQP-1 may be an effective treatment for acute kidney injury caused by sepsis.

Decreased miR-320 expression is associated with breast cancer progression, cell migration, and invasiveness via targeting Aquaporin 1.

Our previous studies have demonstrated that Aquaporin 1 (AQP1) is overexpressed in breast cancer. However, the mechanism remains elusive. MicroRNA 320 (miR-320) downregulation has been reported in various types of cancers, and it may regulate AQP1 expression. In this study, miR-320 and AQP1 expressions were investigated by quantitative reverse transcription-PCR, in situ hybridization, and immunohistochemistry. The clinicopathological implications of these molecules were also analyzed. We found that miR-320 expression is downregulated in both plasma and tumor tissue in human breast cancer patients. Survival analysis showed that reduced expression of miR-320 and overexpression of AQP1 are associated with worse prognosis. Luciferase assays showed that miR-320 negatively regulates AQP1 expression. In addition, cell proliferation, migration, and invasion assays were performed to investigate the effects of miR-320 on breast cancer cells. Our results showed that miR-320 overexpression inhibits cell proliferation, migration, and invasion in breast cancer cells by downregulating AQP1. These observations suggested that miR-320 downregulation may enhance AQP1 expression in breast cancer, favoring tumor progression. Our findings indicated that miR-320 and AQP1 may serve as prognostic biomarkers and therapeutic targets in the treatment of breast cancer.

Immunohistochemical Expression of Aquaporin-1 in Fluoro-Edenite-Induced Malignant Mesothelioma: A Preliminary Report.

Background: The immunohistochemical expression of aquaporin-1 (AQP1) in asbestos-related malignant pleural mesothelioma (MPM) is emerging as a useful prognostic indicator of improved survival. A significantly increased incidence of MPM in a small town in southern Italy was ascribed to exposure to fluoro-edenite (FE), a naturally occurring asbestos fiber. We investigated the immunohistochemical expression of AQP1 in patients affected by FE-related MPM; taking into consideration its suggested independent prognostic role, its possible correlation with clinicopathological parameters and patient outcome was also evaluated. Methods: Ten patients were selected for this study, as neoplastic tissue blocks, clinical and follow-up data were available. The immunohistochemical overexpression of AQP1 was defined as ≥50% of tumor cells showing membranous staining. Results: Six cases showed AQP1 expression in ≥50% of tumor cells; in this group, a significant association of AQP1 overexpression with an increased median overall survival (OS) of 26.3 months was observed. By contrast, four patients exhibited an AQP1 score of <50% of stained cells, with a shorter median OS of 8.9 months. Conclusions: The present study represents further confirmation of the hypothesized prognostic role of AQP1, which seems a reliable prognostic indicator.

CircHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma

Noncoding RNAs plays an important role in hepatocellular carcinoma (HCC). Here, we show that miR-124 was downregulated in HCC tissues and that the ectopic expression of miR-124 inhibited the proliferation and migration of HCC cells. We proposed that aquaporin 3 (AQP3) is a direct target of miR-124. AQP3 was upregulated in HCC tissues and inversely correlated with miR-124 expression. The overexpression of miR-124 decreased AQP3 expression. Indeed, AQP3 overexpression promoted cell proliferation and migration, whereas miR-124 knockdown suppressed cell proliferation and migration. Furthermore, we found that circular RNA HIPK3 (circHIPK3) acted as a miR-124 sponge and regulated the expression of the miR-124 target gene AQP3. circHIPK3 was upregulated in HCC tissues and positively correlated with AQP3 expression. Thus, silencing circHIPK3 inhibited cell proliferation and migration by downregulating AQP3 expression. Moreover, miR-124 inhibition rescued circHIPK3 knockdown induced reduction in cell proliferation and migration, as well as AQP3 expression. In vivo experiments also confirmed that circHIPK3 regulated xenograft tumor growth via the miR-124-AQP3 axis. These observations indicate a possible novel therapeutic strategy involving circular RNAs in HCC.

Ectopic expression of aquaporin-5 in noncancerous epithelial MDCK cells changes cellular morphology and actin fiber formation without inducing epithelial-to-mesenchymal transition.

