Downregulated GPX4 in salivary gland epithelial cells contributes to salivary secretion dysfunction in Sjogren's syndrome via lipid ROS/pSTAT4/AQP5 axis.

Sjogren's syndrome (SS) is an autoimmune disease characterized by dysfunction of exocrine glands, such as salivary glands. However, the molecular mechanism of salivary secretion dysfunction in SS is still unclear. Given the significance of glutathione peroxidase 4 (GPX4) in cellular redox homeostasis, we hypothesized that dysregulation of GPX4 may play a pivotal role in the pathogenesis of salivary secretion dysfunction observed in SS. The salivary gland of SS patients and the SS mouse model exhibited reduced expression of the ferroptosis inhibitor GPX4 and the important protein aquaporin 5 (AQP5), which is involved in salivary secretion. GPX4 overexpression upregulated and GPX4 knockdown downregulated AQP5 expression in salivary gland epithelial cells (SGECs) and salivary secretion. Bioinformatics analysis of GSE databases from SS patients' salivary glands revealed STAT4 as a key intermediary regulator between GPX4 and AQP5. A higher level of nuclear pSTAT4 was observed in the salivary gland of the SS mouse model. GPX4 overexpression inhibited and GPX4 knockdown promoted STAT4 phosphorylation and nuclear translocation in SGECs. CHIP assay confirmed the binding of pSTAT4 within the promoter of AQP5 inhibiting AQP5 transcription. GPX4 downregulation accumulates intracellular lipid ROS in SGECs. Lipid ROS inhibitor ferrostatin-1 treatment during in vitro and in vivo studies confirmed that lipid ROS activates STAT4 phosphorylation and nuclear translocation in SGECs. In summary, the downregulated GPX4 in SGECs contributes to salivary secretion dysfunction in SS via the lipid ROS/pSTAT4/AQP5 axis. This study unraveled novel targets to revitalize the salivary secretion function in SS patients.

Goji Berry Juice Prevents Tumor Necrosis Factor Alpha-Induced Xerostomia in Human Salivary Gland Cells.

Sjögren's syndrome (SS) is an autoimmune disorder characterized by oral dryness that is primarily attributed to tumor necrosis factor alpha (TNF-α)-mediated reduction in saliva production. In traditional Chinese medicine, goji berries are recognized for their hydrating effect and are considered suitable to address oral dryness associated with Yin deficiency. In the present study, we used goji berry juice (GBJ) to investigate the potential preventive effect of goji berries on oral dryness caused by SS. Pretreatment of human salivary gland cells with GBJ effectively prevented the decrease in aquaporin-5 (AQP-5) mRNA and protein levels induced by TNF-α. GBJ also inhibited histone H4 deacetylation and suppressed the generation of intracellular reactive oxygen species (ROS). Furthermore, GBJ pretreatment reserved mitochondrial membrane potential and suppressed the upregulation of Bax and caspase-3, indicating that GBJ exerted an antiapoptotic effect. These findings suggest that GBJ provides protection against TNF-α in human salivary gland cells and prevents the reduction of AQP-5 expression on the cell membrane. Altogether, these results highlight the potential role of GBJ in preventing oral dryness caused by SS.

Loss of aquaporin 5 contributes to the corneal epithelial pathogenesis via Wnt/ß-catenin pathway.

