ctnnb1 - beta-catenin
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Publication
Journal: Genesis (New York, N.Y. : 2000)
December/15/2008
Abstract
Reciprocal signals from embryonic and extra-embryonic tissues pattern the embryo in proximal-distal (PD) and anterior-posterior (AP) fashion. Here we have analyzed three gene trap mutations of Sall4, of which one (Sall4-1a) led to a hypomorphic and recessive phenotype, demonstrating that Sall4-1a has yet undescribed extra-embryonic and embryonic functions in regulating PD and AP axis formation. In Sall4-1a mutants the self-maintaining autoregulatory interaction between Bmp4, Nodal and Wnt, which determines the PD axis was disrupted because of defects in the extra-embryonic visceral endoderm. More severely, two distinct Sall4 gene-trap mutants (Sall4-1a,b), resembling null mutants, failed to initiate Bmp4 expression in the extra-embryonic ectoderm and Nodal in the epiblast and were therefore unable to initiate PD axis formation. Tetraploid rescue underlined the extra-embryonic nature of the Sall4-1a phenotype and revealed a further embryonic function in Wnt/beta-catenin signaling to elongate the AP axis during gastrulation. This observation was supported through genetic interaction with beta-catenin mutants, since compound heterozygous mutants recapitulated the defects of Wnt3a mutants in posterior development.
Publication
Journal: Nature genetics
November/1/2004
Abstract
In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.
Publication
Journal: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
October/19/2019
Abstract
Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer.A total of 56 patients were included in a one-armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes.ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS where in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis.Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR-fusions, ERBB3 and BRCA1/2.
Publication
Journal: Cancer discovery
August/2/2019
Abstract
About one third of cases of hepatocellular carcinoma (HCC) show gain-of-function mutations of CTNNB1 (β-catenin) that correlate with sparse intratumoral T-cell content, as observed previously in an ample spectrum of malignancies, and there is mounting preliminary evidence that such HCC cases are refractory to treatment with PD-1 checkpoint inhibitors. Elegant hepatocarcinogenesis experiments by in vivo gene transfer to mouse hepatocytes show that coexpression of active forms of β-catenin result in poor T-cell infiltrates, faster progression in immunocompetent hosts, and unresponsiveness to immunotherapy with checkpoint inhibitors.See related article by Ruiz de Galarreta et al., p. 1124.
Publication
Journal: Cancer genetics
December/16/2018
Abstract
Aneurysmal bone cyst (ABC) is a benign but locally aggressive, mostly pediatric neoplasm, with characteristic USP6 gene rearrangement that distinguishes it from a secondary ABC and other primary bone tumors. With the advent of next-generation sequencing (NGS) technology, several hitherto unknown USP6 fusion partners have been identified in ABC. Accordingly, we present a case of an 18-year-old male with a solid sub-periosteal primary ABC in the diaphysis of the left femur. Using an NGS-based assay, we identified SPARC-USP6 fusion, which has not previously been described in ABC. Including our case, the list of currently known USP6 fusion partners in primary ABC include: CDH11, CNBP, COL1A1, CTNNB1, EIF1, FOSL2, OMD, PAFAH1B1, RUNX2, SEC31A, SPARC, STAT3 and THRAP3.
Publication
Journal: Molecular and cellular biology
May/25/2015
Abstract
Nucleoporin p62 (Nup62) localizes in the central channel of nuclear pore complexes (NPCs) and regulates nuclear pore permeability and nucleocytoplasmic transport. However, the developmental roles of Nup62 in vertebrates remain largely unclear. Zebrafish Nup62-like protein (Nup62l) is a homolog of mammalian Nup62. The nup62l gene is maternally expressed, but its transcripts are ubiquitously distributed during early embryogenesis and enriched in the head, pharynx, and intestine of developing embryos. Activation of the Wnt/β-catenin pathway positively modulates nup62l transcription, while Bmp signaling acts downstream of Wnt/β-catenin signaling to negatively regulate nup62l expression. Overexpression of nup62l dorsalized embryos and enhanced gastrula convergence and extension (CE) movements. In contrast, knockdown of Nup62l led to ventralized embryos, an impediment to CE movements, and defects in specification of midline organ progenitors. Mechanistically, Nup62l acts as an activator of Wnt/β-catenin signaling through interaction with and facilitation of nuclear import of β-catenin-1/2 in zebrafish. Thus, Nup62l regulates dorsoventral patterning, gastrula CE movements, and proper specification of midline organ precursors through mediating the nuclear import of β-catenins in zebrafish.
