AQP1

Gene Summary

Gene:AQP1; aquaporin 1 (Colton blood group)
Aliases: CO, CHIP28, AQP-CHIP
Location:7p14
Summary:Aquaporins are a family of small integral membrane proteins related to the major intrinsic protein (MIP or AQP0). This gene encodes an aquaporin which functions as a molecular water channel protein. It is a homotetramer with 6 bilayer spanning domains and N-glycosylation sites. The protein physically resembles channel proteins and is abundant in erythrocytes and renal tubes. The gene encoding this aquaporin is a possible candidate for disorders involving imbalance in ocular fluid movement. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:aquaporin-1
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (90)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Adenocarcinoma
  • Ovarian Cancer
  • Neoplasm Grading
  • Salivary Gland Cancer
  • Blood Group Antigens
  • Water
  • Stomach Cancer
  • Western Blotting
  • Young Adult
  • Immunohistochemistry
  • Immunoenzyme Techniques
  • Aquaporin 3
  • Breast Cancer
  • Lung Cancer
  • Aquaporin 4
  • Cell Membrane
  • Brain Tumours
  • Transduction
  • RTPCR
  • Cancer Gene Expression Regulation
  • Gene Expression Profiling
  • Aquaporin 1
  • Messenger RNA
  • Gene Expression
  • Protein Array Analysis
  • Adolescents
  • Brain Tumours
  • Rats, Wistar
  • Vascular Endothelial Growth Factor Receptor-2
  • Chromosome 7
  • Survival Rate
  • Ubiquitin Thiolesterase
  • Tumor Markers
  • Meningeal Neoplasms
  • Lymphatic Metastasis
  • Base Sequence
  • Uterine Cervicitis
  • RNA Interference
  • Aquaporins
  • Tumor Suppressor Proteins
  • Angiogenesis
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AQP1 (cancer-related)

Xia H, Ye J, Bai H, Wang C
[Effects of cetuximab combined with celecoxib on apoptosis and KDR and AQP1 expression in lung cancer].
Zhongguo Fei Ai Za Zhi. 2013; 16(12):625-31 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy is a new development in the treatment of lung cancer. In recent years, cetuximab and celecoxib have been commonly used in this procedure. This study aims to explore the effect of cetuximab combined with celecoxib on apoptosis and KDR and AQP1 expression in lung cancer A549 cells.
METHODS: The cells were cultured in RPMI-1640 and then divided into four groups: control group, 1 nmol/L cetuximab group, 25 µmol/L celecoxib group, and 1 nmol/L cetuximab+25 µmol/L celecoxib group. The treatment time was 48 h. The mRNA and protein expression levels of KDR and AQP1 were detected by RT-PCR and Western blot, respectively. The apoptosis, proliferation, and invasive ability of A549 cells before and after transfection were examined using flow cytometry, MTT, and transwell methods.
RESULTS: Cetuximab and celecoxib inhibited the growth of A549 cells in a dose-dependent manner. Their combination produced a greater growth inhibition than when either was used alone (P<0.01). Cetuximab and celecoxib both induced the apoptosis of A549 cells, and their combination produced a higher apoptosis rate (P<0.01). Cetuximab in combination with celecoxib also induced G1 phase arrest and downregulated the expression of KDR and AQP1 in A549 cells (P<0.05). As a result, the invasion ability of the A549 cells was significantly decreased.
CONCLUSIONS: Cetuximab in combination with celecoxib can synergistically inhibit the growth of A549 cells and downregulate the expression of KDR and AQP1 in A549 cells. The combination of cetuximab and celecoxib is a potential strategy for lung cancer therapy.

Esteva-Font C, Jin BJ, Verkman AS
Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice.
FASEB J. 2014; 28(3):1446-53 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1(+/+) MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm(3) (SE, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm(3), 12 mice) were greatly reduced in AQP1(-/-) MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1(-/-) MMTV-PyVT mice, with reduced vessel density. HIF-1α expression was increased in tumors in AQP1(-/-) MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1(+/+) MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.

El Hindy N, Rump K, Lambertz N, et al.
The functional Aquaporin 1 -783G/C-polymorphism is associated with survival in patients with glioblastoma multiforme.
J Surg Oncol. 2013; 108(7):492-8 [PubMed] Related Publications
BACKGROUND: Despite a dismal prognosis, variability exists regarding the survival-time in patients with glioblastoma-multiforme (GBM), which may be explained by genetic variation. A possible candidate-gene for such variation is Aquaporin-1 (AQP1), since Aquaporin-1-expression influences the pathogenesis and outcome of various malignancies. Functional genetic variants in the promoter of AQP1, modifying Aquaporin-1-expression, could be associated with altered survival in patients with GBM.
METHODS: We sequenced the human AQP1-promoter to detect novel sequence variants, which might impact on Aquaporin-1-expression and tested the hypothesis, that functional single nucleotide polymorphisms are associated with different survival-times of patients suffering from GBM.
RESULTS: Sequencing the AQP1-promoter revealed a novel -783G/C-polymorphism. Reporter-assays showed that substitution of G for C was associated both with increased transcriptional-activation of the AQP1-promoter by serum and with increased AQP1 mRNA expression. Finally, we assessed in a cohort of 155 Caucasian patients with GBM whether the functional single-nucleotide-783G/C-polymorphism is associated with survival-time. Cox-regression analyses revealed the AQP1 -783G/C genotype status as an independent prognostic-factor when jointly considering other predictors of survival. Homozygous CC subjects had a significantly worse outcome compared to GC/GG genotypes (hazard ratio: 3.09; 95% CI, 1.43-6.65; P = 0.004).
CONCLUSIONS: Our findings suggest the novel AQP1 polymorphism as a survival prognosticator in patients suffering from GBM that could help to identify a subgroup of patients at high risk for death. Further studies are necessary to reveal the exact molecular mechanisms.