AQP5 plays a crucial role in maintaining corneal transparency and the barrier function of the cornea. Here, we found that in the corneas of Aqp5-/- mice at older than 6 months, loss of AQP5 significantly increased corneal neovascularization, inflammatory cell infiltration, and corneal haze. The results of immunofluorescence staining showed that upregulation of K1, K10, and K14, and downregulation of K12 and Pax6 were detected in Aqp5-/- cornea and primary corneal epithelial cells. Loss of AQP5 aggravated wound-induced corneal neovascularization, inflammation, and haze. mRNA sequencing, western blotting, and qRT-PCR showed that Wnt2 and Wnt6 were significantly decreased in Aqp5-/- corneas and primary corneal epithelial cells, accompanied by decreased aggregation in the cytoplasm and nucleus of ß-catenin. IIIC3 significantly suppressed corneal neovascularization, inflammation, haze, and maintained corneal transparent epithelial in Aqp5-/- corneas. We also found that pre-stimulated Aqp5-/- primary corneal epithelial cells with IIIC3 caused the decreased expression of K1, K10, and K14, the increased expression of K12, Pax6, and increased aggregation in the cytoplasm and nucleus of ß-catenin. These findings revealed that AQP5 may regulate corneal epithelial homeostasis and function through the Wnt/ß-catenin signaling pathway. Together, we uncovered a possible role of AQP5 in determining corneal epithelial cell fate and providing a potential therapeutic target for corneal epithelial dysfunction.

Aquaporin 5 (AQP5) expression in breast cancer and its clinicopathological characteristics.

The role of aquaporin water channels (AQPs) has become an area of great interest in human carcinogenesis. In this report, we have demonstrated the expression of AQP5 in breast cancer by analyzing 591 tissue samples with 7-year follow-ups. By immunochemistry analysis, AQP5 overexpression was observed in 36% (212/591 cases). Then, we have focused on the clinicopathologic variables among cancer tissue samples with strong AQP5 expression (3+ expression, 60/591 cases). The strong AQP5 expression was positively correlated with tumor grade in BCs (p<0.001) and was more frequent in ER/PR-negative BCs than positive ones (14.9% vs. 3.3% and 13.1% vs. 4.8%, respectively, both p<0.001), while Her2/neu-positive status was positively correlated with strong expression of AQP5 (p = 0.005). Of note, breast cancer patients with positive AQP expression (212/591 cases) showed a less favorable breast cancer specific survival rate over 7 years of follow and we further conclude that AQP5 expression is an independent molecular marker associated with worse clinical outcomes. By fluorescence in situ hybridization (FISH), we have identified evidence of gene amplification in 3 of 30 readable breast cancer and further conclude that, in breast cancer, at least some part of AQP5 overexpression is associated with an aberration in the genome level.

The cell polarity protein Scribble is downregulated by the water channel aquaporin-5 in breast cancer cells.

Breast carcinomas originate from cells in the terminal duct-lobular unit. Carcinomas are associated with increased cell proliferation and migration, altered cellular adhesion, as well as loss of epithelial polarity. In breast cancer, aberrant and high levels of aquaporin-5 (AQP5) are associated with increased metastasis, poor prognosis, and cancer recurrence. AQP5 increases the proliferation and migration of cancer cells, and ectopic expression of AQP5 in normal epithelial cells reduces cell-cell adhesion and increases cell detachment and dissemination from migrating cell sheets, the latter via AQP5-mediated activation of the Ras pathway. Here, we investigated if AQP5 also affects cellular polarity by examining the relationship between the essential polarity protein Scribble and AQP5. In tissue samples from invasive lobular and ductal carcinomas, the majority of cells with high AQP5 expression displayed low Scribble levels, indicating an inverse relationship. Probing for interactions via a Glutathione S-transferase pull-down experiment revealed that AQP5 and Scribble interacted. Moreover, overexpression of AQP5 in the breast cancer cell line MCF7 reduced both size and circularity of three-dimensional (3-D) spheroids and induced cell detachment and dissemination from migrating cell sheets. In addition, Scribble levels were reduced. An AQP5 mutant cell line, which cannot activate Ras (AQP5S156A) signaling, displayed unchanged spheroid size and circularity and an intermediate level of Scribble, indicating that the effect of AQP5 on Scribble is, at least in part, dependent on AQP5-mediated activation of Ras. Thus, our results suggest that high AQP5 expression negatively regulates the essential polarity protein Scribble and thus, can affect cellular polarity in breast cancer.

AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination.