Publication
Journal: Developmental biology
November/29/2018
Abstract
The calvaria (upper part of the skull) is made of plates of bone and fibrous joints (sutures and fontanelles), and the proper balance and organization of these components are crucial to normal development of the calvaria. In a mouse embryo, the calvaria develops from a layer of head mesenchyme that surrounds the brain from shortly after mid-gestation. The mesenchyme just above the eye (supra-orbital mesenchyme, SOM) generates ossification centers for the bones, which then grow toward the apex gradually. In contrast, the mesenchyme apical to SOM (early migrating mesenchyme, EMM), including the area at the vertex, does not generate an ossification center. As a result, the dorsal midline of the head is occupied by sutures and fontanelles at birth. To date, the molecular basis for this regional difference in developmental programs is unknown. The current study provides vital insights into the genetic regulation of calvarial patterning. First, we showed that osteogenic signals were active in both EMM and SOM during normal development, which suggested the presence of an anti-osteogenic factor in EMM to counter the effect of these signals. Subsequently, we identified Lmx1b as an anti-osteogenic gene that was expressed in EMM but not in SOM. Furthermore, head mesenchyme-specific deletion of Lmx1b resulted in heterotopic ossification from EMM at the vertex, and craniosynostosis affecting multiple sutures. Conversely, forced expression of Lmx1b in SOM was sufficient to inhibit osteogenic specification. Therefore, we conclude that Lmx1b plays a key role as an anti-osteogenic factor in patterning the head mesenchyme into areas with different osteogenic competence. In turn, this patterning event is crucial to generating the proper organization of the bones and soft tissue joints of the calvaria.
Publication
Journal: Developmental biology
November/29/2018
Abstract
The highly conserved transcription factor Grainyhead-like 2 (Grhl2) exhibits a dynamic expression pattern in lung epithelium throughout embryonic development. Using a conditional gene targeting approach to delete Grhl2 in the developing lung epithelium, our results demonstrate that Grhl2 plays multiple roles in lung morphogenesis that are essential for respiratory function. Loss of Grhl2 leads to impaired ciliated cell differentiation and perturbed formation of terminal saccules. Critically, a substantial increase in Sox9-positive distal tip progenitor cells was observed following loss of Grhl2, suggesting that Grhl2 plays an important role in branching morphogenesis. Gene transcription profiling of Grhl2-deficient lung epithelial cells revealed a significant down regulation of Elf5, a member of the Ets family of transcription factors. Furthermore, ChIP and comparative genomic analyzes confirmed that Elf5 is a direct transcriptional target of Grhl2. Taken together, these results support the hypothesis that Grhl2 controls normal lung morphogenesis by tightly regulating the activity of distal tip progenitor cells.
Publication
Journal: Peptides
August/14/2016
Abstract
Besides its widely described function in the innate immune response, no other clear physiological function has been attributed so far to the Liver-Expressed-Antimicrobial-Peptide 2 (LEAP2). We used the Xenopus embryo model to investigate potentially new functions for this peptide. We identified the amphibian leap2 gene which is highly related to its mammalian orthologues at both structural and sequence levels. The gene is expressed in the embryo mostly in the endoderm-derived tissues. Accordingly it is induced in pluripotent animal cap cells by FGF, activin or a combination of vegT/β-catenin. Modulating leap2 expression level by gain-of-function strategy impaired normal embryonic development. When overexpressed in pluripotent embryonic cells derived from blastula animal cap explant, leap2 stimulated FGF while it reduced the activin response. Finally, we demonstrate that LEAP2 blocks FGF-induced migration of HUman Vascular Endothelial Cells (HUVEC). Altogether these findings suggest a model in which LEAP2 could act at the extracellular level as a modulator of FGF and activin signals, thus opening new avenues to explore it in relation with cellular processes such as cell differentiation and migration.