Jiang YS, Wang FR
Caloric restriction reduces edema and prolongs survival in a mouse glioma model.
J Neurooncol. 2013; 114(1):25-32 [PubMed] Related Publications
Regardless of their cell type of origin, all aggressive brain tumors, such as malignant gliomas and metastatic tumors produce brain edema, which is an important cause of patient morbidity and mortality. Caloric restriction (CR) has long been recognized as a natural therapy that improves health, promotes longevity, and significantly reduces both the incidence and growth of many tumor types. The aim of present work was to investigate the effect of CR on edema and survival in the mice implanted with U87 gliomas. We found that CR significantly inhibited the intracerebral tumor growth, attenuated brain edema, and ultimately prolonged survival of mice with U87 gliomas. Plasma corticosterone level was found higher and serum VEGF and IGF-1 levels were found lower in CR, when compared to AL group. CR upregulated tight junction proteins including claudin-1, claudin-5 and ZO-1, downregulated VEGF and VEGFR2, enhanced α-SMA expression, and reduced AQP1 expression in U87 gliomas. In addition, CR suppressed inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) formation in U87 gliomas. In conclusion, CR attenuated edema in U87 orthotopic mouse glioma model associated with elevation of corticosterone, suppression of VEGF/VEGFR2, improvement of tight junctions, and suppression of iNOS expression and NO formation. Our results suggested that CR might be an effective therapy for recurrent malignant brain cancers through alleviating associated edema.

Cao XC, Zhang WR, Cao WF, et al.
Aquaporin3 is required for FGF-2-induced migration of human breast cancers.
PLoS One. 2013; 8(2):e56735 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
PURPOSE: The 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.
METHODS: Potential 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.
RESULTS: FGF-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.
CONCLUSIONS: AQP3 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.

Zou LB, Shi S, Zhang RJ, et al.
Aquaporin-1 plays a crucial role in estrogen-induced tubulogenesis of vascular endothelial cells.
J Clin Endocrinol Metab. 2013; 98(4):E672-82 [PubMed] Related Publications
CONTEXT: Aquaporin-1 (AQP1) has been proposed as a mediator of estrogen-induced angiogenesis in human breast cancer and endometrial cancer. Elucidation of the molecular mechanisms governing AQP1-mediated, estrogen-induced angiogenesis may contribute to an improved understanding of tumor development.
OBJECTIVE: Our objective was to identify the estrogen-response element (ERE) in the promoter of the Aqp1 gene and investigate the effects and mechanisms of AQP1 on estrogen-induced tubulogenesis of vascular endothelial cells.
SETTING: The study was conducted in a university hospital in eastern China.
MAIN OUTCOME MEASURES: Immunohistological, real-time PCR and Western blot analyses were used to determine the expression AQP1 mRNA and protein in vascular endothelial cells. Chromatin immunoprecipitation analyses and luciferase reporter assays identified ERE-like motif in the promoter of the Aqp1 gene.
RESULTS: Expression of AQP1 in blood vessels of human breast and endometrial carcinoma tissues were significantly higher than controls. Estradiol (E2) dose-dependently increased the expression levels of AQP1 mRNA and protein in human umbilical vein endothelial cells (HUVECs). A functional ERE-like motif was identified in the promoter of the Aqp1 gene. AQP1 colocalized with ezrin, a component of the ezrin/radixin/moesin protein complex, and, ezrin colocalized with filamentous actin in HUVECs. Knockdown of AQP1 or ezrin with specific small interfering RNA significantly attenuated the formation of transcytoplasmic filamentous actin stress fibers induced by E2 and inhibited E2-enhanced cell proliferation, migration, invasion, and tubule formation of HUVECs.
CONCLUSIONS: Estrogen induces AQP1 expression by activating ERE in the promoter of the Aqp1 gene, resulting in tubulogenesis of vascular endothelial cells. These results provide new insights into the molecular mechanisms underpinning the angiogenic effects of estrogen.

Deb P, Pal S, Dutta V, et al.
Correlation of expression pattern of aquaporin-1 in primary central nervous system tumors with tumor type, grade, proliferation, microvessel density, contrast-enhancement and perilesional edema.
J Cancer Res Ther. 2012 Oct-Dec; 8(4):571-7 [PubMed] Related Publications
OBJECTIVES: Brain edema, a hallmark of malignant brain tumors, continues to be a major cause of mortality. The underlying molecular mechanisms are poorly understood and thought to be mediated through membrane water-channels: aquaporins (AQP1,4,9). The abnormal upregulation of AQP1 in certain glial neoplasms has suggested a potential role in tumor pathogenesis, apart from being a novel target for newer therapeutic regimen. This study was undertaken to evaluate the expression of AQP1 in primary CNS tumors of various histologic types and grades, and its correlation with contrast-enhancement, perilesional edema, histomorphology, proliferation index and microvessel density.
MATERIALS AND METHODS: Biopsy tissues from 30 patients (10 each from gliomas, meningiomas and other primary CNS tumors) were studied. Autopsy brain sections served as control. AQP1-immunoreactivity was correlated with histomorphology, radiology, proliferation index and microvessel density (MVD).
RESULTS: AQP1 expression was increased in gliomas and ependymal tumors as compared to meningiomas. Intratumoral expression was homogenous in high-grade and membranous in low-grade neoplasms, while peritumoral areas showed expression around vessels and reactive astrocytes. High-grade tumors showed peritumoral upregulation, while low-grade had intense intratumoral expression. A trend of positive correlation was observed between AQP1-immunopositivity and increasing grade, higher MIB-1LI, increasing contrast-enhancement and more perilesional edema, and elevated MVD with raised AQP1:MVD ratio.
CONCLUSIONS: AQP1-immunoexpression had a good correlation with high-grade tumors. AQP-upregulation in perilesional areas of high-grade tumors suggests its role in vasogenic edema. Further studies involving other AQP molecules, vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 α (HIF-1α) should be undertaken to evaluate its possible role as a potential surrogate marker of high-grade tumors heralding poor outcome, inhibition of which may serve as the basis for future targeted therapy.