BACKGROUND: Cancer stem cells (CSCs) are regarded as the "seed cells" for tumorigenesis, metastasis, recurrence and drug resistance. However, specific surface markers of CSCs of different origins have not been documented. METHODS: Single-cell sequencing was used to analyze the highly expressed genes in cancer stem cells of gastric cancer patients, and it was verified that AQP5 was specifically highly expressed in gastric cancer stem cells (GC-CSCs) in vivo and in vitro. The effect of AQP5-promoting LGR5 on the malignant biological function of GC-CSCs was investigated. The mechanism by which AQP5 affects GC-CSCs was explored through transcriptome sequencing, proteomic detection, mass spectrometry, etc. RESULTS: We report the identification and validation of AQP5 as a potentially specific surface marker of GC-CSCs. AQP5 was significantly upregulated in CSCs isolated from gastric cancer patients and in spheroid cells, and AQP5 was coexpressed with the canonical stem marker LGR5. Biologically, AQP5 promoted the sphere formation, proliferation, migration and invasion of GC cells in vitro and enhanced tumorigenesis in vivo. Furthermore, AQP5 coordinated with LGR5 and synergistically promoted the tumorigenesis of GC-CSCs. At the mechanistic level, AQP5 activated autophagy by inducing the LC3I/LC3II transformation in GC-CSCs, which was crucial for the biological functions of AQP5. Finally, we demonstrated that AQP5 recruited the E3 ligase TRIM21 to the key autophagy protein ULK1 and induced the K63-mediated ubiquitination of ULK1. CONCLUSIONS: We elucidate a novel surface marker, AQP5, which is specifically expressed by GC-CSCs. Furthermore, our study creates a link between AQP5 and LGR5 and highlights the necessity of targeting both surface markers simultaneously as a promising approach for the treatment of gastric cancer patients.

Mesenchymal stem cells- derived exosomes inhibit the expression of Aquaporin-5 and EGFR in HCT-116 human colorectal carcinoma cell line.

BACKGROUND: Aquaporins are channel proteins, form pores in the membrane of biological cells to facilitate the transcellular and transepithelial water movement. The role of Aquaporins in carcinogenesis has become an area of interest. In this study, we aimed to investigate the effects of adipose-derived mesenchymal stem cells secreted exosomes on the expression of aquaporin 5 and EGFR genes in the HCT-116 tumor cell line. METHODS AND RESULTS: Surface antigenic profile of Ad-MSCs was evaluated using specific markers. Exosomes were purified from the Ad-MSc supernatant while the quality and the shape of isolated exosomes were assessed by western blot and transmission electron microscopy (TEM) respectively. HCT-116 cells were co-cultured with MSC-conditioned medium (MSC-CM) and/or with 100 µg/ml of MSC-derived exosomes for 48 h and. Real-time PCR was carried out to determine the expression of aquaporin5 and EGFR in HCT-116. Relative expression levels were calculated using the 2-ΔΔct method. Our result showed that AQP5 and EGFR mRNA levels were significantly reduced in CM and/or exosomes treated HCT116 compare to the control group (P-value < 0.05). CONCLUSION: The current study showed that MSC derived exosomes could inhibit expression of two important molecules involved in tumor progression. Hence it seems MSCs-derived exosomes may hold a hopeful future as drug delivery vehicles which need the furtherer investigation.

Aquaporin-3 and Aquaporin-5 Facilitate Migration and Cell-Cell Adhesion in Pancreatic Cancer by Modulating Cell Biomechanical Properties.

BACKGROUND: Aquaporins are membrane channels responsible for the bidirectional transfer of water and small non-charged solutes across cell membranes. AQP3 and AQP5 are overexpressed in pancreatic ductal adenocarcinoma, playing key roles in cell migration, proliferation, and invasion. Here, we evaluated AQP3 and AQP5 involvement in cell biomechanical properties, cell-cell adhesion, and cell migration, following a loss-of-function strategy on BxPC-3 cells. RESULTS: Silencing of AQP3 and AQP5 was functionally validated by reduced membrane permeability and had implications on cell migration, slowing wound recovery. Moreover, silenced AQP5 and AQP3/5 cells showed higher membrane fluidity. Biomechanical and morphological changes were assessed by atomic force microscopy (AFM), revealing AQP5 and AQP3/5 silenced cells with a lower stiffness than their control. Through cell-cell adhesion measurements, the work (energy) necessary to detach two cells was found to be lower for AQP-silenced cells than control, showing that these AQPs have implications on cell-cell adhesion. CONCLUSION: These findings highlight AQP3 and AQP5 involvement in the biophysical properties of cell membranes, whole cell biomechanical properties, and cell-cell adhesion, thus having potential implication in the settings of tumor development.

