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1.
Dev Biol ; 380(2): 324-34, 2013 Aug 15.
Article in English | MEDLINE | ID: mdl-23722001

ABSTRACT

The primary axis of cnidarians runs from the oral pole to the apical tuft and defines the major body axis of both the planula larva and adult polyp. In the anthozoan cnidarian Nematostella vectensis, the primary oral-aboral (O-Ab) axis first develops during the early embryonic stage. Here, we present evidence that pharmaceutical activators of canonical wnt signaling affect molecular patterning along the primary axis of Nematostella. Although not overtly morphologically complex, molecular investigations in Nematostella reveal that the O-Ab axis is demarcated by the expression of differentially localized signaling molecules and transcription factors that may serve roles in establishing distinct ectodermal domains. We have further characterized the larval epithelium by determining the position of a nested set of molecular boundaries, utilizing several newly characterized as well as previously reported epithelial markers along the primary axis. We have assayed shifts in their position in control embryos and in embryos treated with the pharmacological agents alsterpaullone and azakenpaullone, Gsk3ß inhibitors that act as canonical wnt agonists, and the Wnt antagonist iCRT14, following gastrulation. Agonist drug treatments result in an absence of aboral markers, a shift in the expression boundaries of oral markers toward the aboral pole, and changes in the position of differentially localized populations of neurons in a dose-dependent manner, while antagonist treatment had the opposite effect. These experiments are consistent with canonical wnt signaling playing a role in an orally localized wnt signaling center. These findings suggest that in Nematostella, wnt signaling mediates O-Ab ectodermal patterning across a surprisingly complex epithelium in planula stages following gastrulation in addition to previously described roles for the wnt signaling pathway in endomesoderm specification during gastrulation and overall animal-vegetal patterning at earlier stages of anthozoan development.


Subject(s)
Anthozoa/embryology , Body Patterning , Ectoderm/embryology , Wnt Signaling Pathway/physiology , Animals , Gastrulation , Larva/growth & development , Opsins/analysis , Wnt2 Protein/physiology , beta Catenin/physiology
2.
Dev Biol ; 356(2): 541-52, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21704027

ABSTRACT

Smooth muscle in the lung is thought to derive from the developing lung mesenchyme. Smooth muscle formation relies upon coordination of both autocrine and paracrine signaling between the budding epithelium and adjacent mesenchyme to govern its proliferation and differentiation. However, the pathways initiating the earliest aspects of smooth muscle specification and differentiation in the lung are poorly understood. Here, we identify the Wnt2 ligand as a critical regulator of the earliest aspects of lung airway smooth muscle development. Using Wnt2 loss and gain of function models, we show that Wnt2 signaling is necessary and sufficient for activation of a transcriptional and signaling network critical for smooth muscle specification and differentiation including myocardin/Mrtf-B and the signaling factor Fgf10. These studies place Wnt2 high in a hierarchy of signaling molecules that promote the earliest aspects of lung airway smooth muscle development.


Subject(s)
Fibroblast Growth Factor 10/genetics , Gene Expression Regulation , Lung/embryology , Muscle, Smooth/embryology , Signal Transduction/physiology , Transcription Factors/genetics , Wnt2 Protein/physiology , Animals , Cells, Cultured , Female , Gene Expression Regulation, Developmental , Lung/metabolism , Mesoderm/embryology , Mice , Muscle, Smooth/metabolism , Polymerase Chain Reaction , Receptors, Platelet-Derived Growth Factor/genetics , beta Catenin/physiology
3.
Gut ; 60(12): 1635-43, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21672941