Jagirdar R, Solenov EI, Hatzoglou C, et al.
Gene expression profile of aquaporin 1 and associated interactors in malignant pleural mesothelioma.
Gene. 2013; 517(1):99-105 [PubMed] Related Publications
Overexpression of AQP1 has recently been shown to be an independent prognostic factor in pleural mesothelioma favoring survival. This paper presents a data mining and bioinformatics approach towards the evaluation of the gene expression profile of AQP1 in malignant pleural mesothelioma and of AQP1 associated markers in the context of mesothelioma disease phenotype, CDKN2A gene deletion, sex and asbestos exposure. The data generated were thus again subjected to differential expression profile analysis. Here we report that AQP1 is overexpressed in epithelioid mesothelioma and identify TRIP6 and EFEMP2 as candidate genes for further investigation in mesothelioma.

Wei M, Shi R, Jiang L, et al.
[Role of aquaporin-1 gene in erythroid differentiation of erythroleukemia K562 cells induced by retinoic acid].
Nan Fang Yi Ke Da Xue Xue Bao. 2012; 32(12):1689-94 [PubMed] Related Publications
OBJECTIVE: To explore the role of aquaporin-1 (AQP1) gene in erythroid differentiation of erythroleukemia K562 cells induced by retinoic acid (RA).
METHODS: K562 cells were cultured in the presence of 1 µmol/L RA for varying lengths of time, and γ-globin mRNA expression and hemoglobin content in the cells were detected by real-time PCR (RT-PCR) and ultraviolet spectrophotometry, respectively, to evaluate the erythroid differentiation of K562 cells. RT-PCR and Western blotting were used to examine AQP1 expression in the cells following RA treatment. A retroviral expression vector of AQP1 small interfering RNA (pSUPER-retro-puro-shAQP1) was constructed and transfected into K562 cells to establish a K562 cell line with stable AQP1 down-regulation (K562-shAQP1), in which the changes in γ-globin and hemoglobin expressions after RA treatment were detected.
RESULTS: RA treatment significantly increased γ-globin and hemoglobin expressions in K562 cells (P<0.01), causing also significantly enhanced AQP1 mRNA and protein expressions over time (P<0.01). Transfection with the recombinant plasmids pSuper-retro-puro-shAQP1 resulted in stable AQP1 suppression in K562 cells (P<0.01), which showed markedly reduced γ-globin and hemoglobin expressions after RA induction as compared to the control K562 cells (P<0.01).
CONCLUSION: K562 cells show a significant increase of AQP1 expression after RA-induced erythroid differentiation, and suppression of AQP1 expression can partially block the effect of RA, suggesting the important role of AQP1 in RA-induced erythroid differentiation of K562 cells.

Nicchia GP, Stigliano C, Sparaneo A, et al.
Inhibition of aquaporin-1 dependent angiogenesis impairs tumour growth in a mouse model of melanoma.
J Mol Med (Berl). 2013; 91(5):613-23 [PubMed] Related Publications
Prohibiting angiogenesis is an important therapeutic approach for fighting cancer and other angiogenic related diseases. Research focused on proteins that regulate abnormal angiogenesis has attracted intense interest in both academia and industry. Such proteins are able to target several angiogenic factors concurrently, thereby increasing the possibility of therapeutic success. Aquaporin-1 (AQP1) is a water channel membrane protein that promotes tumour angiogenesis by allowing faster endothelial cell migration. In this study we test the hypothesis that AQP1 inhibition impairs tumour growth in a mouse model of melanoma. After validating the inhibitor efficacy of two different AQP1 specific siRNAs in cell cultures, RNA interference experiments were performed by intratumoural injections of AQP1 siRNAs in mice. After 6 days of treatment, AQP1 siRNA treated tumours showed a 75 % reduction in volume when compared to controls. AQP1 protein level, in AQP1 knockdown tumours, was around 75 % that of the controls and was associated with a significant 40 % reduced expression of the endothelial marker, Factor VIII. Immunofluorescence analysis of AQP1 siRNA treated tumours showed a significantly lower microvessel density. Time course experiments demonstrated that repeated injections of AQP1 siRNA over time are effective in sustaining the inhibition of tumour growth. Finally, we have confirmed the role of AQP1 in sustaining an active endothelium during angiogenesis and we have shown that AQP1 reduction causes an increase in VEGF levels. In conclusion, this study validates AQP1 as a pro-angiogenic protein, relevant for the therapy of cancer and other angiogenic-related diseases such as psoriasis, endometriosis, arthritis and atherosclerosis.

Stephen JH, Sievert AJ, Madsen PJ, et al.
Spinal cord ependymomas and myxopapillary ependymomas in the first 2 decades of life: a clinicopathological and immunohistochemical characterization of 19 cases.
J Neurosurg Pediatr. 2012; 9(6):646-53 [PubMed] Related Publications
OBJECT: Primary spinal cord ependymomas (EPNs) are rare in children, comprising classical WHO Grade II and III tumors and Grade I myxopapillary ependymomas (MEPNs). Despite their benign histology, recurrences and neural-axis dissemination have been reported in up to 33% MEPNs in the pediatric population. Treatment options beyond resection are limited, and little is known about their tumorigenesis. The purpose of this study was to explore the tumor biology and outcomes in a consecutive series of pediatric patients treated at a single institution.
METHODS: The authors performed a retrospective clinicopathological review of 19 patients at a tertiary referral children's hospital for resection of a spinal cord ependymoma. The population included 8 patients with a pathological diagnosis of MEPN and 11 patients with a pathological diagnosis of spinal EPN (10 cases were Grade II and 1 case was Grade III). The upregulation of the following genes HOXB13, NEFL, PDGFRα, EGFR, EPHB3, AQP1, and JAGGED 1 was studied by immunohistochemistry from archived paraffin-embedded tumor samples of the entire cohort to compare the expression in MEPN versus EPN.
RESULTS: Gross-total resection was achieved in 75% of patients presenting with MEPNs and in 100% of those with EPNs. The average follow-up period was 79 months for the MEPN subset and 53 months for Grade II/III EPNs. Overall survival for both subsets was 100%. However, event-free survival was only 50% for patients with MEPNs. Of note, in all cases involving MEPNs that recurred, the patients had undergone gross-total resection on initial surgery. In contrast, there were no tumor recurrences in patients with EPNs. Immunohistochemistry revealed no significant differences in protein expression between the two tumor types with the exception of EPHB3, which demonstrates a tendency to be positive in MEPNs (6 reactive tumors of 9) rather than in EPN (2 reactive tumors of 10).
CONCLUSIONS: The authors' experience shows that, following a gross-total resection, MEPNs are more likely to recur than their higher-grade counterpart, EPNs. This supports the recommendation for close long-term radiological follow-up of pediatric patients with MEPNs to monitor for recurrence, despite the tumor's low-grade histological feature. No significant difference in the protein expression of HOXB13, NEFL, PDGFRα, EGFR, EPHB3, AQP1, and JAGGED 1 was present in this selected cohort of pediatric patients.

