N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis.
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ABSTRACT:
SUBMITTER: Liu W
PROVIDER: S-EPMC3306556 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundN-myc downstream regulated gene 1 (NDRG1) plays a role in a variety of biological processes including differentiation of osteoclasts. However, it is not known if and how NDRG1 regulates osteogenic differentiation of marrow stromal progenitor cells.MethodsGene expression profiling analysis was performed to study the expression level of Ndrg1 during osteogenic and adipogenic differentiation. Gain-of-function and/or loss-of function experiments were carried out to study the role of NDRG1 in the proliferation and differentiation of marrow stromal progenitor cells and the mechanism underlying the function was investigated. Finally, in vivo transfection of Ndrg1 siRNA was done and its effect on osteogenic and adipogenic differentiation in mice was explored.ResultsGene expression profiling analysis revealed that NDRG1 level was regulated during osteogenic and adipogenic differentiation of progenitor cells. The functional experiments demonstrated that NDRG1 negatively regulated the cell growth, and reciprocally modulated the osteogenic and adipogenic commitment of marrow stromal progenitor cells, driving the cells to differentiate toward adipocytes at the expense of osteoblast differentiation. Moreover, NDRG1 interacted with low-density lipoprotein receptor-related protein 6 (LRP6) in the stromal progenitor cells and inactivated the canonical Wnt/β-catenin signaling cascade. Furthermore, the impaired differentiation of progenitor cells induced by Ndrg1 siRNA could be attenuated when β-catenin was simultaneously silenced. Finally, in vivo transfection of Ndrg1 siRNA to the marrow of mice prevented the inactivation of canonical Wnt signaling in the BMSCs of ovariectomized mice, and ameliorated the reduction of osteoblasts on the trabeculae and increase of fat accumulation in the marrow observed in the ovariectomized mice.ConclusionThis study has provided evidences that NDRG1 plays a role in reciprocally modulating osteogenic and adipogenic commitment of marrow stromal progenitor cells through inactivating canonical Wnt signaling.
| S-EPMC8817551 | biostudies-literature
Project description:β-Sitosterol is a natural compound with demonstrated anti-cancer properties against various cancers. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms are not well understood. This study aims to investigate the impact of β-sitosterol on HCC. In this study, we investigated the effects of β-sitosterol on HCC tumour growth and metastasis using a xenograft mouse model and a range of molecular analyses, including bioinformatics, real-time PCR, western blotting, lentivirus transfection, CCK8, scratch and transwell assays. The results found that β-sitosterol significantly inhibits HepG2 cell proliferation, migration and invasion both in vitro and in vivo. Bioinformatics analysis identifies forkhead box M1 (FOXM1) as a potential target for β-sitosterol in HCC treatment. FOXM1 is upregulated in HCC tissues and cell lines, correlating with poor prognosis in patients. β-Sitosterol downregulates FOXM1 expression in vitro and in vivo. FOXM1 overexpression mitigates β-sitosterol's inhibitory effects on HepG2 cells. Additionally, β-sitosterol suppresses epithelial-mesenchymal transition (EMT) in HepG2 cells, while FOXM1 overexpression promotes EMT. Mechanistically, β-sitosterol inhibits Wnt/β-catenin signalling by downregulating FOXM1, regulating target gene transcription related to HepG2 cell proliferation and metastasis. β-Sitosterol shows promising potential as a therapeutic candidate for inhibiting HCC growth and metastasis through FOXM1 downregulation and Wnt/β-catenin signalling inhibition.
| S-EPMC10844700 | biostudies-literature
Project description:BackgroundNasopharyngeal carcinoma (NPC) is especially prevalent in southeast Asia and southern China, but its molecular mechanisms remain poorly characterized. DNA methylation is associated with initiation and progression of tumors, including NPC. Through a genome-wide DNA methylation screening approach, we discovered ZNF154, but its methylation status and roles in NPC have not been investigated.MethodsThe methylation status of ZNF154 in NPC was detected with Methylation specific-PCR (MSP) and Quantitative Sequenom MassARRAY. The invasion and migration capacities were examined by wound healing and transwell invasion assays. The role of ZNF154 in NPC metastasis was clarified with experimental metastasis assay in vivo. Western blotting analysis was used to investigate protein changes followed by ZNF154 over-expression. Kaplan-Meier analysis was performed to determine the association between ZNF154 methylation and prognosis in NPC.ResultsCompared to immortalized nasopharyngeal tissues and cells, ZNF154 expression was frequently downregulated in NPC tissues and cell lines due to promoter methylation. Demethylation treatment with 5-aza-2-deoxycytidine (5-Aza) restored ZNF154 expression in NPC cell lines. Ectopic overexpression of ZNF154 in NPC cells inhibited cell migration and invasion in vitro and lung nodule formation in an in vivo tumor metastasis assay. Mechanistic investigations suggested ZNF154 inhibits Wnt/β-catenin signalling pathway activation and prevents the EMT in NPC. Furthermore, Kaplan-Meier analysis showed hypermethylation of the ZNF154 promoter was associated with significantly poorer disease-free survival (P = 0.032) and distant metastasis-free survival (P = 0.040) among patients with locoregionally advanced NPC.ConclusionsTaken together, these findings define a novel role for ZNF154 as a tumor suppressor in NPC.