Aquaporin-5 (AQP5) is a plasma membrane water channel mainly expressed in secretory glands. Increased expression of AQP5 is observed in multiple cancers, including breast cancer, where high expression correlates with the degree of metastasis and poor prognosis. Moreover, studies in cancer cells have suggested that AQP5 activates Ras signaling, drives morphological changes, and in particular increased invasiveness. To design intervention strategies, it is of utmost importance to characterize and dissect the cell biological changes induced by altered AQP5 expression. To isolate the effect of AQP5 overexpression from the cancer background, AQP5 was overexpressed in normal epithelial MDCK cells which have no endogenous AQP5 expression. AQP5 overexpression promoted actin stress fiber formation and lamellipodia dynamics. Moreover, AQP5 decreased cell circularity. Phosphorylation of AQP5 on serine 156 in the second intracellular loop has been shown to activate the Ras pathway. When serine 156 was mutated to alanine to mimic the nonphosphorylated state, the decrease in cell circularity was reversed, indicating that the AQP5-Ras axis is involved in the effect on cell shape. Interestingly, the cellular changes mediated by AQP5 were not associated with induction of epithelial-to-mesenchymal transition. Thus, AQP5 may contribute to cancer by altering cellular morphology and actin organization, which increase the metastatic potential.

Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway

Background/Aims: Previous studies have shown that oxidative damage is a main contributor to disc nucleus pulposus (NP) cell apoptosis. Aquaporin-3 (AQP-3) facilitates reactive oxygen species (ROS) scavenging and thus alleviates oxidative injury in other cells. This study aims to investigate the role and mechanism of AQP-3 in regulating NP cell apoptosis under oxidative damage. Methods: Rat NP cells were treated with H₂O₂ for 48 hours, while control NP cells were free of H₂O₂. Recombinant AQP-3 lentiviral vectors were used to investigate the effect of enhanced AQP-3 expression levels in NP cells. NP cell apoptosis was assessed by flow cytometry, caspase-3 activity, gene expression of apoptosis-related molecules (Bax, Bcl-2 and caspase-3), and protein expression of cellular apoptosis markers (cleaved PARP and cleaved caspase-3). Additionally, intracellular ROS content and activity of the p38 MAPK pathway were evaluated. Results: Compared with the control NP cells, oxidative damage in the treatment cells significantly increased cell apoptosis ratios and caspase-3 activity, upregulated gene expression of Bax and caspase-3, downregulated gene expression of Bcl-2, and increased protein expression of cleaved PARP and cleaved caspase-3, as well as increased intracellular ROS content and activity of the p38 MAPK pathway. However, AQP-3 overexpression partly alleviated cell apoptosis, decreased intracellular ROS content, and inhibited the p38 MAPK pathway in NP cells under oxidative damage. Conclusion: Oxidative damage can significantly downregulate AQP-3 expression. Enhancing AQP-3 expression in NP cells partly attenuates cellular apoptosis through regulating the p38 MAPK pathway under oxidative damage.

Immunohistochemical evalulation of activated Ras and Rac1 as potential downstream effectors of aquaporin-5 in breast cancer in vivo

Aberrant levels of aquaporin-5 (AQP5) expression have been observed in several types of cancer, including breast cancer, where AQP5 overexpression is associated with metastasis and poor prognosis. In cultured cancer cells, AQP5 facilitates cell migration and activates Ras signaling. Both increased cell migration and Ras activation are associated with cancer metastasis, but so far it is unknown if AQP5 also affects these processes in vivo. Therefore, we investigated if high AQP5 expression in breast cancer tissue correlated with increased activation of Ras and of Rac1, which is a GTPase also involved in cell migration. This was accomplished by immunohistochemical analysis of invasive ductal carcinoma of breast tissue sections from human patients, followed by qualitative and quantitative correlation analysis between AQP5 and activated Ras and Rac1. Immunohistochemistry revealed that activation of Ras and Rac1 was positively correlated. There was, however, no correlation between high AQP5 expression and activation of Ras, whereas a nonsignificant, but positive, tendency between the levels of AQP5 and activated Rac1 levels was observed. In summary, this is the first report that correlates AQP5 expression levels to downstream signaling partners in breast cancer tissue sections. The results suggest Rac1 as a potential downstream signaling partner of AQP5 in vivo.