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Publication
Journal: Histology and histopathology
February/2/2009
Abstract
Corded and hyalinized endometrioid carcinoma (CHEC), showing spindle and/or corded (SPICO) cells often in the background of hyalinized stroma, is a rare variant of uterine endometrioid carcinomas. The aim of our study was to explore the status of cell-adhesion molecules (beta-catenin, E-cadherin) in CHECs and to survey whether immunostains for beta-catenin and p53 can help to distinguish CHECs from their morphological mimics: malignant mixed mullerian tumors (MMMTs) and uterine tumors resembling ovarian sex-cord tumors (UTROSCTs). Immunohistochemistry was performed and scored for each element as follows: 0: negative, 1+: <10% positive cells, 2+: 10-30%, 3+: >30%. The SPICO patterns were classified as spindle/fusiform; 3, corded; 1, and both; 2. SPICO components consisted of <10%: 4, 10-30%: 1, >30%: 1. Five contained squamous components. In SPICO elements of all CHECs, nuclear beta-catenin expression (score: 1+; 1, 2+; 2, 3+; 3) and complete loss of membranous expression of E-cadherin was observed. In contrast, comparable components (sarcomatous ones for eight MMMTs or sex-cord-like ones for six UTROSCTs) showed no nuclear positivity for beta-catenin. p53 expression was observed in SPICO (64.7%), sarcomatous (87.5%), and sex-cord-like (50%) components, and sarcomatous areas of most MMMTs notably showed diffuse and intense staining. Sequence analysis of PCR amplification products of exon 3 of the beta-catenin gene revealed mutation in all cases, except two lacking SPICO components represented on microdissected areas. Our results suggest that alterations in beta-catenin/E-cadherin complex play a critical role in SPICO features. Immunostain for beta-catenin and p53 is a promising approach for distinguishing CHECs from MMMTs and UTROSCTs.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
October/22/2003
Abstract
E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/beta-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently downregulated in lung cancer, and that loss of E-cadherin or beta-catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a beta-catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li+, a GSK3 beta inhibitor, led to E-cadherin induction in an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free beta-catenin and E-cadherin. Among known transcriptional suppressors of E-cadherin, ZEB1 was uniquely correlated with E-cadherin loss in lung cancer cell lines, and its inhibition by RNA interference resulted in E-cadherin induction. Pharmacologic reversal of E-cadherin and WNT7a losses was achieved with Li+, histone deacetylase inhibition, or in some cases only with combined inhibitors. Our findings provide support that E-cadherin induction by WNT/beta-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and that loss of WNT7a expression may be important in lung cancer development or progression by its effects on E-cadherin.
Publication
Journal: Nature communications
December/6/2018
Abstract
Canonical Wnt signaling is crucial for vascularization of the central nervous system and blood-brain barrier (BBB) formation. BBB formation and modulation are not only important for development, but also relevant for vascular and neurodegenerative diseases. However, there is little understanding of how Wnt signaling contributes to brain angiogenesis and BBB formation. Here we show, using high resolution in vivo imaging and temporal and spatial manipulation of Wnt signaling, different requirements for Wnt signaling during brain angiogenesis and BBB formation. In the absence of Wnt signaling, premature Sphingosine-1-phosphate receptor (S1pr) signaling reduces VE-cadherin and Esama at cell-cell junctions. We suggest that Wnt signaling suppresses S1pr signaling during angiogenesis to enable the dynamic junction formation during anastomosis, whereas later S1pr signaling regulates BBB maturation and VE-cadherin stabilization. Our data provides a link between brain angiogenesis and BBB formation and identifies Wnt signaling as coordinator of the timing and as regulator of anastomosis.