| S-EPMC5689643 | biostudies-literature
Project description:The metastasis of esophageal squamous cell carcinoma (ESCC) is a leading cause of death worldwide, however, it has a poor prognosis. Ginsenoside Rh4 is a rare saponin that has been shown to have potential antitumor effectiveness in ESCC. However, the utility of Rh4 in ESCC metastasis and its undiscovered mode of action has not yet been explored. In this study, we found that Rh4 could inhibit ESCC metastasis by regulating the Wnt/β-catenin signaling pathway and the level of c-Myc, which is an important transcription factor in cancer. In in vitro experiments, Rh4 could inhibit the migration and invasion of ESCC cells without affecting cell viability. In in vivo experiments, Rh4 restrained ESCC metastasis to the lymph nodes and lungs via the suppression of epithelial-mesenchymal transition (EMT). The Wnt agonist HLY78 promoted EMT and migration of ESCC cells, whereas treatment of Rh4 can attenuate the promotion effect of HLY78. The siRNA knocking out c-Myc can also significantly reduce the expression of EMT-related marker proteins. This study illustrates a new concept for further research on the mechanism of Rh4 in ESCC.
| S-EPMC9331240 | biostudies-literature
Project description:The Wnt/beta-catenin signalling pathway appears to operate to maintain the undifferentiated state of preadipocytes by inhibiting adipogenic gene expression. To define the mechanisms regulating suppression of Wnt/beta-catenin signalling, we analysed the beta-catenin expression in response to activation of transcription factors that regulate adipogenesis. The results show an extensive down-regulation of nuclear beta-catenin that occurs during the first few days of differentiation of 3T3-L1 preadipocytes and coincides with the induction of the adipogenic transcription factors, C/EBPbeta (CCAAT-enhancer-binding protein) and PPARgamma (peroxisome-proliferator-activated receptor). To assess the role of each of these factors in this process, we conditionally overexpressed C/EBPbeta in Swiss mouse fibroblasts using the TET-off system. Abundant expression of C/EBPbeta alone had minimal effect on beta-catenin expression, whereas expression of C/EBPbeta, in the presence of dexamethasone, induced PPARgamma expression and caused a measurable decrease in beta-catenin. In addition, exposure of cells expressing both C/EBPbeta and PPARgamma to a potent PPARgamma ligand resulted in an even greater decrease in beta-catenin by mechanisms that involve the proteasome. Our studies also suggest a reciprocal relationship between PPARgamma activity and beta-catenin expression, since ectopic production of Wnt-1 in preadipocytes blocked the induction of PPARgamma gene expression. Moreover, by suppressing beta-catenin expression, ectopic expression of PPARgamma in Wnt-1-expressing preadipocytes rescued the block in adipogenesis after their exposure to the PPARgamma ligand, troglitazone.
| S-EPMC1223802 | biostudies-other
Project description:MIR17HG, located on chromosome 13, is a class of Pri-miRNAs that generates six miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92-1. These miRNAs are ubiquitously overexpressed in diverse tumour types and exhibit complex biological links to tumour metastasis. We demonstrated that MIR17HG-derived miR-18a and miR-19a coordinately mediate gastric cancer cell metastasis by directly inhibiting SMAD2 expression and upregulating Wnt/β-catenin signalling. Based on previous studies, we hypothesised that an investigation of MIR17HG inhibition would be beneficial to clinical gastric cancer treatment, and systematically coupled bioinformatics analyses brought interferon regulatory factor-1 (IRF-1) to our attention. We then established stable clones in gastric cancer cells containing a doxycycline-inducible IRF-1 expression system and found that the expression of IRF-1 downregulates the embedded miRNAs of MIR17HG in gastric cancer cells and inhibits gastric cancer cell metastasis by attenuating Wnt/β-catenin signalling. Further rescue assays confirmed the crucial roles of miR-18a and miR-19a in the IRF-1-mediated inhibition of Wnt/β-catenin signalling. We also demonstrated that IRF-1 binds to the transcriptional site in the MIR17HG promoter and inhibits MIR17HG expression. Moreover, IFN-γ induced the IRF-1-mediated downregulation of MIR17HG in gastric cancer cells. Our hypothesis was supported by the results of immunohistochemistry analyses of clinical gastric cancer samples, and we also demonstrated the role of IRF-1 in inhibiting MIR17HG expression and tumour metastasis in vivo. We conclude that IRF-1 inhibits gastric cancer metastasis by downregulating MIR17HG-miR-18a/miR-19a axis expression and attenuating Wnt/β-catenin signalling.