ABSTRACT

OBJECTIVES: Interaction between neoplastic and stromal cells plays an important role in tumour progression. It was recently found that WNT2 was frequently overexpressed in fibroblasts isolated from tumour tissue tumour fibroblasts (TF) compared with fibroblasts from non-tumour tissue normal fibroblasts in oesophageal squamous cell carcinoma (OSCC). This study aimed to investigate the effect of TF-secreted Wnt2 in OSCC development via the tumour-stroma interaction. METHODS: Quantitative PCR, western blotting, immunohistochemistry and immunofluorescence were used to study the expression pattern of Wnt2 and its effect on the Wnt/ß-catenin pathway. A Wnt2-secreting system was established in Chinese hamster ovary cells and its conditioned medium was used to study the role of Wnt2 in cell proliferation and invasion. RESULTS: Expression of Wnt2 could only be detected in TF but not in OSCC cancer cell lines. In OSCC tissues, Wnt2(+) cells were mainly detected in the boundary between stroma and tumour tissue or scattered within tumour tissue. In this study, Wnt2-positive OSCC was defined when five or more Wnt2(+) cells were observed in 200× microscopy field. Interestingly, Wnt2-positive OSCC (22/51 cases) was significantly associated with lymph node metastases (p=0.001), advanced TNM stage (p=0.001) and disease-specific survival (p<0.0001). Functional study demonstrated that secreted Wnt2 could promote oesophageal cancer cell growth by activating the Wnt/ß-catenin signalling pathway and subsequently upregulated cyclin D1 and c-myc expression. Further study found that Wnt2 could enhance cell motility and invasiveness by inducing epithelial-mesenchymal transition. CONCLUSIONS: TF-secreted Wnt2 acts as a growth and invasion-promoting factor through activating the canonical Wnt/ß-catenin signalling pathway in oesophageal cancer cells.


Subject(s)
Esophageal Neoplasms/metabolism , Wnt Signaling Pathway/physiology , Wnt2 Protein/metabolism , Animals , Blotting, Western , CHO Cells , Cell Line, Tumor , Cell Movement/physiology , Cell Proliferation , Cricetinae , Esophageal Neoplasms/physiopathology , Fibroblasts/metabolism , Fibroblasts/physiology , Neoplasm Invasiveness/physiopathology , Reverse Transcriptase Polymerase Chain Reaction , Wnt2 Protein/physiology
4.
Circ Res ; 108(4): 427-36, 2011 Feb 18.
Article in English | MEDLINE | ID: mdl-21193738

ABSTRACT

RATIONALE: Vascular smooth muscle cell (VSMC) proliferation causes intimal thickening in atherosclerosis and restenosis. Previously, we demonstrated that Wnt/ß-catenin signaling upregulates VSMC proliferation in vitro. OBJECTIVE: We examined this pathway in vivo and investigated the involvement of specific Wnt proteins in VSMC proliferation. METHODS AND RESULTS: Left carotid arteries of TOPgal (ß-catenin signaling reporter) transgenic mice were ligated to induce intimal thickening. ß-Catenin signaling was induced in the media and intima at 3 and 28 days after ligation, respectively, and was associated with VSMC proliferation and cyclin D1 expression. In vitro, a Wnt agonist promoted mouse VSMC proliferation, whereas Wnt inhibitory factor (WIF)-1 retarded platelet-derived growth factor-BB (PDGF-BB)-induced VSMC proliferation. Microarray analysis and quantitative PCR detected a significant induction of Wnt2 and Wnt4 mRNA in PDGF-BB-treated (proliferating) VSMCs compared to quiescent VSMCs. Western blotting revealed this increase was only translated into protein for Wnt4. Specific silencing RNA knockdown of Wnt4, but not Wnt2, significantly reduced VSMC proliferation. Recombinant Wnt4, but not Wnt2, significantly increased VSMC proliferation by ≈2-fold and silencing RNA knockdown revealed this is via Frizzled 1. Immunohistochemistry showed that increased Wnt4 protein correlated with VSMC proliferation and cyclin D1 expression (P<0.05 and P<0.001, respectively) during intimal thickening after rat carotid artery injury. Importantly, we also showed that intimal thickening and VSMC proliferation after carotid artery ligation was significantly retarded in Wnt4(+/-) compared to Wnt4(+/+) mice. CONCLUSIONS: This study demonstrates that Wnt/ß-catenin signaling occurs in proliferating VSMCs during intimal thickening and indicates that this is a result of Wnt4 upregulation.