Publication
Journal: Frontiers in bioscience (Elite edition)
June/2/2011
Abstract
The molecular mechanisms and candidate genes involved in metastasis to the brain need elucidation. In the present study brain metastases were analyzed regarding changes of E-cadherin (CDH1) and beta-catenin (CTNNB1). Loss of heterozygosity (LOH) of the CDH1 gene was detected in 42.2% of samples. The highest frequency of LOHs was observed in metastases from primary sites of lung adenocarcinoma and small cell lung cancer. Metastases from breast and colon demonstrated changes in 55.6% and 50% of cases. Downregulation of E-cadherin protein was observed in 83% of samples. Only 21.1% of samples with E-cadherin LOH had beta-catenin located in the nucleus. Image analysis showed that the quantities of E-cadherin and beta-catenin were significantly positively correlated (P = 0.008). Changes of E-cadherin were frequent in brain metastases that we investigated. Lack of mutations of beta-catenin, the fact that it was not frequently found in the nucleus and the positive correlation between the two proteins may suggest that the break-up of adherens junctions, and not the activation of wnt signaling, is responsible for metastasis formation.
Publication
Journal: PloS one
June/15/2011
Abstract
Female germ cells are essential for organogenesis of the ovary; without them, ovarian follicles do not form and functional and structural characteristics of the ovary are lost. We and others showed previously that when either Wnt4 or beta-catenin was inactivated in the fetal ovary, female germ cells underwent degeneration. In this study, we set out to understand whether these two factors belong to the same pathway and how they maintain female germ cell survival. We found that activation of beta-catenin in somatic cells in the Wnt4 knockout ovary restored germ cell numbers, placing beta-catenin downstream of WNT4. In the absence of Wnt4 or beta-catenin, female germ cells entered meiosis properly; however, they underwent apoptosis afterwards. Activin betaB (Inhbb), a subunit of activins, was upregulated in the Wnt4 and beta-catenin knockout ovaries, suggesting that Inhbb could be the cause for the loss of female germ cells, which are positive for activin receptors. Indeed, removal of Inhbb in the Wnt4 knockout ovaries prevented female germ cells from undergoing degeneration. We conclude that WNT4 maintains female germ cell survival by inhibiting Inhbb expression via beta-catenin in the somatic cells. Maintenance of female germ cells hinge upon a delicate balance between positive (WNT4 and beta-catenin) and negative (activin betaB) regulators derived from the somatic cells in the fetal ovary.
Publication
Journal: World journal of gastroenterology
October/2/2019
Abstract
DNA mutational analysis of pancreatic cystic fluid (CF) is a useful adjunct to the evaluation of pancreatic cysts. KRAS/GNAS or RAF/PTPRD/CTNNB1/RNF43 mutations are highly specific to precancerous or advanced neoplasia. Several studies recently demonstrated the ability of next-generation sequencing (NGS) analysis to detect DNA mutations in pancreatic CF, but few studies have performed a systematic comparative analysis between pancreatic CF and neoplastic surgical tissue (NT). The value of CF-NGS analysis indicators for determining surgical resection necessitates evaluation.To confirm whether CF genomic profiles are a reliable malignancy predictor by comparing NGS mutational analyses of CF and NT.Patients requiring surgery for high-risk pancreatic cysts were included in a multicenter prospective pilot study. DNA from CF (collected by endoscopic ultrasound-guided fine needle aspiration (known as EUS-FNA)) and NT (collected by surgery) were analyzed by NGS. The primary objective was to compare the mutation profiles of paired DNA samples. The secondary objective was to correlate the presence of specific mutations (KRAS/GNAS, RAF/ PTPRD/CTNNB1/RNF43/POLD1/TP53) with a final cancer diagnosis. Sensitivity and specificity were also evaluated.Between December 2016 and October 2017, 20 patients were included in this pilot study. Surgery was delayed for 3 patients. Concordant CF-NT genotypes were found in 15/17 paired DNA, with a higher proportion of mutated alleles in CF than in NT. NGS was possible for all pancreatic CF collected by EUS-FNA. In 2 cases, the presence of a KRAS/GNAS mutation was discordant between CF and NT. No mutations were found in 3 patients with NT or pancreatic cysts with high-grade dysplasia. The sensitivity and specificity of KRAS/GNAS mutations in CF to predict an appropriate indication for surgical resection were 0.78 and 0.62, respectively. The sensitivity and specificity of RAF/PTPRD/CTNNB1 /RNF43/POLD1/TP53 mutations in CF were 0.55 and 1.0, respectively.Mutational analyses of CF and NT were highly concordant, confirming the value of NGS analysis of CF in the preoperative malignancy assessment. However, these results need to be confirmed on a larger scale.
