Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Kidney Int ; 91(2): 412-422, 2017 02.
Article in English | MEDLINE | ID: mdl-28341240

ABSTRACT

Neutrophil gelatinase-associated lipocalin (Ngal) is a biomarker for acute and chronic renal injuries, including polycystic kidney disease (PKD). However, the effect of Ngal on PKD progression remains unexplored. To study this, we generated 3 strains of mice with different expression levels of Ngal within an established PKD model (Pkd1L3/L3): Pkd1L3/L3 (with endogenous Ngal), Pkd1L3/L3; NgalTg/Tg (with endogenous and overexpression of exogenous kidney-specific Ngal) and Pkd1L3/L3; Ngal-/- mice (with Ngal deficiency). Knockout of endogenous Ngal had no effect on phenotypes, cystic progression, or survival of the PKD mice. However, the transgenic mice had a significantly longer lifespan, smaller (but not fewer) renal cysts, and less interstitial fibrosis than the mice without or with endogenous Ngal. Western-blot analyses showed significant increases in Ngal and cleaved caspase-3 and decreases in α-smooth muscle actin, hypoxia-inducible factor 1-α, pro-caspase 3, proliferating cell nuclear antigen, Akt, mammalian target of rapamycin, and S6 Kinase in the transgenic mice as compared with the other 2 strains of PKD mice. Thus, overexpression of exogenous kidney-specific Ngal reduced cystic progression and prolonged the lifespan in PKD mice, was associated with reductions in interstitial fibrosis and proliferation, and augmented apoptosis.


Subject(s)
Kidney/metabolism , Lipocalin-2/metabolism , Polycystic Kidney Diseases/metabolism , Actins/metabolism , Animals , Apoptosis , Cadherins/genetics , Caspase 3/metabolism , Cell Proliferation , Disease Models, Animal , Disease Progression , ErbB Receptors/metabolism , Female , Fibrosis , Genetic Predisposition to Disease , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney/pathology , Lipocalin-2/genetics , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Phosphorylation , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Proliferating Cell Nuclear Antigen/metabolism , Promoter Regions, Genetic , Ribosomal Protein S6 Kinases/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , TRPP Cation Channels/genetics , TRPP Cation Channels/metabolism , Time Factors
2.
Carcinogenesis ; 30(9): 1475-86, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19483190

ABSTRACT

Receptor tyrosine kinase EphB3 is expressed in cells in the bottom of intestinal crypts near stem cell niches. Loss of Ephb3 has recently been reported to produce invasive colorectal carcinoma in Apc(Min/+) mice and EphB-mediated compartmentalization was demonstrated to be a mechanism suppressing colorectal cancer progression; however, it is unknown whether other factors contribute to EphB-mediated tumor suppression. EphA4-ephrin-A and EphB4-ephrin-B2 signaling have been reported to promote mesenchymal-to-epithelial transition (MET). Here, we examine whether EphB3-ephrin-B interaction has a similar effect and investigate its role in tumor suppression. We found in a clinical cohort that EphB3 expression was significantly reduced in advanced Dukes' stage tumor specimens, so we over-expressed EphB3 in HT-29 cells by stable transfection. EphB3 over-expression inhibited HT-29 growth in monolayer cultures, anchorage-independent growth in soft agar and xenograft growth in nude mice and initiated morphological, behavioral and molecular changes consistent with MET. Specifically, EphB3 over-expression re-organized cytoskeleton (converting spreading cells to a cobble-like epithelial morphology, patterning cortical actin cytoskeleton and polarizing E-cadherin and ZO-1), induced functional changes favoring MET (decreased transwell migration, increased apoptosis and Ca(2+)-dependent cell-cell adhesion), decreased mesenchymal markers (fibronectin and nuclear beta-catenin), increased epithelial markers (ZO-1, E-cadherin and plakoglobin) and inactivated CrkL-Rac1, a known epithelial-to-mesenchymal transition signaling pathway. Additionally, cross talk from Wnt signaling potentiated the restoration of epithelial cell polarity. Noteworthily, the same factors contributing to MET, owing to EphB3 signaling, also facilitated tumor suppression. We conclude that EphB3-ephrin-B interaction promotes MET by re-establishing epithelial cell-cell junctions and such an MET-promoting effect contributes to EphB3-mediated tumor suppression.


Subject(s)
Cell Communication , Colonic Neoplasms/prevention & control , Receptor, EphB3/physiology , Tumor Suppressor Proteins/physiology , Adaptor Proteins, Signal Transducing/physiology , Animals , Cell Polarity , Colonic Neoplasms/pathology , Epithelial Cells/pathology , HT29 Cells , Humans , Male , Mesoderm/pathology , Mice , Mice, Inbred BALB C , Neoplasm Invasiveness , Neoplasm Transplantation , Nuclear Proteins/physiology , Signal Transduction , Transplantation, Heterologous , Wnt Proteins/physiology
3.
Cancer Epidemiol Biomarkers Prev ; 14(2): 437-43, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15734970

ABSTRACT

PURPOSE: We hypothesize that changes in the transcription of up-regulated genes are biologically meaningful and may be linked to variations in tumor behavior and clinical features. This study aimed to find individual up-regulated genes responsible for clinicopathologic variations in human colorectal cancer. EXPERIMENTAL DESIGN: Genes up-regulated concurrently in four microarray experiments were taken as candidate genes; 20 candidate genes were verified using real-time reverse transcription-PCR in these four experiments, along with 27 new samples. The presence or absence of up-regulation of these genes was correlated with 10 clinicopathologic variables from 31 patients. The mRNA transcript levels of these 20 candidate genes in the 31 paired samples were also correlated with each other to disclose any expression relationship. RESULTS: Forty percent (8/20) of the candidate genes were verified by real-time reverse transcription-PCR to have a tumor/normal expression ratio > 2. Up-regulation of THY1 and PHLAD1 was associated with the presence of anemia in colon cancer patients (P = 0.036 and 0.009, respectively). Up-regulation of HNRPA1 was more significant in cancer growing in the right-sided colon than the left side (P = 0.027). Up-regulated GPX2 was related to a higher degree of tumor differentiation (P = 0.019). c-MYC was significantly over-expressed in specimens from male compared with female colon cancer patients (P = 0.012). GRO1 was significantly up-regulated in patients younger than 65 years old (P = 0.010) and was found to be frequently over-expressed when cancers were less invasive. In addition, we found that normalized transcript levels of HNRPA1 were tightly associated with that of c-MYC (r = 0.948). CONCLUSIONS: Validation of microarray data using another independent laboratory approach is mandatory and statistical correlation between gene expression status and the patient's clinical features may reveal individual genes relevant to tumor behavior and clinicopathologic variations in human colorectal cancer.


Subject(s)
Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Oligonucleotide Array Sequence Analysis , Up-Regulation , Adult , Aged , Aged, 80 and over , Chemokine CXCL1 , Chemokines, CXC/genetics , DNA, Complementary , Female , Genes, myc , Glutathione Peroxidase/genetics , Heterogeneous Nuclear Ribonucleoprotein A1 , Heterogeneous-Nuclear Ribonucleoprotein Group A-B , Humans , Intercellular Signaling Peptides and Proteins/genetics , Male , Middle Aged , RNA, Messenger , Reverse Transcriptase Polymerase Chain Reaction , Ribonucleoproteins/genetics , Thy-1 Antigens/genetics , Thymus Hormones/genetics , Transcription Factors/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...