Aquaporin-5 in breast cancer.

The water channel aquaporin-5 (AQP5) is essential in transepithelial water transport in secretory glands. AQP5 is ectopically overexpressed in breast cancer, where expression is associated with lymph node metastasis and poor prognosis. Besides the role in water transport, AQP5 has been found to play a role in cancer metastasis, migration, and proliferation. AQP5 has also been shown to be involved in the dysregulation of epithelial cell-cell adhesion; frequently observed in cancers. Insight into the underlying molecular mechanisms of how AQP5 contributes to cancer development and progression is essential for potentially implementing AQP5 as a prognostic biomarker and to develop targeted intervention strategies for the treatment of breast cancer patients.

AQP5 pathogenic variants induce palmoplantar keratoderma Bothnia type in two Chinese families.

Palmoplantar keratoderma Bothnia type (PPKB) is caused by AQP5 pathogenic variants. The mechanisms of this disease and the genotype-phenotype correlation are still not fully understood. We report two pedigrees with PPKB caused by a recurrent variant c.367A>T and a novel variant c.530T>A in the AQP5 gene, respectively. We also summarize the cases with AQP5 variants identified, and found that there seemed to be no significant genotype-phenotype correlation of this disease. Moreover, we noticed that the epidermis of the patient had strong proliferation and immature differentiation potential as well as recognizing the possible important role of TRPV4 in the pathogenesis of PPKB.

Up-regulation of Aquaporin 5 Defines Spasmolytic Polypeptide-Expressing Metaplasia and Progression to Incomplete Intestinal Metaplasia.

BACKGROUND & AIMS: Metaplasia in the stomach is highly associated with development of intestinal-type gastric cancer. Two types of metaplasias, spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM), are considered precancerous lesions. However, it remains unclear how SPEM and IM are related. Here we investigated a new lineage-specific marker for SPEM cells, aquaporin 5 (AQP5), to assist in the identification of these 2 metaplasias. METHODS: Drug- or Helicobacter felis (H felis) infection-induced mouse models were used to identify the expression pattern of AQP5 in acute or chronic SPEM. Gene-manipulated mice treated with or without drug were used to investigate how AQP5 expression is regulated in metaplastic lesions. Metaplastic samples from transgenic mice and human gastric cancer patients were evaluated for AQP5 expression. Immunostaining with lineage-specific markers was used to differentiate metaplastic gland characteristics. RESULTS: Our results revealed that AQP5 is a novel lineage-specific marker for SPEM cells that are localized at the base of metaplastic glands initially and expand to dominate glands after chronic H felis infection. In addition, AQP5 expression was up-regulated early in chief cell reprogramming and was promoted by interleukin 13. In humans, metaplastic corpus showed highly branched structures with AQP5-positive SPEM. Human SPEM cells strongly expressing AQP5 were present at the bases of incomplete IM glands marked by TROP2 but were absent from complete IM glands. CONCLUSIONS: AQP5-expressing SPEM cells are present in pyloric metaplasia and TROP2-positive incomplete IM and may be an important component of metaplasia that can predict a higher risk for gastric cancer development.

Induction of salivary gland-like cells from epithelial tissues transdifferentiated from mouse embryonic fibroblasts.