Publication
Journal: Oncogene
April/9/2007
Abstract
Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with several trypsin-like serine proteases and is required for mouse placental development and embryo survival. Here we show that the essential function of HAI-1 in placentation and all other embryonic processes is to restrict the activity of the type II transmembrane serine protease, matriptase. Enzymatic gene trapping of matriptase combined with HAI-1 immunohistochemistry revealed that matriptase is co-expressed with HAI-1 in both extraembryonic and embryonic tissues. As early as embryonic day 8.5, matriptase and HAI-1 were expressed in a population of chorionic trophoblasts. Ablation of HAI-1 disrupted the epithelial integrity of this cell population, causing disorganized laminin deposition and altered expression of E-cadherin and beta-catenin. This led to a complete loss of undifferentiated chorionic trophoblasts after embryonic day 9.5 and prevented the formation of the placental labyrinth. Genetic ablation of matriptase activity in HAI-1-deficient embryos, however, restored the integrity of chorionic trophoblasts and enabled placental labyrinth formation and development to term. Furthermore, matriptase/HAI-1 double-deficient mice were phenotypically indistinguishable from matriptase single-deficient littermates.
Publication
Journal: Clinical and experimental pharmacology & physiology
January/25/2010
Abstract
1. The present study was designed to investigate whether the M(3) muscarinic acetylcholine receptors (mAChR) is associated with beta-catenin in the ventricular myocardium during ischaemic myocardial injury and to determine the possible mechanism/s involved. 2. Rat hearts were subjected to coronary artery ligation for 1 and 6 h or 1 month to establish a myocardial ischaemia (MI) model. In the acute MI model, 16 rats were randomized into four groups: (i) control; (ii) ischaemia (rats were subjected to 20 min coronary occlusion); (iii) choline (10 mg/kg, i.v., choline chloride, an M(3) receptor agonist, was administered 15 min before occlusion); and (iv) 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; 0.12 mg/kg 4-DAMP, an M(3) receptor antagonist, was administered 20 min before occlusion, followed 5 min later by 10 mg/kg, i.v., choline chloride). Immunochemistry, western blot analysis and immunoprecipitation were used to determine the expression and localization of beta-catenin and the M(3) mAChR. 3. Myocardial ischaemia caused a time-dependent increase in the expression of beta-catenin. Moreover, a physical association was found between beta-catenin and the M(3) mAChR in intercalated discs. This association was enhanced by prolonged ischaemia. Administration of choline before ischaemia not only increased beta-catenin expression, but also strengthened the association between beta-catenin and the M(3) mAChR. However, blockade of M(3) mAChR by 4-DAMP completely inhibited the effect of choline on the expression of beta-catenin. In addition, MI increased phosphorylation of the M(3) mAChR. 4. The results indicate that increased beta-catenin activity is associated with M(3) mAChR during MI. This association is likely to play a role in heart signal transduction during ischaemia between neighbouring ventricular myocardiocum.
Publication
Journal: Proceedings of the National Academy of Sciences of the United States of America
August/10/2005
Abstract
E-cadherin controls a wide array of cellular behaviors, including cell-cell adhesion, differentiation, and tissue development. We show here that E-cadherin is cleaved specifically by ADAM (a disintegrin and metalloprotease) 10 in its ectodomain. Analysis of ADAM10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes. ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration. Furthermore, the shedding of E-cadherin by ADAM10 modulates the beta-catenin subcellular localization and downstream signaling. ADAM10 overexpression in epithelial cells increased the expression of the beta-catenin downstream gene cyclin D1 dose-dependently and enhanced cell proliferation. In ADAM10-deficient mouse embryos, the C-terminal E-cadherin fragment is not generated, and the full-length protein accumulates, highlighting the in vivo relevance for ADAM10 in E-cadherin shedding. Our data strongly suggest that this protease constitutes a major regulatory element for the multiple functions of E-cadherin under physiological as well as pathological conditions.
