Dataset Information

Long non-coding RNA TRPM2-AS regulates microRNA miR-138-5p and PLAU (Plasminogen Activator, Urokinase) to promote the progression of gastric adenocarcinoma.

ABSTRACT: Gastric adenocarcinoma (GAC) is a common malignant tumor, accounting for 95% of gastric cancers. However, the effects and regulatory mechanisms of long non-coding RNA TRPM2-AS (TRPM2-AS) in GAC have not been fully explored. Our study investigates the action mechanism of TRPM2-AS in GAC. After performing quantitative Real-Time polymerase chain reaction or western blotting, we found that the levels of TRPM2-AS and Plasminogen Activator, Urokinase (PLAU) were upregulated in GAC, whereas the level of miR-138-5p was downregulated. Cell function experiments proved that silencing TRPM2-AS suppressed proliferation and migration and induced apoptosis in GAC cells. Bioinformatic analysis and luciferase assay identified the interaction between TRPM2-AS, miR-138-5p, and PLAU. In addition, the inhibitory effect of silencing TRPM2-AS on GAC cells could be partially relieved by PLAU overexpression. In conclusion, our study revealed that TRPM2-AS sponging miR-138-5p to upregulate PLAU could contribute to GAC progression, which might be useful for identifying biomarkers for GAC therapy.AbbreviationGastric adenocarcinoma (GAC); Long non-coding RNA (lncRNA); lncRNA TRPM2 antisense RNA (TRPM2-AS); Plasminogen Activator, Urokinase (PLAU); Wild-type (WT); mutant (MUT).

SUBMITTER: Sun J

PROVIDER: S-EPMC8809918 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Long non-coding RNA TRPM2-AS regulates microRNA miR-138-5p and PLAU (Plasminogen Activator, Urokinase) to promote the progression of gastric adenocarcinoma.

Sun Jun J Zhou Fang F Xue Juan J Ji Chunyan C Qu Yinzong Y Pan Yuwei Y

Bioengineered 20211201 2

Gastric adenocarcinoma (GAC) is a common malignant tumor, accounting for 95% of gastric cancers. However, the effects and regulatory mechanisms of long non-coding RNA TRPM2-AS (TRPM2-AS) in GAC have not been fully explored. Our study investigates the action mechanism of TRPM2-AS in GAC. After performing quantitative Real-Time polymerase chain reaction or western blotting, we found that the levels of TRPM2-AS and Plasminogen Activator, Urokinase (PLAU) were upregulated in GAC, whereas the level o ...[more]

PMID: 34696681

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Project description:BackgroundPrevious studies have revealed the role of dysregulated urokinase plasminogen activator (encoded by PLAU) expression and activity in several pathways associated with cancer progression. However, systematic investigation into the association of PLAU expression with factors that modulate PDAC (pancreatic ductal adenocarcinoma) progression is lacking, such as those affecting stromal (pancreatic stellate cell, PSC)-cancer cell interactions, tumour immunity, PDAC subtypes and clinical outcomes from potential PLAU inhibition.MethodsThis study used an integrated bioinformatics approach to identify prognostic markers correlated with PLAU expression using different transcriptomics, proteomics, and clinical data sets. We then determined the association of dysregulated PLAU and correlated signatures with oncogenic pathways, metastatic phenotypes, stroma, immunosuppressive tumour microenvironment (TME) and clinical outcome. Finally, using an in vivo orthotopic model of pancreatic cancer, we confirmed the predicted effect of inhibiting PLAU on tumour growth and metastasis.ResultsOur analyses revealed that PLAU upregulation is not only associated with numerous other prognostic markers but also associated with the activation of various oncogenic signalling pathways, aggressive phenotypes relevant to PDAC growth and metastasis, such as proliferation, epithelial-mesenchymal transition (EMT), stemness, hypoxia, extracellular cell matrix (ECM) degradation, upregulation of stromal signatures, and immune suppression in the tumour microenvironment (TME). Moreover, the upregulation of PLAU was directly connected with signalling pathways known to mediate PSC-cancer cell interactions. Furthermore, PLAU upregulation was associated with the aggressive basal/squamous phenotype of PDAC and significantly reduced overall survival, indicating that this subset of patients may benefit from therapeutic interventions to inhibit PLAU activity. Our studies with a clinically relevant orthotopic pancreatic model showed that even short-term PLAU inhibition is sufficient to significantly halt tumour growth and, importantly, eliminate visible metastasis.ConclusionElevated PLAU correlates with increased aggressive phenotypes, stromal score, and immune suppression in PDAC. PLAU upregulation is also closely associated with the basal subtype type of PDAC; patients with this subtype are at high risk of mortality from the disease and may benefit from therapeutic targeting of PLAU.

Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

Dataset Information

Long non-coding RNA TRPM2-AS regulates microRNA miR-138-5p and PLAU (Plasminogen Activator, Urokinase) to promote the progression of gastric adenocarcinoma.

Publications

Long non-coding RNA TRPM2-AS regulates microRNA miR-138-5p and PLAU (Plasminogen Activator, Urokinase) to promote the progression of gastric adenocarcinoma.

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