Salivary gland hypofunction due to radiation therapy for head and neck cancer or Sjögren syndrome may cause various oral diseases, which can lead to a decline in the quality of life. Cell therapy using salivary gland stem cells is a promising method for restoring hypofunction. Herein, we show that salivary gland-like cells can be induced from epithelial tissues that were transdifferentiated from mouse embryonic fibroblasts (MEFs). We introduced four genes, Dnp63a, Tfap2a, Grhl2, and Myc (PTMG) that are known to transdifferentiate fibroblasts into oral mucosa-like epithelium in vivo into MEFs. MEFs overexpressing these genes showed epithelial cell characteristics, such as cobblestone appearance and E-cadherin positivity, and formed oral epithelial-like tissue under air-liquid interface culture conditions. The epithelial sheet detached from the culture dish was infected with adenoviruses encoding Sox9 and Foxc1, which we previously identified as essential factors to induce salivary gland formation. The cells detached from the cell sheet formed spheres 10 days after infection and showed a branching morphology. The spheres expressed genes encoding basal/myoepithelial markers, cytokeratin 5, cytokeratin 14, acinar cell marker, aquaporin 5, and the myoepithelial marker α-smooth muscle actin. The dissociated cells of these primary spheres had the ability to form secondary spheres. Taken together, our results provide a new strategy for cell therapy of salivary glands and hold implications in treating patients with dry mouth.

Deficiency of CARMA3 attenuates the development of bleomycin induced pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) has attracted more and more attention due to its irreversibility and high mortality rate. Currently, there is no effective treatment option is available to reverse the disease. Caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA3) has been recognized as a proinflammatory molecule involved in many lung diseases, such as Allergic airway inflammation and lung cancer. Bleomycin (Bleo), as an alkaline sugar peptide antibiotics, is often used as a first-line anti-tumor agent. Its toxic effect is to induce pulmonary fibrosis (PF) and its clinical symptoms, so it has been widely used in the construction of pulmonary fibrosis model. METHODS: Wild type mice (WT, n = 20) and CARMA3 knockout mice (CARMA3-KO, n = 20) were generated and injected with bleomycin or saline via trachea. The severity of fibrosis was evaluated by fibrosis markers and lung histological morphology. Furthermore, the amount of alveolar epithelial cells and inflammation in lung tissue were examined. Finally, epithelial-mesenchymal transition was further investigated. RESULTS: We found CARMA3 expression in the mice alveolar epithelial cells. And compared with WT mice, CARMA3-KO mice showed reduced deposition of collagen fibers, inflammation and destruction of alveolar epithelial cells in lung tissue. In addition, after bleomycin induction, the expressions of proinflammatory factors and collagen-related factors in CARMA3-KO mice were much lower than those in WT mice. The epithelial-mesenchymal transformation phenotype was also improved in CARMA3-KO mice compared to WT mice. CONCLUSION: Our Results shows that CARMA3 plays an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. CARMA3 could alleviate the fibrosis by improving inflammation, deposition of collagen and damage of alveolar epithelial cells, which revealed that CARMA3 may be a potential target for pulmonary fibrosis.

Uterine kisspeptin receptor critically regulates epithelial estrogen receptor α transcriptional activity at the time of embryo implantation in a mouse model.

Embryo implantation failure is a major cause of infertility in women of reproductive age and a better understanding of uterine factors that regulate implantation is required for developing effective treatments for female infertility. This study investigated the role of the uterine kisspeptin receptor (KISS1R) in the molecular regulation of implantation in a mouse model. To conduct this study, a conditional uterine knockout (KO) of Kiss1r was created using the Pgr-Cre (progesterone receptor-CRE recombinase) driver. Reproductive profiling revealed that while KO females exhibited normal ovarian function and mated successfully to stud males, they exhibited significantly fewer implantation sites, reduced litter size and increased neonatal mortality demonstrating that uterine KISS1R is required for embryo implantation and a healthy pregnancy. Strikingly, in the uterus of Kiss1r KO mice on day 4 (D4) of pregnancy, the day of embryo implantation, KO females exhibited aberrantly elevated epithelial ERα (estrogen receptor α) transcriptional activity. This led to the temporal misexpression of several epithelial genes [Cftr (Cystic fibrosis transmembrane conductance regulator), Aqp5 (aquaporin 5), Aqp8 (aquaporin 8) and Cldn7 (claudin 7)] that mediate luminal fluid secretion and luminal opening. As a result, on D4 of pregnancy, the lumen remained open disrupting the final acquisition of endometrial receptivity and likely accounting for the reduction in implantation events. Our data clearly show that uterine KISS1R negatively regulates ERα signaling at the time of implantation, in part by inhibiting ERα overexpression and preventing detrimentally high ERα activity. To date, there are no reports on the regulation of ERα by KISS1R; therefore, this study has uncovered an important and powerful regulator of uterine ERα during early pregnancy.

