Browse
Submit Data
Databases
API
Help

Dataset Information

30 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway.

ABSTRACT: Gastric cancer (GC), characterized by uncontrolled growth, is a common malignant tumor of the digestive system. The Wnt signaling pathway plays an important role in the tumorigenesis and proliferation of GC. Many studies on this signaling pathway have focused on its intracellular regulatory mechanism, whereas little attention has been given to extracellular regulatory factors. Dickkopf-1 (Dkk1) is a secretory glycoprotein, and it can bind inhibit activation of the Wnt pathway. However, the regulation and mechanism of DKK1 in the proliferation of GC remain unclear. FOXC1 plays an important role in organ development and tumor growth, but its role in GC tumor growth remains unknown. In this study, we found that the FOXC1 is highly expressed in patients with GC and high expression of FOXC1 correlates to poor prognosis. In addition, we found that the Wnt signaling pathway in GC cells with high FOXC1 expression was strongly activated. FOXC1 negatively regulates DKK1 expression by binding to its promoter region, thereby promoting the activation of Wnt pathway. FOXC1 can also form a complex with unphosphorylated β-catenin protein in the cytoplasm and then dissociates from β-catenin in the nucleus, thereby promoting the entry of β-catenin into the nucleus and regulating expression of c-MYC, which promotes the proliferation of GC cells. Our study not only reveals the function and mechanism of FOXC1 in GC, but also provides a potential target for clinic GC treatment.

SUBMITTER: Jiang J

PROVIDER: S-EPMC8111291 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

LGR5 regulates gastric adenocarcinoma cell proliferation and invasion via activating Wnt signaling pathway.

Project description:LGR5 plays a critical role in tissue development and the maintenance of adult stem cells in gastrointestinal tract. However, the oncogenic role of LGR5 in the development of gastric adenocarcinoma remains elusive. Here, we show that LGR5 promotes gastric adenocarcinoma cell proliferation and metastasis. We find that knock down of LGR5 or suppression of Wnt signaling pathway by inhibitor C59 arrests gastric adenocarcinoma cell proliferation and invasion. Moreover, treatment of Wnt3a, the activator of Wnt signaling pathway, partially recovers the proliferation defect observed in LGR5 knockdown gastric adenocarcinoma cells. Moreover, LGR5 facilitates β-catenin nuclear accumulation, a surrogate marker of the activation of Wnt signaling pathway. In addition, C59 treatment suppresses transcription of Axin2 and TCF1, both of which are the target genes of β-catenin in gastric adenocarcinoma cells. Gastric adenocarcinoma cells with overexpressed LGR5 form a large quantity of visible actin filaments and pseudopods, suggesting that LGR5 significantly enhances the ability of cell movement, which might capacitate gastric adenocarcinoma cells with enhanced LGR5 expression to gain invasive and migratory properties. Taken together, our results show that LGR5 contributes to cell proliferation and invasion through the activation of Wnt/β-catenin-signaling pathway in gastric adenocarcinoma cells.

| S-EPMC6082861 | biostudies-literature

MicroRNA-142-3p Negatively Regulates Canonical Wnt Signaling Pathway.

Project description:Wnt/?-catenin signaling pathway plays essential roles in mammalian development and tissue homeostasis. MicroRNAs (miRNAs) are a class of regulators involved in modulating this pathway. In this study, we screened miRNAs regulating Wnt/?-catenin signaling by using a TopFlash based luciferase reporter. Surprisingly, we found that miR-142 inhibited Wnt/?-catenin signaling, which was inconsistent with a recent study showing that miR-142-3p targeted Adenomatous Polyposis Coli (APC) to upregulate Wnt/?-catenin signaling. Due to the discordance, we elaborated experiments by using extensive mutagenesis, which demonstrated that the stem-loop structure was important for miR-142 to efficiently suppress Wnt/?-catenin signaling. Moreover, the inhibitory effect of miR-142 relies on miR-142-3p rather than miR-142-5p. Further, we found that miR-142-3p directly modulated translation of Ctnnb1 mRNA (encoding ?-catenin) through binding to its 3' untranslated region (3' UTR). Finally, miR-142 was able to repress cell cycle progression by inhibiting active Wnt/?-catenin signaling. Thus, our findings highlight the inhibitory role of miR-142-3p in Wnt/?-catenin signaling, which help to understand the complex regulation of Wnt/?-catenin signaling.

| S-EPMC4922628 | biostudies-literature

PEDV nsp16 negatively regulates innate immunity to promote viral proliferation.