Pan XY, Guo H, Han J, et al.
Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells.
Eur J Pharmacol. 2012; 683(1-3):27-34 [PubMed] Related Publications
Ginsenoside Rg3 (Rg3), one of the bioactive extracts found in ginseng root, was reported to have anti-cancer activity in various cancer models. The anti-proliferation effect of Rg3 on prostate cancer cells has been well reported. To test whether Rg3 has an anti-metastatic effect on prostate cancer, we treated a highly metastatic PC-3M prostate cancer cell line with Rg3. We found that Rg3 (10μM) led to remarkable inhibition of PC-3M cell migration. Simultaneously, exposure to Rg3 suppressed expression of the aquaporin 1 (AQP1) water channel protein, which has previously been reported to be involved in cell migration. Overexpression of AQP1 attenuated Rg3-induced inhibition of cell migration, and introduction of a shRNA targeting AQP1 abrogated the inhibitory effect of Rg3, although the basal level of cell migration was decreased by RNA interference. In mechanism study, estrogen receptor- and glucocorticoid receptor-dependent pathways are proved uninvolved in the AQP1 regulation by Rg3. However, Rg3 treatment triggered the activation of p38 MAPK; and SB202190, a specific inhibitor of p38 MAPK, antagonized the Rg3-induced regulation of AQP1 and cell migration, suggesting a crucial role for p38 in the regulation process. Deletion analysis of the promoter region of AQP1 was also conducted using dual-luciferase assay, which indicated that the -1000 bp to -200 bp promoter region was involved in the AQP1 regulation by Rg3. In all, we conclude that Rg3 effectively suppresses migration of PC-3M cells by down-regulating AQP1 expression through p38 MAPK pathway and some transcription factors acting on the AQP1 promoter.

Fossdal G, Vik-Mo EO, Sandberg C, et al.
Aqp 9 and brain tumour stem cells.
ScientificWorldJournal. 2012; 2012:915176 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Several studies have implicated the aquaporins (aqp) 1, 4, and 9 in the pathogenesis of malignant brain tumours, suggesting that they contribute to motility, invasiveness, and oedema formation and facilitate metabolism in tumour cells under hypoxic conditions. We have studied the expression of aqp1, 4, and 9 in biopsies from glioblastomas, isolated tumour stem cells grown in a tumoursphere assay and analyzed the progenitor and differentiated cells from these cultures. We have compared these to the situation in normal rat brain, its stem cells, and differentiated cells derived thereof. In short, qPCR in tumour tissue showed presence of aqp1, 4, and 9. In the tumour progenitor population, aqp9 was markedly more highly expressed, whilst in tumour-derived differentiated cells, aqp4 was downregulated. However, immunostaining did not reveal increased protein expression of aqp9 in the tumourspheres containing progenitor cells; in contrast, its expression (both mRNA and protein) was high in differentiated cultures. We, therefore, propose that aquaporin 9 may have a central role in the tumorigenesis of glioblastoma.

Wang SL, Gao RT
Gene transfer-mediated functional restoration for irradiated salivary glands.
Chin J Dent Res. 2011; 14(1):7-13 [PubMed] Related Publications
Radiation therapy for malignant tumours in the head and neck region are inevitably associated with significant long-term injury to the salivary glands, often resulting in salivary gland hypofunction. The subsequent lack of saliva production leads to many functional and quality-of-life problems for affected patients and there is no effective method to eliminating this problem caused by radiation treatments. Although many studies have been done in animal models, the mechanism of this injury in humans is still unclear. In this review, an animal model (miniature pigs) used in irradiated research is mainly discussed. This review also presents the progress made to date on the gene transfer-mediated functional restoration of irradiated salivary glands and the possibilities provided by future interventions to prevent radiation damage to salivary glands.

Shao C, Sun W, Tan M, et al.
Integrated, genome-wide screening for hypomethylated oncogenes in salivary gland adenoid cystic carcinoma.
Clin Cancer Res. 2011; 17(13):4320-30 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
PURPOSE: Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy that is poorly understood. To look for relevant oncogene candidates under the control of promoter methylation, an integrated, genome-wide screen was conducted.
EXPERIMENTAL DESIGN: Global demethylation of normal salivary gland cell strains using 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A (TSA), followed by expression array analysis was conducted. ACC-specific expression profiling was generated using expression microarray analysis of primary ACC and normal samples. Next, the two profiles were integrated to identify a subset of genes for further validation of promoter demethylation in ACC versus normal. Finally, promising candidates were further validated for mRNA, protein, and promoter methylation levels in larger ACC cohorts. Functional validation was then conducted in cancer cell lines.
RESULTS: We found 159 genes that were significantly re-expressed after 5-aza-dC/TSA treatment and overexpressed in ACC. After initial validation, eight candidates showed hypomethylation in ACC: AQP1, CECR1, C1QR1, CTAG2, P53AIP1, TDRD12, BEX1, and DYNLT3. Aquaporin 1 (AQP1) showed the most significant hypomethylation and was further validated. AQP1 hypomethylation in ACC was confirmed with two independent cohorts. Of note, there was significant overexpression of AQP1 in both mRNA and protein in the paraffin-embedded ACC cohort. Furthermore, AQP1 was upregulated in 5-aza-dC/TSA-treated SACC83. Finally, AQP1 promoted cell proliferation and colony formation in SACC83.
CONCLUSIONS: Our integrated, genome-wide screening method proved to be an effective strategy for detecting novel oncogenes in ACC. AQP1 is a promising oncogene candidate for ACC and is transcriptionally regulated by promoter hypomethylation.