Publication
Journal: Molecular vision
August/24/2010
Abstract
OBJECTIVE
Our recent reports indicated that the molecular changes of pterygia are similar to tumor cells. We believe that pterygia may have a similar mechanism in oncogenesis. Many studies have revealed that E-cadherin associated protein expression decreases in many tumors and pterygia. E-cadherin may be a marker for both tumor metastasis and prognosis. However, no studies have examined the reason for E-cadherin protein inactivation in pterygia. Therefore, this study aimed to analyze the association of E-cadherin promoter hypermethylation with protein inactivation in pterygial tissues.
METHODS
E-cadherin methylation-status and the expression of E-cadherin and beta-catenin protein were studied using methylation-specific PCR and immunohistochemistry, respectively, on 120 pterygial specimens and 30 normal conjunctivas.
RESULTS
Hypermethylation of E-cadherin gene promoter was detected in 32 (26.7%) of the 120 pterygial specimens. A total of 79 (65.8%) pterygial specimens tested positive for E-cadherin protein expression and 41 (34.2%) specimens tested negative. The E-cadherin staining was limited to the membrane of the epithelial layer. There was a reverse correlation between E-cadherin gene promoter hypermethylation and E-cadherin protein expression (p<0.0001). Aberrant localization of beta-catenin was higher in the E-cadherin negative group than in E-cadherin positive group.
CONCLUSIONS
Our study demonstrates E-cadherin gene promoter hypermethylation were associated with low or absent expression of E-cadherin. Moreover, loss of E-cadherin protein may contribute to aberrant localization of beta-catenin. These data provide evidence that methylation exists in pterygia and may play a role in their development.
Publication
Journal: Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology
May/7/2009
Abstract
OBJECTIVE
To explore the possible mechanism of action of Wnt/beta-catenin signaling pathway in hepatocarcinogenesis by investigating the different expressions of the main members on this signaling pathway in hepatocellular carcinoma cell line HepG2 and L02 cell line.
METHODS
The mRNAs of Wnt1, Wnt4, beta-catenin, cyclinD1 and c-myc genes were amplified by means of semiquantitative reverse transcription polymerase chain reaction (RT-PCR) in normal liver cell line L02 and hepatocellular carcinoma cell line HepG2, respectively. At the same time, the proteins expression of beta-catenin which was the key member in the Wnt/beta-catenin signaling pathway was examined by immunocytochemical method and Western blot technique.
RESULTS
In normal liver cell line L02, the mRNAs of Wnt1, Wnt4, cyclin D1 and c-myc genes were not detected except for the gene of beta-catenin. In hepatocellular carcinoma cell line HepG2, the mRNAs of Wnt1, beta-catenin, cyclin D1 and c-myc genes were detected except for the gene of Wnt4. Meanwhile, found that beta-catenin proteins were accumulated in the cytoplasm and/or nucleus in HepG2 but only in cell membrane in L02.Using Western blot technique, found that beta-catenin proteins expression was higher in HepG2 than in L02.
CONCLUSIONS
The Wnt/beta-catenin signaling transduction pathway is activated with aberrant expression of Wnt1 in hepatocellular carcinoma cell line HepG2.
Publication
Journal: Developmental biology
February/6/2007
Abstract
The transcription factor Pax6 regulates multiple aspects of central nervous system (CNS) development. At the cellular level, the Pax6 mutation was reported to affect homophilic and heterophilic cellular adhesion, neuron polarity and neurite outgrowth. These abnormalities were observed in multiple regions of Pax6-mutant CNS, suggesting a common function for Pax6 in regulating cytoskeletal dynamics. However, target genes mediating Pax6 function in cytoskeletal dynamics remain largely unknown. Using DNA microarrays, we identified delta-catenin (delta-catenin /neurojugin) as a potential direct target of Pax6 in the CNS. delta-catenin encodes a large cytoskeletal protein that localizes at adherens junction in the CNS and that can modulate neurite outgrowth and N-cadherin turnover. delta-catenin was found to be co-expressed with Pax6 in several regions of the developing CNS. In Pax6 mutant embryos, delta-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in delta-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates delta-catenin expression during CNS development in mice.