Project description:Type-I IFNs (IFN-I) provide a key mediator of innate antiviral response during virus proliferation. Porcine epidemic diarrhea virus (PEDV), which causes diarrhea in swine of all ages, is a worldwide-distributed alphacoronavirus with economic importance. Here, we screened PEDV RNA modification enzymes involved in regulating antiviral response. Whereas the PEDV nsp13 barely regulates type I IFN, inflammatory cytokines (IL-6, TNF-a) and MHCII, nsp16 and nsp14 (to a lesser extent) down-regulate these antiviral effectors. Importantly, we found nsp16 KDKE tetrad appears to play a key role in interferon inhibition by mutating the D129 catalytic residue. Mechanistically, nsp16 down-regulates the activities of RIG-I and MDA5 mediated IFN-? and ISRE. In turn, the mRNA levels of IFIT family members (IFIT1, IFIT2, IFIT3) was inhibited in cells overexpressing nsp16. In addition, nsp10 enhanced the inhibitory effect of nsp16 on IFN-?. Altogether these results indicate PEDV nsp16 negatively regulates innate immunity to promote viral proliferation. Findings from this study provides novel perspective to advance the understanding in the pathogenesis of PEDV.

| S-EPMC7114654 | biostudies-literature

Duck Plague Virus Negatively Regulates IFN Signaling to Promote Virus Proliferation <i>via</i> JNK Signaling Pathway.

Project description:Duck plague virus (DPV), a member of the alphaherpesvirus subfamily, can cause severe damage and immunosuppression in ducks and geese in China. Since lacking an available cell model, the antiviral signal transduction pathways induction and regulation mechanisms related to DPV infection in duck cells are still enigmatic. Our previous study developed a monocyte/macrophages cell model, which has been applied to study innate immunity with DPV. In the present study, we compared and analyzed transcriptome associated with the DPV infection of CHv (virulent strain) and CHa (avirulent strain) at 48hpi based on the duck monocyte/macrophages cell model and RNA-seq technology. Differentially expressed genes (DEGs) analysis showed 2,909 and 2,438 genes altered in CHv and CHa infected cells compared with control cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the DEGs were mainly involved in biological processes such as metabolic pathways, viral infectious diseases, immune system, and signal transduction. The CHv and CHa virus differentially regulated MAPK, NF-κB, and IFN signaling pathways based on transcriptome sequencing data and RT-qPCR results. The JNK inhibitor SP600125 enhanced the IFN signaling, but potentially reduced the VSV and DPV titers in the cell culture supernatant, indicating that JNK negatively regulates the IFN pathway and the inflammatory pathway to promote virus proliferation. The research results may provide promising information to understand the pathogenesis of DPV and provide a novel mechanism by which DPV modulates antiviral signaling and facilitate virus proliferation through hijacking the JNK pathway, which provides a new means for the prevention and control of DPV infection.

| S-EPMC9275408 | biostudies-literature

Wnt Pathway Inhibitor DKK1: A Potential Novel Biomarker for Adiposity.

Project description:Emerging evidence indicates that ectopic skeletal muscle adiposity may be a risk factor for type 2 diabetes (T2D), especially in persons of African ancestry. In vitro studies suggest that a Wnt pathway inhibitor, Dickkopf-related protein 1 (DKK1), plays a role in adiposity regulation and could be a biomarker for adiposity in humans. The objective of this study was to test whether serum DKK1 levels relate to adiposity measures in a cohort from an African ancestry population at high risk for T2D. Fasting serum DKK1 was measured in a sample of 159 men of African ancestry aged ?40 years (mean age ± SD, 63.5 ± 8.2 years; mean body mass index, 27.8 ± 4.5 kg/m2). Anthropometrics included total-body and trunk adiposity measured by dual-energy x-ray absorptiometry and lower-leg skeletal muscle density measured by CT [which reflects the intramuscular adiposity content (mg/cm3)]. Serum DKK1 was positively correlated with BMI (r = 0.20; P = 0.01), waist circumference (r = 0.15; P = 0.046), DXA total-body adiposity (r = 0.24; P = 0.003), and DXA trunk adiposity (r = 0.21; P = 0.009), independent of age and height. In addition, serum DKK1 was inversely correlated with skeletal muscle density (r = -0.25; P = 0.002), independent of age, BMI, and calf muscle area. No significant correlation was found between serum DKK1 and fasting serum glucose or insulin levels or insulin resistance estimated by homeostasis model assessment. These findings suggest that higher levels of serum DKK1 may be associated with greater overall, central, and ectopic skeletal muscle adiposity. Further studies are needed to unravel the potential role of DKK1 in the regulation of adiposity in humans.

| S-EPMC6364619 | biostudies-other

CDK5 Regulatory Subunit-Associated Protein 1-like 1 Negatively Regulates Adipocyte Differentiation through Activation of Wnt Signaling Pathway.

Project description:CDK5 Regulatory Subunit-Associated Protein 1-like 1 (CDKAL1) was identified as a susceptibility gene for type 2 diabetes and body mass index in genome-wide association studies. Although it was reported that CDKAL1 is a methylthiotransferase essential for tRNALys(UUU) and faithful translation of proinsulin generated in pancreatic ? cells, the role of CDKAL1 in adipocytes has not been understood well. In this study, we found that CDKAL1 is expressed in adipose tissue and its expression is increased during differentiation. Stable overexpression of CDKAL1, however, inhibited adipocyte differentiation of 3T3-L1 cells, whereas knockdown of CDKAL1 promoted differentiation. CDKAL1 increased protein levels of ?-catenin and its active unphosphorylated form in the nucleus, thereby promoting Wnt target gene expression, suggesting that CDKAL1 activated the Wnt/?-catenin pathway-a well-characterized inhibitory regulator of adipocyte differentiation. Mutant experiments show that conserved cysteine residues of Fe-S clusters of CDKAL1 are essential for its anti-adipogenic action. Our results identify CDKAL1 as novel negative regulator of adipocyte differentiation and provide insights into the link between CDKAL1 and metabolic diseases such as type 2 diabetes and obesity.

| S-EPMC5544666 | biostudies-literature

Diverse mechanisms of Wnt activation and effects of pathway inhibition on proliferation of human gastric carcinoma cells.