Subject(s)
Cell Proliferation , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Signal Transduction/physiology , Tunica Intima/cytology , Wnt Proteins/physiology , beta Catenin/physiology , Animals , Cyclin D1/physiology , Frizzled Receptors/physiology , Mice , Mice, Mutant Strains , Mice, Transgenic , Models, Animal , Muscle, Smooth, Vascular/physiology , Myocytes, Smooth Muscle/physiology , Tunica Intima/physiology , Up-Regulation/physiology , Wnt Proteins/genetics , Wnt2 Protein/genetics , Wnt2 Protein/physiology , Wnt4 Protein , beta Catenin/genetics
5.
Biol Psychiatry ; 68(6): 521-7, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20570247

ABSTRACT

BACKGROUND: Despite recent interest in glycogen synthase kinase-3beta (GSK-3beta) as a target for the treatment of mood disorders, there has been very little work related to these illnesses on the upstream signaling molecules that regulate this kinase as well as downstream targets. METHODS: With a focused microarray approach we examined the influence of different classes of antidepressants on Wnt signaling that controls GSK-3beta activity as well as the transcription factors that contribute to the actions of GSK-3beta. RESULTS: The results demonstrate that Wnt2 is a common target of different classes of antidepressants and also show differential regulation of Wnt-GSK-3beta signaling genes. Increased expression and function of Wnt2 was confirmed by secondary measures. Moreover, with a viral vector approach we demonstrate that increased expression of Wnt2 in the hippocampus is sufficient to produce antidepressant-like behavioral actions in well-established models of depression and treatment response. CONCLUSIONS: These findings demonstrate that Wnt2 expression and signaling is a common target of antidepressants and that increased Wnt2 is sufficient to produce antidepressant effects.


Subject(s)
Antidepressive Agents/pharmacology , Gene Expression Regulation/drug effects , Signal Transduction/drug effects , Wnt2 Protein/biosynthesis , Animals , Antidepressive Agents/administration & dosage , Behavior, Animal/drug effects , Behavior, Animal/physiology , Dependovirus/genetics , Electroshock/methods , Gene Expression Regulation/genetics , Gene Transfer Techniques , Genetic Vectors , Hippocampus/metabolism , Male , Oligonucleotide Array Sequence Analysis/methods , Rats , Rats, Sprague-Dawley , Signal Transduction/genetics , Signal Transduction/physiology , Wnt2 Protein/physiology
6.
Dev Cell ; 18(2): 275-87, 2010 Feb 16.
Article in English | MEDLINE | ID: mdl-20159597

ABSTRACT

Little is understood about the molecular mechanisms underlying the morphogenesis of the posterior pole of the heart. Here we show that Wnt2 is expressed specifically in the developing inflow tract mesoderm, which generates portions of the atria and atrio-ventricular canal. Loss of Wnt2 results in defective development of the posterior pole of the heart, resulting in a phenotype resembling the human congenital heart syndrome complete common atrio-ventricular canal. The number and proliferation of posterior second heart field progenitors is reduced in Wnt2(-/-) mutants. Moreover, these defects can be rescued in a temporally restricted manner through pharmacological inhibition of Gsk-3beta. We also show that Wnt2 works in a feedforward transcriptional loop with Gata6 to regulate posterior cardiac development. These data reveal a molecular pathway regulating the posterior cardiac mesoderm and demonstrate that cardiovascular defects caused by loss of Wnt signaling can be rescued pharmacologically in vivo.


Subject(s)
Fetal Heart/embryology , Fetal Heart/physiology , GATA6 Transcription Factor/physiology , Wnt2 Protein/physiology , Animals , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Female , Fetal Heart/drug effects , GATA6 Transcription Factor/genetics , Gene Expression Regulation, Developmental/drug effects , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta , Heart Defects, Congenital/embryology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/physiopathology , Humans , Lithium Chloride/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Models, Cardiovascular , Phenotype , Pregnancy , Signal Transduction , Wnt2 Protein/deficiency , Wnt2 Protein/genetics
7.
Biol Reprod ; 82(5): 865-75, 2010 May.
Article in English | MEDLINE | ID: mdl-20107203