Unraveling Human AQP5-PIP Molecular Interaction and Effect on AQP5 Salivary Glands Localization in SS Patients.

Saliva secretion requires effective translocation of aquaporin 5 (AQP5) water channel to the salivary glands (SGs) acinar apical membrane. Patients with Sjögren's syndrome (SS) display abnormal AQP5 localization within acinar cells from SGs that correlate with sicca manifestation and glands hypofunction. Several proteins such as Prolactin-inducible protein (PIP) may regulate AQP5 trafficking as observed in lacrimal glands from mice. However, the role of the AQP5-PIP complex remains poorly understood. In the present study, we show that PIP interacts with AQP5 in vitro and in mice as well as in human SGs and that PIP misexpression correlates with an altered AQP5 distribution at the acinar apical membrane in PIP knockout mice and SS hMSG. Furthermore, our data show that the protein-protein interaction involves the AQP5 C-terminus and the N-terminal of PIP (one molecule of PIP per AQP5 tetramer). In conclusion, our findings highlight for the first time the role of PIP as a protein controlling AQP5 localization in human salivary glands but extend beyond due to the PIP-AQP5 interaction described in lung and breast cancers.

Activation of Aquaporin 5 by carcinogenic Helicobacter pylori infection promotes epithelial-mesenchymal transition via the MEK/ERK pathway.

BACKGROUND: Helicobacter pylori (H. pylori) is a major risk factor for gastric cancer. The water channel protein Aquaporin 5 (AQP5) is involved in the tumorigenesis and progression of various cancers. In this study, we aimed to explore the role of AQP5 in H. pylori-induced gastric carcinogenesis. MATERIALS AND METHODS: We collected 160 samples which inculded CNAG, IM, Dys and gastric cancer from patients who underwent endoscopy and detected the expression of AQP5. In vivo and vitro H. pylori infection models, we explored the relationship between AQP5 and H. pylori. Plasmid, siRNA and inhibitors were used to investigated the relationship between AQP5 and EMT and the role of AQP5 in H. pylori-induced gastric carcinogenesis. RESULT: AQP5 expression was gradually increased in human gastric tissues with the progression of chronic nonatrophic gastritis to gastric cancer and associated with the H. pylori infection status. In vivo and in vitro studies showed that H. pylori infection induced AQP5 expression in gastric epithelial cells in a CagA-dependent manner. Knockdown of AQP5 reversed H. pylori-induced cell proliferation and invasion, and -suppressed cell apoptosis. Additionally, knockdown of AQP5 suppressed H. pylori-induced Epithelial-mesenchymal transition (EMT) phenotypes by regulating transcriptional factors, mesenchymal markers, and epithelial markers. CONCLUSIONS: We explored the underlying mechanism and our results indicated that knockdown of AQP5 significantly suppressed H. pylori infection-induced phosphorylation of ERK1/2, MEK and the expression levels of downstream genes. Treatment with an ERK inhibitor suppressed the EMT induced by H. pylori infection. Taken together, this study suggest that pathogenic H. pylori infection promotes AQP5 expression to induce the EMT via the MEK/ERK signaling pathway.

Pannexin 1 Mediates Gastric Cancer Cell Epithelial-Mesenchymal Transition via Aquaporin 5.