Down-regulation of aquaporin 5-mediated epithelial-mesenchymal transition and anti-metastatic effect by natural product Cairicoside E in colorectal cancer.

Epithelial-mesenchymal transition (EMT) has emerged as an important determinant role in colorectal cancer (CRC) metastasis. It has been reported that aquaporin 5 (AQP5) is closely linked to CRC metastasis. However, the effect of AQP5 on the EMT process of CRC remains unknown. The current study showed that overexpression of AQP5 activated EMT in CRC cells. Cairicoside E (CE), a natural resin glycoside compound isolated from Ipomoea cairica, showed promising cytotoxic activity in our previous report. Further investigation found that CE inhibited the expression of AQP5 and the EMT process. Moreover, the inhibitory effect of CE on EMT was reversed by overexpression of AQP5. Importantly, CE also suppressed the EMT and p-Smad2/3 induced by TGF-β1. On the other hand, overexpression of AQP5 up-regulated the p-Smad2/3, which resulted in the activation of EMT. After silencing of AQP5, CE had no significant effect on EMT markers and p-Smad2/3 induced by TGF-β1, indicating that CE inhibited the EMT through down-regulation of AQP5 and suppression of p-Smad2/3. CE also inhibited the AQP5 expression in the lung metastatic nodules of HCT-116 cells in vivo. Our findings suggested that CE may serve as a promising drug for the treatment of CRC metastasis.

Abstract 5530: Evidence linking aquaporin-3 loss to increased invasiveness in bladder cancer

Abstract Bladder cancer (BCa) is the most common type of urothelial cancer (UC). According to American Cancer Society, in 2016, diagnoses of 76,960 new cases of bladder cancer (BCa) and 16,390 BCa associated deaths have been estimated. More than 90% of bladder cancer starts in the innermost transitional epithelium (urothelium) of the bladder. Aquaporin 3 (AQP3), one of 13 members of a transmembrane channel forming protein family (AQP0-12), has an N-terminal basolateral sorting signal and localizes to the basolateral membrane in epithelial tissues. Recent studies have shown that AQP3 expression is decreased in UC thus supporting a new hypothesis that alteration of the expression of AQP3 plays a role in the pathogenesis of UC. However, it remains to be determined whether AQP3 is involved in the invasion and metastasis of UC cells. In the present study, human bladder cancer cell lines of different grades, SW780 (G1) and TCCSUP (G4) were studied. Transcript and protein levels of AQP3 expression were significantly higher in low grade, SW780 cells when compared to the higher-grade TCCSUP cells. Inhibition of AQP3 by CuSO4 or siRNA specific knockdown of AQP3 resulted in increased migration in the wound-healing scratch assay. Over-expression of AQP3 plasmid resulted in reduced migration. It is known that epithelial cell polarity contributes to tumor suppression and that loss of E-cadherin is a crucial step in epithelial-to-mesenchymal transition (EMT). Our results indicate that AQP3 overexpression induced expression of E-cadherin, consistent with a role for AQP3 as a tumor suppressor by maintaining epithelial cell polarity and inhibiting EMT in BCa. Conversely, reduced AQP3 levels leading to reduced E-cadherin levels in high-grade BCa cells may result in loss of cell polarity, increased invasiveness and increased EMT. Citation Format: Arpita Roy, Dinuka M. DeSilva, Donald P. Bottaro. Evidence linking aquaporin-3 loss to increased invasiveness in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5530. doi:10.1158/1538-7445.AM2017-5530

Role of Aquaporin 1 Signalling in Cancer Development and Progression.

Cancer is a major health burden worldwide. Despite the advances in our understanding of its pathogenesis and continued improvement in cancer management and outcomes, there remains a strong clinical demand for more accurate and reliable biomarkers of metastatic progression and novel therapeutic targets to abrogate angiogenesis and tumour progression. Aquaporin 1 (AQP1) is a small hydrophobic integral transmembrane protein with a predominant role in trans-cellular water transport. Recently, over-expression of AQP1 has been associated with many types of cancer as a distinctive clinical prognostic factor. This has prompted researchers to evaluate the link between AQP1 and cancer biological functions. Available literature implicates the role of AQP1 in tumour cell migration, invasion and angiogenesis. This article reviews the current understanding of AQP1-facilitated tumour development and progression with a focus on regulatory mechanisms and downstream signalling pathways.

