Tissue transglutaminase-1 promotes stemness and chemoresistance in gastric cancer cells by regulating Wnt/β-catenin signaling

Huang, Haitao; Chen, Zhiqi; Ni, Xiuqin

doi:10.1177/1535370216670541

Cited by 25 publications

(27 citation statements)

References 36 publications

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“…Santos et al reported that SOX9 upregulation promotes stemness and chemoresistance in gastric cancer cells through activation of Wnt/β-catenin signaling 21. Similarly, the Wnt/β-catenin signaling pathway is involved in tissue transglutaminase-1-induced chemoresistance in gastric cancer cells 22. These studies, combined with our findings, suggest that DAP3 silencing-induced chemoresistance is likely mediated through activation of β-catenin signaling.…”

Section: Discussionsupporting

confidence: 79%

Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

Jia

Cheng

et al. 2019

Journal of Investigative Medicine

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Previously, we demonstrated that death-associated protein-3 (DAP3) loss drives chemoresistance in gastric cancer cells. In the present study, we aimed to determine the underlying molecular mechanism. The effect of DAP3 silencing on β-catenin signaling was assessed. The direct mediator of DAP3 silencing-induced chemoresistance was identified. Depletion of DAP3 stimulates nuclear accumulation of β-catenin and enhances β-catenin-dependent transcriptional activity in gastric cancer cells. However, the protein kinase B , , extracellular regulated protein kinase and signal transducer and activator of transcription 3 signaling pathways remain unaffected by DAP3 loss. We found that the downstream target gene LGR5 (leucine-rich G-protein coupled receptor 5) is upregulated in DAP3-depleted gastric cancer cells. Moreover, knockdown of LGR5 resensitizes DAP3-depleted gastric cancer cells to 5-fluorouracil (5-FU) and oxaliplatin. We also observed that ectopic expression of LGR5 reduces apoptosis in gastric cancer cells on treatment with 5-FU and oxaliplatin, which is accompanied by prevention of caspase-3 cleavage. The antiapoptotic protein Bcl-2 is identified as a key mediator of LGR5-induced apoptosis resistance in gastric cancer cells. The present findings indicate that DAP3 deficiency-induced chemoresistance in gastric cancer is at least partially mediated through the β-catenin/LGR5/Bcl-2 axis. Targeting LGR5 may provide a novel strategy to overcome chemoresistance in DAP3-deficient gastric cancer cells.

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Section: Discussionsupporting

confidence: 79%

Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

Jia

Cheng

et al. 2019

Journal of Investigative Medicine

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“…In addition, researchers found that the mechanism by which TGM1 regulates the development of gastric cancer may be related to the Wnt signaling pathway. When the expression of TGM1 is inhibited, Wnt signaling pathway activity is significantly reduced 61 . Similar to our research, Zhong et al found that the level of TGM1 was increased in ESCC 56 .…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate aberrantly methylated and differentially expressed genes in Esophageal squamous cell carcinoma

Han

Yang

Hosseini

et al. 2020

Sci Rep

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Aberrant methylated genes (DMGs) play an important role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to integrate three cohorts profile datasets to ascertain aberrant methylated-differentially expressed genes and pathways associated with ESCC by comprehensive bioinformatics analysis. We downloaded data of gene expression microarrays (GSE20347, GSE38129) and gene methylation microarrays (GSE52826) from the Gene Expression Omnibus (GEO) database. Aberrantly differentially expressed genes (DEGs) were obtained by GEO2R tool. The David database was then used to perform Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses on selected genes. STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network, then the modules in the PPI networks were analyzed with MCODE and the hub genes chose from the PPI networks were verified by Oncomine and TCGA database. In total, 291 hypomethylation-high expression genes and 168 hypermethylation-low expression genes were identified at the screening step, and finally found six mostly changed hub genes including KIF14, CDK1, AURKA, LCN2, TGM1, and DSG1. Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process. After validation in multiple databases, most hub genes remained significant. Patients with high expression of AURKA were associated with shorter overall survival. To summarize, we have identified six feasible aberrant methylated-differentially expressed genes and pathways in ESCC by bioinformatics analysis, potentially providing valuable information for the molecular mechanisms of ESCC. Our data combined the analysis of gene expression profiling microarrays and gene methylation profiling microarrays, simultaneously, and in this way, it can shed a light for screening and diagnosis of ESCC in future. Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide, with incidence rates ranking fourth and eighth in China and worldwide, respectively 1,2. ESCC is a serious threat to human health, and its five-year survival rate is less than 10%, making it a leading cause of cancer-related death 3. So far,

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“…[68] Transglutaminase-1 (TGM1) can suppress the Wnt signaling pathway and involve in development of gastric cancer. [69] By constructing a miRNA-mRNA network, miR-183 was shown to have the highest connectivity to target genes and to target, MMP9, TOP2A, AURKA, MCM2, IVL, FOS, and CYP2C9. MiR-183 might play an oncogenic role by suppressing apoptosis and promoting proliferation in ESCC by regulating PDCD4 expression.…”

Section: Discussionmentioning

confidence: 99%

Identification of crucial miRNAs and genes in esophageal squamous cell carcinoma by miRNA-mRNA integrated analysis

Zhong

Huang

et al. 2019

Medicine

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Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood. The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein–protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database. In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC. Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.

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Tissue transglutaminase-1 promotes stemness and chemoresistance in gastric cancer cells by regulating Wnt/β-catenin signaling

Cited by 25 publications

References 36 publications

Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

Depletion of death-associated protein-3 induces chemoresistance in gastric cancer cells through the β-catenin/LGR5/Bcl-2 axis

Identification of candidate aberrantly methylated and differentially expressed genes in Esophageal squamous cell carcinoma

Identification of crucial miRNAs and genes in esophageal squamous cell carcinoma by miRNA-mRNA integrated analysis

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