| S-EPMC6560107 | biostudies-literature
Project description:MicroRNAs (miRNAs) inhibit or improve the malignant progression of hepatocellular carcinoma (HCC). We previously reported that compared to health controls, patients with liver cirrhosis present the highest levels of circulating miR-885-5p, followed by those with chronic hepatitis B and those with HCC. However, the molecular involvement of miR-885-5p in HCC metastasis is presently unclear. Here, we demonstrated that the expression of miR-885-5p negatively correlated with the invasive and metastatic capabilities of human HCC tissue samples and cell lines. We found that miR-885-5p expression levels correlated with the survival of patients with HCC. Overexpression of miR-885-5p decreased metastasis of HCC cells in vitro and in vivo. Inhibition of miR-885-5p improved proliferation of non-metastatic HCC cells. Furthermore, we disclosed that miR-885-5p targeted gene encoding ?-catenin CTNNB1, leading to decreased activity of the Wnt/?-catenin signaling pathway. The present study indicates that miR-885-5p suppresses the metastasis of HCC and inhibits Wnt/?-catenin signaling pathway by its CTNNB1 target, which suggests that miR-885-5p to be a promising negative regulator of HCC progression and as a novel therapeutic agent to treat HCC.
| S-EPMC5342721 | biostudies-literature
Project description:BackgroundThe mechanisms underlying metastasis of colorectal cancer (CRC) remain unclear. C14orf159 is a mitochondrial matrix protein converting D-glutamate to 5-oxo-D-proline. Other metabolic functions of C14orf159, especially on mitochondrial metabolism, and its contribution to CRC metastasis, are not elucidated.MethodsMetabolome analysis by gas chromatography-mass spectrometry, RNA-sequencing analysis, flow cytometry, migration and invasion assay, sphere-formation assay using C14orf159-knockout and -stable expressing cells, immunohistochemistry of C14orf159 in human CRC specimens, and xenograft experiments using Balb/c nude mice were conducted.ResultsC14orf159 maintained the mitochondrial membrane potential of human CRC cells, and its involvement in amino acid and glutathione metabolism was demonstrated. In human CRC specimens, a decrease in C14orf159 expression at the invasive front of the tumour and in metastasis was determined. C14orf159 was also shown to attenuate the migration, invasion, and spheroid growth of CRC cells in vitro and colorectal tumour growth and metastasis in vivo. Mechanistically, C14orf159 reduced the expression of genes involved in CRC metastasis, including members of the Wnt and MMP family, by maintaining the mitochondrial membrane potential.ConclusionsOur findings link mitochondrial membrane potential to Wnt/β-catenin signalling and reveal a previously unrecognised function of the mitochondrial matrix protein C14orf159 as a suppressor of CRC metastasis.
| S-EPMC8651639 | biostudies-literature
Project description:Dysregulation of cholesterol is a common characteristic of human cancers including prostate cancer. This study observed an aberrant accumulation of cholesteryl ester in metastatic lesions using Raman spectroscopic analysis of lipid droplets in human prostate cancer patient tissues. Inhibition of cholesterol esterification in prostate cancer cells significantly suppresses the development and growth of metastatic cancer lesions in both orthotopic and intracardiac injection mouse models. Gene expression profiling reveals that cholesteryl ester depletion suppresses the metastatic potential through upregulation of multiple regulators that negatively impact metastasis. In addition, Wnt/β-catenin, a vital pathway for metastasis, is downregulated upon cholesteryl ester depletion. Mechanistically, inhibition of cholesterol esterification significantly blocks secretion of Wnt3a through reduction of monounsaturated fatty acid levels, which limits Wnt3a acylation. These results collectively validate cholesterol esterification as a novel metabolic target for treating metastatic prostate cancer. Mol Cancer Res; 16(6); 974-85. ©2018 AACR.
| S-EPMC5984676 | biostudies-literature
Project description:Osteoblast differentiation from mesenchymal cells is regulated by multiple signalling pathways. Here we have analysed the roles of Fibroblast Growth Factor (FGF) and canonical Wingless-type MMTV integration site (Wnt/β-Catenin) signalling pathways on zebrafish osteogenesis. We have used transgenic and chemical interference approaches to manipulate these pathways and have found that both pathways are required for osteoblast differentiation in vivo. Our analysis of bone markers suggests that these pathways act at the same stage of differentiation to initiate expression of the osteoblast master regulatory gene osterix (osx). We use two independent approaches that suggest that osx is a direct target of these pathways. Firstly, we manipulate signalling and show that osx gene expression responds with similar kinetics to that of known transcriptional targets of the FGF and Wnt pathways. Secondly, we have performed ChIP with transcription factors for both pathways and our data suggest that a genomic region in the first intron of osx mediates transcriptional activation. Based upon these data, we propose that FGF and Wnt/β-Catenin pathways act in part by directing transcription of osx to promote osteoblast differentiation at sites of bone formation.
| S-EPMC4686927 | biostudies-literature