ABSTRACT

WNTs are secreted extracellular signaling molecules that transduce their signals by binding to G protein-coupled receptors of the frizzled (FZD) family. They control diverse developmental processes, such as cell fate specification, cell proliferation, cell differentiation, and apoptosis. Although WNT signaling has been shown to be essential for development of the ovary, its mechanistic role in folliculogenesis within the adult ovary has not been studied extensively. Therefore, the objective of this study was to investigate the regulation and function of WNT2 signaling in mouse granulosa cells. Immunostaining identified WNT2 as being expressed in granulosa cells throughout folliculogenesis, but with varying signal strength: in sequential sections, WNT2 immunoreactivity was strongest in healthy antral follicles but weak in atretic follicles. Knockdown of WNT2 expression using transfected short interfering RNA decreased DNA synthesis in granulosa cells, whereas WNT2 overexpression using a recombinant viral vector enhanced it. WNT2 knockdown led to accumulation of glycogen synthase kinase-3beta (GSK3B) in the cytoplasm but reduced the expression of beta-catenin. Conversely, WNT2 overexpression reduced the expression of GSK3B in the cytoplasm and induced beta-catenin translocation from the membrane into the nucleus. Beta-catenin knockdown also inhibited DNA synthesis in granulosa cells and neutralized the effect of WNT2 overexpression. WNT2/beta-catenin signaling had a slight effect on the apoptosis of granulosa cells. Taken together, the data indicate that WNT2 regulates beta-catenin localization in granulosa cells, and WNT2/beta-catenin signaling contributes to regulating their proliferation.


Subject(s)
DNA/biosynthesis , Granulosa Cells/metabolism , Signal Transduction/physiology , Wnt2 Protein/physiology , beta Catenin/metabolism , Animals , Cell Proliferation , Female , Gene Knockdown Techniques , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Mice , Ovarian Follicle/growth & development , Ovarian Follicle/metabolism , Second Messenger Systems/physiology
8.
Pediatr Cardiol ; 31(3): 342-8, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19967349

ABSTRACT

Cardiac development is comprised of a series of morphological events tightly controlled both spatially and temporally. The molecular pathways controlling early cardiac differentiation are poorly understood, but Wnt signaling is emerging as a critical pathway for multiple aspects of early cardiovascular development. The Wnt pathway plays multiple roles in regulating cellular behavior including proliferation, differentiation, cell migration, and cell polarity. Recent data have demonstrated that Wnt activity is important for early precardiac mesoderm differentiation but must be inhibited in subsequent steps for cardiomyocyte differentiation to proceed. Given the important role that Wnt signaling plays in both the differentiation of cardiomyocytes from pluripotential stem cells and tissue regeneration in general, an increased understanding of this pathway is likely to enhance our knowledge about both cardiovascular development and reparative mechanisms.


Subject(s)
Cardiovascular System/embryology , Signal Transduction , Wnt1 Protein/physiology , Wnt2 Protein/physiology , beta Catenin/physiology , Animals , Cell Differentiation , Cell Movement , Cell Proliferation , Humans , Models, Animal , Pluripotent Stem Cells , Wnt1 Protein/genetics , Wnt2 Protein/genetics , beta Catenin/genetics
9.
Angiogenesis ; 12(3): 251-65, 2009.
Article in English | MEDLINE | ID: mdl-19444628

ABSTRACT

Recently, we have shown that Wnt2 is an autocrine growth and differentiation factor for hepatic sinusoidal endothelial cells. As Wnt signaling has become increasingly important in vascular development and cancer, we analyzed Wnt signaling in non-sinusoidal endothelial cells of different vascular origin (HUVEC, HUAEC, HMVEC-LLy). Upon screening the multiple components of the Wnt pathway, we demonstrated lack of Wnt2 expression, but presence of Frizzled-4, one of its receptors, in cultured non-sinusoidal endothelial cells. Treatment of these cells by exogenous Wnt2 induced endothelial proliferation and sprouting angiogenesis in vitro. Upon analysis of Wnt2 tissue expression as a basis for paracrine Wnt2 effects on non-sinusoidal endothelial cells in vivo, Wnt2 was found to be expressed in densely vascularized murine malignant tumors and in wound healing tissues in close proximity to CD31+ endothelial cells. By gene profiling, stanniocalcin-1 (STC1), a known regulator of angiogenesis, was identified as a target gene of Wnt2 signaling in HUVEC down-regulated by Wnt2 treatment. Tumor-conditioned media counter-acted Wnt2 and up-regulated STC1 expression in HUVEC. In conclusion, we provide evidence that Wnt2 acts as an angiogenic factor for non-sinusoidal endothelium in vitro and in vivo whose target genes undergo complex regulation by the tissue microenvironment.