Warth A, Muley T, Meister M, et al.
Loss of aquaporin-4 expression and putative function in non-small cell lung cancer.
BMC Cancer. 2011; 11:161 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Aquaporins (AQPs) have been recognized to promote tumor progression, invasion, and metastasis and are therefore recognized as promising targets for novel anti-cancer therapies. Potentially relevant AQPs in distinct cancer entities can be determined by a comprehensive expression analysis of the 13 human AQPs.
METHODS: We analyzed the presence of all AQP transcripts in 576 different normal lung and non-small cell lung cancer (NSCLC) samples using microarray data and validated our findings by qRT-PCR and immunohistochemistry.
RESULTS: Variable expression of several AQPs (AQP1, -3, -4, and -5) was found in NSCLC and normal lung tissues. Furthermore, we identified remarkable differences between NSCLC subtypes in regard to AQP1, -3 and -4 expression. Higher transcript and protein levels of AQP4 in well-differentiated lung adenocarcinomas suggested an association with a more favourable prognosis. Beyond water transport, data mining of co-expressed genes indicated an involvement of AQP4 in cell-cell signalling, cellular movement and lipid metabolism, and underlined the association of AQP4 to important physiological functions in benign lung tissue.
CONCLUSIONS: Our findings accentuate the need to identify functional differences and redundancies of active AQPs in normal and tumor cells in order to assess their value as promising drug targets.

Li Q, Zhang B
Expression of aquaporin-1 in nasopharyngeal cancer tissues.
J Otolaryngol Head Neck Surg. 2010; 39(5):511-5 [PubMed] Related Publications
OBJECTIVE: To investigate the expression of aquaporin-1 (AQP1) in nasopharyngeal tumour and nontumour tissues.
METHOD: Thirty nasopharyngeal biopsy samples were collected and examined with both immunohistochemistry and real-time fluorescence quantitative polymerase chain reaction (RT-PCR) to detect the expression level of AQP1 in tissues.
RESULTS: Immunohistochemistry data suggested that AQP1 was expressed in both nasopharyngeal tumour and normal tissues, but tumour tissues were stained a lot stronger than nontumour tissues. RT-PCR analysis further confirmed the overexpression of AQP1 in tumour tissues; migrated tumour tissue had even higher expression.
CONCLUSION: The expression level of aquaporin-1 in nasopharyngeal cancer tissue could be involved in tumour migration.

Freeman A, Hetzel U, Cripps P, Mobasheri A
Expression of the plasma membrane markers aquaporin 1 (AQP1), glucose transporter 1 (GLUT1) and Na, K-ATPase in canine mammary glands and mammary tumours.
Vet J. 2010; 185(1):90-3 [PubMed] Related Publications
This study investigated the expression of the plasma membrane markers aquaporin 1 (AQP1), glucose transporter 1 (GLUT1) and the alpha1 subunit of Na, K-ATPase in normal canine mammary glands and in benign and malignant mammary tumours, using immunohistochemistry and semi-quantitative histomorphometry. AQP1 immunoreactivity was absent from the majority of specimens studied. GLUT1 immunoreactivity was observed in normal mammary tissue and particularly in the epithelial and mesenchymal cells of benign, and in the epithelial cells of malignant tumours, respectively. Na, K-ATPase immunoreactivity was present in normal and neoplastic mammary epithelium and was significantly increased in the epithelium of both benign and malignant tumours. These results suggest that GLUT1 is more highly expressed in neoplastic epithelium and mesenchyme and that Na, K-ATPase is more highly expressed in neoplastic mammary epithelium. In consequence, these membrane proteins may have potential as diagnostic and prognostic biomarkers of canine mammary neoplasia.

Ishiyama G, Lopez IA, Beltran-Parrazal L, Ishiyama A
Immunohistochemical localization and mRNA expression of aquaporins in the macula utriculi of patients with Meniere's disease and acoustic neuroma.
Cell Tissue Res. 2010; 340(3):407-19 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Meniere's disease is nearly invariably associated with endolymphatic hydrops (the net accumulation of water in the inner ear endolymphatic space). Vestibular maculae utriculi were acquired from patients undergoing surgery for Meniere's disease and acoustic neuroma and from autopsy (subjects with normal hearing and balance). Quantitative immunostaining was conducted with antibodies against aquaporins (AQPs) 1, 4, and 6, Na(+)K(+)ATPase, Na(+)K(+)2Cl co-transporter (NKCC1), and alpha-syntrophin. mRNA was extracted from the surgically acquired utricles from subjects with Meniere's disease and acoustic neuroma to conduct quantitative real-time reverse transcription with polymerase chain reaction for AQP1, AQP4, and AQP6. AQP1 immunoreactivity (-IR) was located in blood vessels and fibrocytes in the underlying stroma, without any apparent alteration in Meniere's specimens when compared with acoustic neuroma and autopsy specimens. AQP4-IR localized to the epithelial basolateral supporting cells in Meniere's disease, acoustic neuroma, and autopsy. In specimens from subjects with Meniere's disease, AQP4-IR was significantly decreased compared with autopsy and acoustic neuroma specimens. AQP6-IR occurred in the sub-apical vestibular supporting cells in acoustic neuroma and autopsy samples. However, in Meniere's disease specimens, AQP6-IR was significantly increased and diffusely redistributed throughout the supporting cell cytoplasm. Na(+)K(+)ATPase, NKCC1, and alpha-syntrophin were expressed within sensory epithelia and were unaltered in Meniere's disease specimens. Expression of AQP1, AQP4, or AQP6 mRNA did not differ in vestibular endorgans from patients with Meniere's disease. Changes in AQP4 (decreased) and AQP6 (increased) expression in Meniere's disease specimens suggest that the supporting cell might be a cellular target.