Project description:Human gastric carcinomas are among the most treatment-refractory epithelial malignancies. Increased understanding of the underlying molecular aberrations in such tumors could provide insights leading to improved therapeutic approaches. In this study, we characterized diverse genetic aberrations leading to constitutive Wnt signaling activation in a series of human gastric carcinoma cell lines. Downregulation of TCF signaling by stable transduction of dominant negative TCF4 (DNTCF4) resulted in inhibition of proliferation in Wnt-activated AGS tumor cells. c-Myc downregulation and the associated upregulation of its repression target, p21 observed in these tumor cells, as well as the profound growth inhibition induced by c-Myc small hairpin RNA (shRNA) implied their c-Myc addiction. In striking contrast, Wnt-activated MKN-28 and MKN-74 tumor cells appeared refractory to DNTCF4 inhibition of proliferation despite comparably decreased c-Myc expression levels. The resistance of these same tumor cells to growth inhibition by c-Myc shRNA established that their refractoriness to DNTCF was because of their independence from c-Myc for proliferation. There was no correlation between this resistance phenotype and the presence or absence of constitutive mitogen-activated protein kinase (MAPK) and/or AKT pathway activation, commonly observed in gastrointestinal tumors. However, in both DNTCF-sensitive and -resistant tumor cells with MAPK and/or AKT pathway activation, the ability of small molecule antagonists directed against either pathway to inhibit tumor cell growth was enhanced by Wnt pathway inhibition. These findings support the concept that although certain Wnt-activated tumors may escape c-Myc dependence for proliferation, disruption of other oncogenic pathways can unmask cooperative antiproliferative effects for Wnt pathway downregulation.

| S-EPMC3965355 | biostudies-literature

Sestrin2 inhibits YAP activation and negatively regulates corneal epithelial cell proliferation.

Project description:Corneal wound healing is essential for the maintenance of corneal integrity and transparency and involves a series of physiological processes that depend on the proliferation of epithelial cells. However, the molecular mechanisms that control corneal epithelial cell proliferation are poorly understood. Here, we show that Sestrin2, a stress-inducible protein, is downregulated in the corneal epithelium during wound healing and that the proliferation of epithelial basal cells is enhanced in Sestrin2-deficient mice. We also show that YAP, a major downstream effector of the Hippo signaling pathway, regulates cell proliferation during corneal epithelial wound repair and that Sestrin2 suppresses its activity. Moreover, increased levels of reactive oxygen species in the Sestrin2-deficient corneal epithelium promote the nuclear localization and dephosphorylation of YAP, activating it to enhance the proliferation of corneal epithelial cells. These results reveal that Sestrin2 is a negative regulator of YAP, which regulates the proliferative capacity of basal epithelial cells, and may serve as a potential therapeutic target for corneal epithelial damage.

| S-EPMC7338388 | biostudies-literature

Aflatoxin B1 negatively regulates Wnt/β-catenin signaling pathway through activating miR-33a.

Project description:MicroRNAs are known to play an important role in modulating gene expression in various diseases including cancers and cardiovascular disorders, but only a few of them are associated with the pathology of aflatoxin B1 (AFB1), a potent mycotoxin. Here, we discovered a novel regulatory network between AFB1, miR-33a and β-catenin in human carcinoma cells. The level of miR-33a was up-regulated in hepatocellular carcinoma (HCC) cells treated with AFB1, while in the same cells causing the decrease in β-catenin expression when treated at their IC50 values. miR-33a, specifically miR-33a-5p, was demonstrated to down-regulate the expression of β-catenin, affect the β-catenin pathway, and inhibit cell growth. Also, by employing a luciferase assay, we found that miR-33a down-regulated β-catenin by directly binding to the 3'-UTR of β-catenin. These results suggested that AFB1 might down-regulate β-catenin by up-regulating miR-33a. This understanding opens new lines of thought in the potential role of miR-33a in the clinical therapy of cancer.

| S-EPMC3754916 | biostudies-literature

The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair.

Project description:Dkk1 is a secreted antagonist of the Wnt/?-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine.We used doubleridge mice (Dkk1d/d), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/?-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2'-deoxyuridine incorporation, and immunostaining.Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of ?-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/d mice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/?-catenin, ERK/Elk-1, and c-Jun pathways.Dkk1, an antagonist of Wnt/?-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.

| S-EPMC3551610 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data