Subject(s)
Endothelial Cells/drug effects , Glycoproteins/genetics , Neovascularization, Physiologic/drug effects , Wnt2 Protein/pharmacology , Angiogenesis Inducing Agents/pharmacology , Animals , CHO Cells , Cells, Cultured , Cricetinae , Cricetulus , Down-Regulation/drug effects , Endothelial Cells/metabolism , Endothelial Cells/physiology , Glycoproteins/metabolism , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neovascularization, Physiologic/genetics , Rats , Rats, Sprague-Dawley , Wnt2 Protein/physiology
10.
Neoplasma ; 56(2): 119-23, 2009.
Article in English | MEDLINE | ID: mdl-19239325

ABSTRACT

UNLABELLED: The binding of the Wnt ligand to its receptor Frizzled, activates the Wnt canonical signaling pathway in carcinogenesis as well as many cellular processes, including cellular proliferation and differentiation. Wnt-2, one of 19 members of the Wnt gene family, is frequently overexpressed in malignant tissues. Here, in order to investigate the role of Wnt-2 in colorectal carcinogenesis, we examined the expression of the Wnt-2 protein in 120 colorectal cancers by immunohistochemistry. Wnt-2 protein was expressed in the cell membrane and cytoplasm and up-regulated in 74 (61.7%) of 120 colorectal cancers. Statistically, overexpression of Wnt-2 protein was not associated with the clinical and pathological parameters studied, including tumor location, tumor size, clinical stage, lymph node metastasis, and 5-year survival (P > 0.05). These results indicate that up-regulation of the Wnt-2 protein might play a role in the development of colorectal cancers, as an early event of carcinogenesis. KEYWORDS: Wnt-2 protein, expression, immunohistochemistry, tissue microarray, colon cancer.


Subject(s)
Colorectal Neoplasms/chemistry , Wnt2 Protein/analysis , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Humans , Immunohistochemistry , Survival Rate , Wnt2 Protein/physiology
11.
BMC Cell Biol ; 8: 12, 2007 Mar 26.
Article in English | MEDLINE | ID: mdl-17386109

ABSTRACT

BACKGROUND: Norrin is a potent Wnt pathway ligand. Aberrant activation of this signaling pathway can result in colon tumors but the role of norrin-based signaling in the genesis of colon cancer, and its relationship to activation of the pathway by traditional Wnt ligands, is not defined. RESULTS: Fresh normal human colon tissue and all the cell lines studied expressed mRNA for Fz4, LRP5 and norrin, except Colo205 which lacked Fz4 expression. Canonical Wnt pathway throughput was increased slightly in NCM460 following treatment with Wnt3a CM but was inhibited by Wnt2 and Wnt1. The colon cancer cell line, RKO, responded to Wnt3a CM, Wnt2 and Wnt1 by increasing canonical Wnt pathway throughput. Wnt5a did not affect Wnt pathway throughput in either cell line. Wnt2, but not Wnt3a, abrogated Fz4 expression in NCM460, but not in RKO or another colon cancer cell line, HCT116. This effect on Fz4 was confirmed at both the RNA and protein levels via RT-PCR and a norrin binding assay. The expression of all others 9 Fz receptors did not change after treatment of NCM460 cells with Wnt2. CONCLUSION: The data suggests that colonic mucosa and colon tumors may possess two autoregulatory positive Wnt feedback loops, one through canonical signals induced by Wnt:Fz interactions and one through signals resulting from norrin:Fz4 interactions. The latter interactions may be modulated via regulation of Fz4 expression by Wnt2. Retention of Fz4 by cancers, in contrast to the loss of Fz4 by normal mucosal cells, could provide a selective advantage to the tumor cells. Fz4 expression may play a critical role in responses to Wnt signaling in the tumor microenvironment.


Subject(s)
Colon/metabolism , Colonic Neoplasms/genetics , Frizzled Receptors/genetics , Frizzled Receptors/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Wnt2 Protein/physiology , Cells, Cultured , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Eye Proteins/metabolism , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Nerve Tissue Proteins/metabolism , Signal Transduction , Transfection
12.
Neuron ; 50(6): 813-5, 2006 Jun 15.
Article in English | MEDLINE | ID: mdl-16772162

ABSTRACT

Activity-dependent dendritic growth is dependent upon intracellular calcium signaling. Yet the specific mechanisms by which calcium signals lead to morphologic changes in dendrites are not well understood. A paper in this issue of Neuron by Wayman et al. describes a novel calcium-dependent signaling cascade linking neuronal activity and calcium influx to expression of Wnt-2, a member of a family of proteins that controls elaboration of dendrites.