Pannexin 1 (PANX1) has been implicated in cancer emergence and progression. However, its roles in gastric cancer remain unclear. In the present study, the function and molecular mechanisms of PANX1 in gastric cancer were investigated in vitro. Two gastric cancer cell lines exhibiting low and high PANX1 expression (SNU-16 and HCG-27, respectively) were transfected using a PANX1-containing plasmid or PANX1 transcript-targeting short hairpin (sh)RNA. In addition, HCG-27 cells and PANX1-overexpressing SNU-16 cells were subjected to short interfering (si)RNA-mediated aquaporin 5 (AQP5) knockdown. In vitro cell migration (scratch) and transwell invasion assays were performed to evaluate the cell migratory and invasive abilities. Real-time fluorescence quantitative PCR was used to detect transcripts encoding epithelial-mesenchymal transition markers. Immunofluorescence and Western blotting were conducted to quantify corresponding proteins. In SNU-16 cells, PANX1 overexpression induced conversion from round (cobblestone-like) to elongated (spindle-like) morphologies and enhanced the cell migratory and invasive abilities. PANX1 knockdown had the opposite effect in HGC-27 cells. In PANX1-overexpressing SNU-16 cells, expression of SLUG, vimentin, and AQP5 was significantly upregulated, whereas expression of E-cadherin was downregulated. In HGC-27 cells, PANX1 knockdown showed the opposite effect. In both PANX1-overexpressing SNU-16 cells and untransfected HGC-27 cells, silencing of AQP5 expression significantly inhibited PANX1-induced upregulation of SLUG and vimentin expression, as well as downregulation of E-cadherin expression and enhanced migratory and invasive abilities. In summary, elevated PANX1 expression induces gastric cancer cell epithelial-mesenchymal transition and the associated promotion of migratory and invasive abilities by inducing expression of AQP5, which facilitates SLUG-mediated regulation of vimentin and E-cadherin expression.

McH-lpr/lpr-RA1 mice: A novel spontaneous mouse model of autoimmune sialadenitis.

Many studies of the autoimmune disease Sjögren's syndrome have been performed using spontaneous mouse models. In the present study, we describe the characteristics of McH/lpr-RA1 mice and propose their use as a novel murine model of autoimmune sialadenitis. The McH/lpr-RA1 mouse is a recombinant congenic strain derived from generation F54 or more of MRL-Faslpr x (MRL- Faslpr x C3H- Faslpr) F1. We show for the first time that this mouse spontaneously develops autoimmune sialadenitis and vasculitis in submandibular gland tissues. Sialadenitis was accompanied by extensive inflammatory cell infiltration and tissue destruction. Immunohistochemical studies revealed that the salivary gland lesions strongly expressed four sialadenitis-related molecules: SSA and SSB (autoantigens of Sjögren's syndrome), gp91phox (an accelerator of reactive oxygen species production) and single strand DNA (a marker of apoptotic cells). In contrast, expression of aquaporin-5 (AQP5), which stimulates salivary secretion was weak or negligible. Statistical correlation analyses indicated that the apoptosis of salivary gland cells provoked by oxidative stress contributed to the severe sialadenitis and reduced expression of AQP5. Our study has demonstrated that McH/lpr-RA1 mice spontaneously develop the pathognomonic features of autoimmune sialadenitis and thus could be used as a new animal model of Sjögren's syndrome.

AQP3 and AQP5-Potential Regulators of Redox Status in Breast Cancer.

Breast cancer is still one of the leading causes of mortality in the female population. Despite the campaigns for early detection, the improvement in procedures and treatment, drastic improvement in survival rate is omitted. Discovery of aquaporins, at first described as cellular plumbing system, opened new insights in processes which contribute to cancer cell motility and proliferation. As we discover new pathways activated by aquaporins, the more we realize the complexity of biological processes and the necessity to fully understand the pathways affected by specific aquaporin in order to gain the desired outcome-remission of the disease. Among the 13 human aquaporins, AQP3 and AQP5 were shown to be significantly upregulated in breast cancer indicating their role in the development of this malignancy. Therefore, these two aquaporins will be discussed for their involvement in breast cancer development, regulation of oxidative stress and redox signalling pathways leading to possibly targeting them for new therapies.