Shen L, Zhu Z, Huang Y, et al.
Expression profile of multiple aquaporins in human gastric carcinoma and its clinical significance.
Biomed Pharmacother. 2010; 64(5):313-8 [PubMed] Related Publications
BACKGROUND: New evidence for involvement of aquaporins (AQPs) in cell migration and proliferation adds AQPs to an expanding list of effectors in tumor biology. But there is few report concerning the expression and role of AQPs in human gastric carcinogenesis so far. The aim of this current study was to investigate the expression profile of AQPs in human gastric carcinoma and its significance.
METHODS: We screened the expression profile of AQP0 approximately AQP12 in gastric adenocarcinoma tissues and corresponding normal mucosa from 89 patients with gastric cancer by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis and immunochemical assay. The relationship between AQPs expression and clinicopathologic characteristics of patients was evaluated.
RESULTS: Based on RT-PCR of 13 AQPs examined, AQP1, 3, 4, 5 and 11 were expressed in human gastric cancers or normal gastric tissues, and AQP3, 4 and 5 exhibited differential expression between human gastric carcinomas and corresponding normal tissues, which was confirmed by Western blot analyses. Immunohistochemical assay showed that AQP4 protein was expressed mainly in the membrane of parietal cell and chief cell in the normal gastric mucosa, and absent in carcinoma tissues. AQP3 and AQP5 were detected remarkably stronger in the carcinoma tissues than that in normal mucosa by immunofluorescence. AQP3 expression in cases with undifferentiated tumor was more than that in cases with well-differentiated tumor. Both AQP3 and AQP5 expression were associated with lymph node metastasis and lymphovascular invasion in patients.
CONCLUSIONS: These findings of differential expressions of AQPs and their correlation with clinicopathologic characteristics implicated AQPs might play a role in human gastric carcinogenesis.

Kim JW, Hwang I, Kim MJ, Jang SJ
Clinicopathological characteristics and predictive markers of early gastric cancer with recurrence.
J Korean Med Sci. 2009; 24(6):1158-64 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Early gastric cancer (EGC) is a "curable" disease with a high cure rate made possible through proper surgical treatment; nonetheless, some patients sustain a disease recurrence after curative resection. The aim of this study was to identify the clinicopathological characteristics of recurrent EGC and determine predictable immunohistochemical markers for recurrence. We investigated the clinicopathological features of 1,786 EGC cases, and using tissue microarray, the expression of c-erbB-2, EGFR, MLH1, MSH2, p53, and AQP1 was examined in group with recurrence and control group without recerrence. In the clinical analysis, 32 of 1,786 (1.79%) patients showed recurrence, with a 2.04% five-year cumulative recurrence rate. Age, submucosal invasion, and lymph node metastasis significantly correlated with tumor recurrence (P=0.044, 0.019, and <0.001, respectively). Multivariate analysis showed lymph node status and old age (>or=57 yr) as independent risk factors of recurrence. In a case-control study, immunopositivity for c-erbB-2 was significantly associated with disease recurrence (P=0.024). There is the probability that EGC patients with old age (>or=57 yr), lymph node metastasis, submucosal invasion, and c-erbB-2 immunopositivity will experience recurrence; therefore, it is critical that patients with these risk factors be followed-up closely and considered candidates for adjuvant treatment.

Huang Y, Murakami T, Sano F, et al.
Expression of aquaporin 1 in primary renal tumors: a prognostic indicator for clear-cell renal cell carcinoma.
Eur Urol. 2009; 56(4):690-8 [PubMed] Related Publications
BACKGROUND: Aquaporin 1 (AQP1) is a water channel expressed in many epithelial tissues and endothelium, including the proximal nephron of the kidney.
OBJECTIVE: We measured AQP1 expression in primary renal cell carcinomas (RCCs) and evaluated its significance and prognostic utility.
DESIGN, SETTING, AND PARTICIPANTS: We examined AQP1 expression in 559 sporadic renal tumors as well as in 43 normal kidney tissue samples and collected clinicopathologic and prognostic data.
MEASUREMENTS: AQP1 expression was measured by using real-time quantitative polymerase chain reaction (PCR).
RESULTS AND LIMITATIONS: All normal kidney samples presented substantial AQP1 expression. Among tumor subtypes, AQP1 expression was significantly higher in clear-cell and papillary RCCs, whereas it was lower in chromophobe RCCs, oncocytomas, and collecting-duct carcinomas. In clear-cell RCC, AQP1 was significantly higher in patients without symptomatic presentation or whose tumors were smaller, lower grade, or either lower stage or lacking in microvascular invasion. Von Hippel-Lindau (VHL) tumor suppressor gene mutational status did not affect expression level. Cox univariate and multivariate analyses strongly associated high AQP1 expression with better prognosis in cancer-specific and cancer-free survival tests in all patient cohorts, as well as in cancer-specific survival in a cohort of patients with advanced metastatic RCC. The time-dependent receiver operation characteristic (ROC) analyses, combined with logistic regression models, revealed that the addition of the AQP1 parameter to the University of California Los Angeles Integrated Staging System (UISS) prognostic score can improve the accuracy of predictions of both cancer death and recurrence for all patient cohorts as well as of cancer death for advanced cases within a 5-yr follow-up period in clear-cell RCC. High AQP1 expression was also associated with better outcome in a univariate cancer-specific survival test in papillary RCCs.
CONCLUSIONS: AQP1 shows RCC subtype-specific expression, and its expression level provides useful prognostic information for patients with clear-cell RCC.