Publication
Journal: PloS one
September/9/2012
Abstract
Abnormal activation of the canonical Wnt signaling pathway has been implicated in carcinogenesis. Transcription of Wnt target genes is regulated by nuclear β-catenin, whose over-expression is observed in Hepatocellular Carcinoma (HCC) tissue. Cyr61, a member of the CCN complex family of multifunctional proteins, is also found over-expressed in many types of tumor and plays dramatically different roles in tumorigenesis. In this study, we investigated the relationship between Cyr61 and β-catenin in HCC. We found that while Cyr61 protein was not expressed at a detectable level in the liver tissue of healthy individuals, its expression level was elevated in the HCC and HCC adjacent tissues and was markedly increased in cancer-adjacent hepatic cirrhosis tissue. Over-expression of Cyr61 was positively correlated with increased levels of β-catenin in human HCC samples. Activation of β-catenin signaling elevated the mRNA level of Cyr61 in HepG2 cells, while inhibition of β-catenin signaling reduced both mRNA and protein levels of Cyr61. We identified two TCF4-binding elements in the promoter region of human Cyr61 gene and demonstrated that β-catenin/TCF4 complex specifically bound to the Cyr61 promoter in vivo and directly regulated its promoter activity. Furthermore, we found that over-expression of Cyr61 in HepG2 cells promoted the progression of HCC xenografts in SCID mice. These findings indicate that Cyr61 is a direct target of β-catenin signaling in HCC and may play an important role in the progression of HCC.
Publication
Journal: Gastroenterology
July/15/2009
Abstract
OBJECTIVE
Much is known about the genes and mutations that cause colorectal cancer (CRC), yet only a few have been associated with CRC metastasis. We performed expression-profiling experiments to identify genetic markers of risk and to elucidate the molecular mechanisms of CRC metastasis.
METHODS
We compared gene expression patterns between metastatic and nonmetastatic stage-matched human colorectal carcinomas by microarray analysis. Correlations between BAMBI and metastasis-free survival were examined by quantitative real-time polymerase chain reaction (PCR) using an independent set of human colon carcinomas. Human colon cancer cell lines were analyzed for BAMBI regulation, cell motility, and experimental metastasis.
RESULTS
We established a signature of 115 genes that differentiated metastatic from nonmetastatic primary tumors. Among these, the transforming growth factor (TGF) beta inhibitor BAMBI was highly expressed in approximately half of metastatic primary tumors and metastases but not in nonmetastatic tumors. BAMBI is a target of canonical Wnt signaling that involves the beta-catenin coactivator BCL9-2. We observed an inverse correlation between level of BAMBI expression and metastasis-free survival time of patients. BAMBI inhibits TGF-beta signaling and increases migration in colon cancer cells. In mice, overexpression of BAMBI caused colon cancer cells to form tumors that metastasized more frequently to liver and lymph nodes than control cancer cells.
CONCLUSIONS
BAMBI regulates CRC metastasis by connecting the Wnt/beta-catenin and TGF-beta-signaling pathways. The metastatic expression signature we describe, along with BAMBI levels, can be used in prognosis. Developmental signaling pathways appear to act in hierarchies and cooperate in tumor cell migration, invasion, and metastasis.
Publication
Journal: The Journal of cell biology
July/19/2009
Abstract
Compartmentalization of the plasma membrane in a cell is fundamental for its proper functions. In this study, we present evidence that mammalian Fat4 and Dachsous1 cadherins regulate the apical plasma membrane organization in the embryonic cerebral cortex. In neural progenitor cells of the cortex, Fat4 and Dachsous1 were concentrated together in a cell-cell contact area positioned more apically than the adherens junction (AJ). These molecules interacted in a heterophilic fashion, affecting their respective protein levels. We further found that Fat4 associated and colocalized with the Pals1 complex. Ultrastructurally, the apical junctions of the progenitor cells comprised the AJ and a stretch of plasma membrane apposition extending apically from the AJ, which positionally corresponded to the Fat4-Dachsous1-positive zone. Depletion of Fat4 or Pals1 abolished this membrane apposition. These results highlight the importance of the Fat4-Dachsous1-Pals1 complex in organizing the apical membrane architecture of neural progenitor cells.
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