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YRDC is upregulated in non-small cell lung cancer and promotes cell proliferation by decreasing cell apoptosis.

ABSTRACT: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality worldwide. yrdC N6-threonylcarbamoltransferase domain containing protein (YRDC) has been demonstrated to be involved in the formation of threonylcarbamoyladenosine in transfer ribonucleic acid. However, the molecular mechanisms underlying NSCLC progression remain largely unclear. The present study revealed that YRDC was upregulated in NSCLC samples compared with adjacent non-cancerous tissues by analyzing datasets obtained from the Gene Expression Omnibus and The Cancer Genome Atlas. Higher expression of YRDC was associated with overall survival time and disease-free survival time in patients with NSCLC, particularly in lung adenocarcinoma. Furthermore, knockdown of YRDC in NSCLS cell lines significantly suppressed cell growth and cell colony formation in vitro. Additionally, the results demonstrated that silencing of YRDC induced apoptosis of A549 cells. Then, the protein-protein interaction networks associated with yrdC N6-threonylcarbamoltransferase domain containing protein (YRDC) in NSCLC were subsequently constructed to investigate the potential molecular mechanism underlying the role of YRDC in NSCLC. The results revealed that YRDC was involved in the regulation of spliceosomes, ribosomes, the p53 signaling pathway, proteasomes, the cell cycle and DNA replication. The present study demonstrated that YRDC may serve as a novel biomarker for the prognosis prediction and treatment of NSCLC.

SUBMITTER: Shen H

PROVIDER: S-EPMC7285791 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBufadienolides derived from the skin of toads are often regarded as the main active components with antitumor effects. 19-Hydroxybufalin (19-HB) is a monomer of bufadienolides; however, its effects and underlying molecular mechanisms on tumor growth remain to be ascertained. In this report, we focused on the antitumor effects of 19-HB on non-small cell lung cancer to provide a scientific basis for its further development and utilization.MethodsThe antitumor effects of 19-HB on the human NSCLC cell lines NCI-H1299 and NCI-H838 were examined in vitro. The cells were treated with different concentrations of 19-HB, and the inhibition of cell growth was measured by CCK-8 and colony formation assays. Furthermore, cell apoptosis was analyzed by flow cytometry, TUNEL staining, JC-1 staining, and western blotting. The effects on migration and invasion were evaluated by wound-healing assay, transwell assay, and western blotting. Finally, the antitumor effects of 19-HB were evaluated in vivo using a xenograft mouse model.Results19-HB-treated NSCLC cells showed inhibited cell viability and increased apoptosis. The expression levels of cleaved caspase-3, cleaved-PARP, and Bax/Bcl-2 were upregulated, while the mitochondrial membrane potential decreased. In contrast, migration, invasion, as well as the expression of MMP2, MMP7, MMP9, the epithelial-mesenchymal transition-related proteins N-cadherin and Vimentin, and the transcription factors Snail and Slug were inhibited. Furthermore, the expression levels of the key molecules in the Wnt/β-catenin signaling pathway (CyclinD1, c-Myc, and β-catenin) were decreased. In vivo, the growth of xenograft tumors in nude mice was also significantly inhibited by 19-HB, and there were no significant changes in biochemical indicators of hepatic and renal function.Conclusions19-HB inhibited the proliferation, migration, and invasion, and promoted the apoptosis of NSCLC cells via the Wnt/β-catenin pathway. In addition, 19-HB inhibited the growth of xenograft tumors in nude mice with little toxicity to the liver and kidney. Thus, 19-HB may be a potential antitumor agent for treating NSCLC.

Project description:Background:CircLARP4 is reported to act as a tumor suppressor in some cancers. However, the detailed roles and molecular basis of circLARP4 in non-small cell lung cancer (NSCLC) tumorigenesis are still unclear. The aim of the study is to explore the potential roles and molecular basis of circLARP4 in NSCLC tumorigenesis. Materials and Methods:qRT-PCR was taken to detect circLARP4 and miR-135b expressions. MTT assay, ?transwell invasion assay and flow cytometry analysis were applied to evaluate cell proliferation, invasion and apoptosis, respectively. Glycolysis was assessed by measuring hexokinase2 (HK2) expression, glucose consumption and lactate production. Association between circLARP4 and miR-135a was examined by luciferase reporter and RIP assays. The changes of the phosphatase and tension homolog (PTEN)/protein kinase B (AKT)/hypoxia-inducible factor-1? (HIF-1?) pathway were evaluated by Western blot. The nude mouse xenograft models were applied to verify the regulation of circLARP4 in vivo. Results:CircLARP4 was decreased in NSCLC tissues and cells. CircLARP4 overexpression blocked cell proliferation and invasion, and facilitated apoptosis in NSCLC cells. Meanwhile, circLARP4 overexpression suppressed glycolysis in NSCLC cells, as evidenced by the reduced HK2, glucose consumption and lactate production levels. Further analyses proved a downregulation of miR-135b by circLARP4 in a ceRNA-dependent manner in NSCLC cells. CircLARP4-mediated tumor? suppression on NSCLC progression was partially overturned by overexpressing miR-135b. Moreover, we confirmed that circLARP4 had antitumor effect on xen?ograft tumors and downregulated miR-135b. Furthermore, circLARP4 overexpression inhibited the PTEN/AKT/HIF-1? pathway in NSCLC cells and xenograft tumors by downregulating miR-135b. Conclusion:Our findings suggested that ?circLARP4 suppressed NSCLC progression by sponging miR-135b through inactivation of the PTEN/AKT/HIF-1? pathway, which broadens our understanding concerning the roles of circLARP4 in NSCLC tumorigenesis.

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YRDC is upregulated in non-small cell lung cancer and promotes cell proliferation by decreasing cell apoptosis.

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