Galamb O, Sipos F, Solymosi N, et al.
Diagnostic mRNA expression patterns of inflamed, benign, and malignant colorectal biopsy specimen and their correlation with peripheral blood results.
Cancer Epidemiol Biomarkers Prev. 2008; 17(10):2835-45 [PubMed] Related Publications
PURPOSE: Gene expression profile (GEP)-based classification of colonic diseases is a new method for diagnostic purposes. Our aim was to develop diagnostic mRNA expression patterns that may establish the basis of a new molecular biological diagnostic method.
EXPERIMENTAL DESIGN: Total RNA was extracted, amplified, and biotinylated from frozen colonic biopsies of patients with colorectal cancer (n=22), adenoma (n=20), hyperplastic polyp (n=11), inflammatory bowel disease (n=21), and healthy normal controls (n=11), as well as peripheral blood samples of 19 colorectal cancer and 11 healthy patients. Genome-wide gene expression profile was evaluated by HGU133plus2 microarrays. To identify the differentially expressed features, the significance analysis of microarrays and, for classification, the prediction analysis of microarrays were used. Expression patterns were validated by real-time PCR. Tissue microarray immunohistochemistries were done on tissue samples of 121 patients.
RESULTS: Adenoma samples could be distinguished from hyperplastic polyps by the expression levels of nine genes including ATP-binding cassette family A, member 8, insulin-like growth factor 1 and glucagon (sensitivity, 100%; specificity, 90.91%). Between low-grade and high-grade dysplastic adenomas, 65 classifier probesets such as aquaporin 1, CXCL10, and APOD (90.91/100) were identified; between colorectal cancer and adenoma, 61 classifier probesets including axin 2, von Willebrand factor, tensin 1, and gremlin 1 (90.91/100) were identified. Early- and advanced-stage colorectal carcinomas could be distinguished using 34 discriminatory transcripts (100/66.67).
CONCLUSIONS: Whole genomic microarray analysis using routine biopsy samples is suitable for the identification of discriminative signatures for differential diagnostic purposes. Our results may be the basis for new GEP-based diagnostic methods.

Yin T, Yu S, Xiao L, et al.
Correlation between the expression of aquaporin 1 and hypoxia-inducible factor 1 in breast cancer tissues.
J Huazhong Univ Sci Technolog Med Sci. 2008; 28(3):346-8 [PubMed] Related Publications
The correlation between aquaporin 1 (AQP1) and hypoxia-inducible factor 1 (HIF 1) in breast cancer tissues was preliminarily studied. In 155 cases of breast cancer, the expression levels of AQP1 were detected by immunohistochemistry in HIF1-positive group or HIF1-negative group, and the correlation between AQP1 and HIF1 was analyzed. The overexpression of AQP1 and HIF1 were observed in 155 cases of breast cancer tissues. The expression level of AQP1 in HIF1-positive group was significantly higher than that in HIF1-negative group. The positive expression rate of AQP1 was 296.55+/-24.67 and 168.37+/-37.53 in HIF1-positive group and HIF1-negative group respectively with the difference being very significant between them (P<0.001). It was concluded that AQP1 was overexpressed in the HIF1-positive group and there were some correlations between AQP1 and HIF1, suggesting they interact each other and regulate the oncogenesis of breast cancer.

Kopantzev EP, Monastyrskaya GS, Vinogradova TV, et al.
Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma.
Lung Cancer. 2008; 62(1):23-34 [PubMed] Related Publications
We, for the first time, directly compared gene expression profiles in human non-small cell lung carcinomas (NSCLCs) and in human fetal lung development. Previously reported correlations of gene expression profiles between lung cancer and lung development, deduced from matching data on mouse development and human cancer, have brought important information, but suffered from different timing of mouse and human gene expression during fetal development and fundamental differences in tumorigenesis in mice and humans. We used the suppression subtractive hybridization technique to subtract cDNAs prepared from human fetal lung samples at weeks 10-12 and 22-24 and obtained a cDNA library enriched in the transcripts more abundant at the later stage. cDNAs sequencing and RT-PCR analysis of RNAs from human fetal and adult lungs revealed 12 differentially transcribed genes: ADH1B, AQP1, FOLR1, SLC34A2, CAV1, INMT, TXNIP, TPM4, ICAM-1, HLA-DRA, EFNA1 and HLA-E. Most of these genes were found up-regulated in mice and rats at later stages than in human lung development. In surgical samples of NSCLC, these genes were down-regulated as compared to surrounding normal tissues and normal lungs, thus demonstrating opposite expression profiles for the genes up-regulated during fetal lung development.

Hayashi Y, Edwards NA, Proescholdt MA, et al.
Regulation and function of aquaporin-1 in glioma cells.
Neoplasia. 2007; 9(9):777-87 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Glioblastoma multiformes (GBMs) express increased aquaporin (AQP) 1 compared to normal brain. AQPs may contribute to edema, cell motility, and shuttling of H(2)O and H(+) from intracellular to extracellular space. We sought to gain insight into AQP1 function in GBM. In cultured 9L gliosarcoma cells, AQP1 expression was induced by dexamethasone, platelet-derived growth factor, NaCl, hypoxia, D-glucose (but not L-glucose), and fructose. Induction of AQP1 expression correlated with the level of glycolysis, maximized by increasing medium D-glucose or fructose and decreasing O(2), and was quantified by measuring lactate dehydrogenase (LDH) activity and medium lactate concentration. Upregulation of the protease cathepsin B was also observed in 9L cells cultured under glycolytic conditions. Immunohistochemical staining of human GBM specimens revealed increased coincident expression of AQP1, LDH, and cathepsin B in glioma cells associated with blood vessels at the tumor periphery. GBMs are known to exhibit aerobic glycolysis. Increased glucose metabolism at the tumor periphery may provide a scenario by which upregulation of AQP1, LDH, and cathepsin B contributes to acidification of the extracellular milieu and to invasive potential of glioma cells in perivascular space. The specific upregulation and metabolic consequences of increased AQP1 in gliomas may provide a therapeutic target, both as a cell surface marker and as a functional intervention.