Subject(s)
Calcium Signaling/physiology , Dendrites/physiology , Wnt2 Protein/physiology , Animals , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Dendrites/enzymology , Humans
13.
Oncogene ; 25(21): 3084-92, 2006 May 18.
Article in English | MEDLINE | ID: mdl-16407829

ABSTRACT

Aberrant activation of the Wnt signaling pathway has been reported during neoplastic progression in Barrett's esophagus (BE). However, mutations in APC and CTNNB1 genes were rarely observed. In this study, expression pattern of Wnt ligands, Frizzled receptors and APC, as well as the methylation status of the APC, SFRP1 and SFRP2 promoter genes were investigated in normal esophageal mucosa and in preneoplastic and neoplastic lesions of BE patients. Promoter methylation of APC was found in all BE samples and in 95% of esophageal adenocarcinomas (EAC). Full methylation of APC correlated with lack of expression. In EAC, nuclear translocation of beta-catenin was observed regardless of the expression of APC. WNT2 expression was higher in dysplasia and EAC than in BE, with 20/26 (77%) of the EAC showing high expression of WNT2. SFRP1 methylation occurred in all BE samples and in 96% of EAC, while SFRP2 was methylated in 73% of the normal squamous esophageal mucosa samples. In conclusion, (1) alterations of key regulators of the Wnt signaling are frequent in the pathogenesis of BE; (2) the APC and SFRP1 genes are inactivated by promoter methylation in BE; (3) the WNT2 gene is upregulated along the progression from low-grade dysplasia to EAC.


Subject(s)
Adenocarcinoma/metabolism , Barrett Esophagus/metabolism , DNA Methylation , Esophageal Neoplasms/metabolism , Gene Silencing , Genes, APC , Precancerous Conditions/metabolism , Signal Transduction , Wnt Proteins/physiology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Barrett Esophagus/genetics , Barrett Esophagus/pathology , Cell Division/drug effects , Cell Line, Tumor/drug effects , Cell Line, Tumor/metabolism , CpG Islands , DNA Methylation/drug effects , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Decitabine , Disease Progression , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Gene Expression Regulation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing/drug effects , Genes, APC/drug effects , Humans , Intercellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Mucous Membrane/metabolism , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Promoter Regions, Genetic/drug effects , Promoter Regions, Genetic/genetics , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , RNA, Small Interfering/pharmacology , Signal Transduction/drug effects , Transfection , Wnt2 Protein/biosynthesis , Wnt2 Protein/genetics , Wnt2 Protein/physiology , beta Catenin/biosynthesis , beta Catenin/genetics
14.
Cancer Res ; 66(1): 267-82, 2006 Jan 01.
Article in English | MEDLINE | ID: mdl-16397240

ABSTRACT

To identify genetic alterations underlying rectal carcinogenesis, we used global gene expression profiling of a series of 17 locally advanced rectal adenocarcinomas and 20 normal rectal mucosa biopsies on oligonucleotide arrays. A total of 351 genes were differentially expressed (P < 1.0e-7) between normal rectal mucosa and rectal carcinomas, 77 genes had a >5-fold difference, and 85 genes always had at least a 2-fold change in all of the matched samples. Twelve genes satisfied all three of these criteria. Altered expression of genes such as PTGS2 (COX-2), WNT1, TGFB1, VEGF, and MYC was confirmed, whereas our data for other genes, like PPARD and LEF1, were inconsistent with previous reports. In addition, we found deregulated expression of many genes whose involvement in rectal carcinogenesis has not been reported. By mapping the genomic imbalances in the tumors using comparative genomic hybridization, we could show that DNA copy number gains of recurrently aneuploid chromosome arms 7p, 8q, 13q, 18q, 20p, and 20q correlated significantly with their average chromosome arm expression profile. Taken together, our results show that both the high-level, significant transcriptional deregulation of specific genes and general modification of the average transcriptional activity of genes residing on aneuploid chromosomes coexist in rectal adenocarcinomas.


Subject(s)
Adenocarcinoma/genetics , Aneuploidy , Rectal Neoplasms/genetics , Wnt2 Protein/physiology , beta Catenin/physiology , Adenocarcinoma/metabolism , Gene Dosage , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/physiology , Multigene Family , Nucleic Acid Hybridization , Rectal Neoplasms/metabolism , Signal Transduction
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