Aquaporin 3 facilitates chemoresistance in gastric cancer cells to cisplatin via autophagy.

Cisplatin (cDDP) remains one of the first-line chemotherapeutic agents for gastric cancer (GC) treatment, and resistance to cDDP is the major limitation in its clinical application. Mechanisms of cDDP resistance have been shown to be varied and complicated. Aquaporin 3 (AQP3) has been demonstrated to be overexpressed in GC tissues and is thought to be involved in GC carcinogenesis and progression. However, the role of AQP3 in chemosensitivity of GC to cytotoxic agents remains unknown. In this study, we show that AQP3 overexpression induced resistance to cDDP in AGS cells (P<0.05), and AQP3 knockdown increased the chemosensitivity in MGC803 and SGC7901 cells (P<0.05). Moreover, cDDP treatment enhanced AQP3 expression in MGC803, SGC7901 and AGS cells. AQP3 overexpression promoted the conversion of LC3-I to LC3-II in AGS cells, whereas AQP3 knockdown inhibited this conversion in MGC803 and SGC7901 cells. AQP3 upregulation increased Atg5 and Beclin-1 expression, and inhibited P62 expression in AGS cells, whereas AQP3 knockdown showed the opposite results in MGC803 and SGC7901 cells. Chloroquine (CQ), an autophagy inhibitor, enhanced the cytotoxicity of cDDP in GC cells, and CQ reversed the chemoresistance to cDDP caused by AQP3 overexpression in GC cells. Together, our data demonstrate that AQP3 facilitates cisplatin resistance in gastric cancer cells via autophagy, and suggest that the development of AQP3-based tumor therapeutics could play a key role in future GC treatment strategies.

Overexpression of Aquaporin-1 is a Prognostic Factor for Biochemical Recurrence in Prostate Adenocarcinoma.

Aquaporins (AQP) are transmembrane proteins that provide channels for water and solutes, and some are involved in tumor progression and invasion. We evaluated the expression of AQP-1, AQP-3, and AQP-5 and their clinicopathological significance in prostate adenocarcinomas (PCA). Prostatectomy specimens (n = 99) were retrieved from the surgical pathology archives and clinicopathological data were obtained from the medical database at Kyungpook National University Hospital. Immunohistochemical staining for AQP-1, AQP-3, and AQP-5 was performed on tissue microarrays comprising paired malignant and benign prostatic tissues. Seventeen PCA cases (17.2%) showed AQP-1 overexpression, specifically 7 tumors (9.7%) with lower Gleason scores (GS) and 10 tumors (37.0%) with higher GS, with statistical significance (P = 0.001). AQP-1 overexpression was significantly associated with higher GS (P = 0.001), higher pathologic T (pT) stages (P = 0.024), and biochemical recurrence (BR) (P = 0.002). The difference in AQP-3 and AQP-5 expression between neoplastic and non-neoplastic tissues was not established and there were no correlations with clinicopathological parameters. AQP-1 overexpression was evident in tumors with higher GS, it was less evident in tumors with lower GS, and it was associated with BR and a higher pT stage. AQP-1 overexpression is associated with prostate cancer progression.

The role of aquaporin-5 in cancer cell migration: A potential active participant

Emerging data identifies the water channel aquaporin-5 as a major player in multiple cancers. Over-expression of aquaporin-5 has been associated with increased metastasis and poor prognosis, suggesting that aquaporin-5 may enhance cancer cell migration. This review aims to highlight the current knowledge and hypothesis regarding downstream signaling partners of aquaporin-5 in relation to cancer cell migration. The molecular mechanisms that link aquaporin-5 to cell migration are not completely understood. Aquaporin-5 may promote cell movement by increasing water uptake into the front of the cell allowing local swelling. Aquaporin-5 may also activate extracellular-regulated kinases, increasing proliferation and potentially stimulating the migration machinery. Thus, further studies are warranted to identify the underlying mechanisms and signaling pathways. This will reveal whether aquaporin-5 and downstream effectors could be targets for developing new cancer therapeutics.