Aishima S, Kuroda Y, Nishihara Y, et al.
Down-regulation of aquaporin-1 in intrahepatic cholangiocarcinoma is related to tumor progression and mucin expression.
Hum Pathol. 2007; 38(12):1819-25 [PubMed] Related Publications
Aquaporin-1 (AQP-1) has been found to be important in bile formation across cell membranes of the biliary epithelium, and thus it has been suggested that AQP-1 is involved in the pathogenesis of hepatobiliary disease. To clarify the role of AQP-1 in the development of intrahepatic cholangiocarcinoma, we determined AQP-1 expression in the normal bile duct, 21 cases of biliary dysplasia, and in 112 cases of intrahepatic cholangiocarcinoma by immunohistochemical analysis. Mucus core protein 5AC expression, a poor prognostic marker of intrahepatic cholangiocarcinoma, was also assessed in intrahepatic cholangiocarcinoma cases. High (>50%) expression of AQP-1 was detected in 16% (9/58) of the normal large bile ducts examined, and in 48% (10/21) of the biliary dysplasia samples originating from large bile ducts. High (>50%), low (40 mm) and poorly differentiated histology were significantly more prevalent in the negative AQP-1 group than in the high AQP-1 group. Low or negative AQP-1 expression was associated with positive lymph node metastasis (P=.0001). AQP-1 expression was found to inversely correlate with that of mucus core protein 5AC, and their distributions tended to be complementary. The low and negative AQP-1 expression was an independent prognostic factor by multivariate survival analysis. We concluded that AQP-1 is up-regulated in biliary dysplasia, as compared with in the normal large bile duct, and down-regulation of AQP-1 is associated with mucin production and aggressive progression of intrahepatic cholangiocarcinoma.

McCoy E, Sontheimer H
Expression and function of water channels (aquaporins) in migrating malignant astrocytes.
Glia. 2007; 55(10):1034-43 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Aquaporins (AQP) constitute the principal pathway for water movement across biological membranes. Consequently, their expression and function is important for cell volume regulation. Glioma cells quickly adjust their cell volume in response to osmotic challenges or spontaneously as they invade into the narrow and tortuous extracellular spaces of the brain. These cell volume changes are likely to engage water movements across the cell membrane through AQP. AQP expression in glioma cells is poorly understood. In this study, we examined the expression of AQP in several commonly used human glioma cell lines (D54, D65, STTG1, U87, U251) and in numerous acute patient biopsies by PCR, Western blot, and immunocytochemistry and compared them to nonmalignant astrocytes and normal brain. All glioma patient biopsies expressed AQP1, AQP4 and some expressed AQP5. However, when isolated and grown as cell lines they lose all AQP proteins except a few cell lines that maintain expression of AQP1 (D65, U251, GBM62). Reintroducing either AQP1 or AQP4 stably into glioma cell lines allowed us to show that each AQP is sufficient to restore water permeability. Yet, only the presence of AQP1, but not AQP4, enhanced cell growth and migration, typical properties of gliomas, while AQP4 enhanced cell adhesion suggesting differential biological roles for AQP1 and AQP4 in glioma cell biology.

Murakami T, Sano F, Huang Y, et al.
Identification and characterization of Birt-Hogg-Dubé associated renal carcinoma.
J Pathol. 2007; 211(5):524-31 [PubMed] Related Publications
The Birt-Hogg-Dubé (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP-sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline-mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real-time quantitative PCR (RQ-PCR) was very low. Renal tumour subtype/nephron segment-specific gene expression detected by RQ-PCR demonstrated that the tumour expressed relatively high amounts of alpha-methylacyl-CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11-beta-hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub-classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron-associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD-mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification.

Tanimizu N, Miyajima A, Mostov KE
Liver progenitor cells develop cholangiocyte-type epithelial polarity in three-dimensional culture.
Mol Biol Cell. 2007; 18(4):1472-9 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Cholangiocytes are cellular components of the bile duct system of the liver, which originate from hepatoblasts during embryonic liver development. Although several transcription factors and signaling molecules have been implicated in bile duct development, its molecular mechanism has not been studied in detail. Here, we applied a three-dimensional (3D) culture technique to a liver progenitor cell line, HPPL, to establish an in vitro culture system in which HPPL acquire differentiated cholangiocyte characteristics. When HPPL were grown in a gel containing Matrigel, which contains extracellular matrix components of basement membrane, HPPL developed apicobasal polarity and formed cysts, which had luminal space inside. In the cysts, F-actin bundles and atypical protein kinase C were at the apical membrane, E-cadherin was localized at the lateral membrane, and beta-catenin and integrin alpha6 were located at the basolateral membrane. HPPL in cysts expressed cholangiocyte markers, including cytokeratin 19, integrin beta4, and aquaporin-1, but not a hepatocyte marker, albumin. Furthermore, HPPL transported rhodamine 123, a substrate for multidrug resistance gene products, from the basal side to the central lumen. These data indicate that HPPL develop cholangiocyte-type epithelial polarity in 3D culture. Phosphatidylinositol 3-kinase signaling was essential for proliferation and survival of HPPL in culture, whereas laminin-1 was a crucial component of Matrigel for inducing epithelial polarization of HPPL. Because HPPL cysts display structural and functional similarities with bile ducts, the 3D culture of HPPL recapitulates in vivo cholangiocyte differentiation and is useful to study the molecular mechanism of bile duct development in vitro.

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