Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization

Tian, Sai; Fu, Lu; Zhang, Jinbo; Xu, Jia; Li, Yuan; Qin, Jiang‐Jiang; Zhang, Weidong

doi:10.3389/fimmu.2021.761326

Cited by 11 publications

(9 citation statements)

References 63 publications

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“…It was previously thought to be an evolutionarily-related regulator of mitosis [ 34 ]. Recently, in the context of tumors, it has been shown to be associated with DNA methylation [ 35 ] and synergistic with P53 to promote tumor progression [ 36 ], but the correlation of lactic acid metabolism and immunotherapy has rarely been mentioned; Polo-like kinase 1 (Plk1) plays a key role in mitosis, which regulates cell proliferation. Studies on its transformation were mainly based on its phosphorylation and protein interaction [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel Risk Score Model of Lactate Metabolism for Predicting over Survival and Immune Signature in Lung Adenocarcinoma

Jiang

Luo

Zhang

et al. 2022

Cancers

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Background: The role of lactate acid in tumor progression was well proved. Recently, it was found that lactate acid accumulation induced an immunosuppressive microenvironment. However, these results were based on a single gene and it was unclear that lactate acid genes were associated with immunotherapy and able to predict overall survival. Methods: Genes and survival data were acquired from TCGA, GEO and GENECARDS. PCA and TSNE were used to distinguish sample types according to lactate metabolism-associated gene expression. A Wilcox-test examined the expression differences between normal and tumor samples. The distribution in chromatin and mutant levels were displayed by Circo and MAfTools. The lactate metabolism-associated gene were divided into categories by consistent clustering and visualized by Cytoscape. Immune cell infiltration was evaluated by CIBERSORT and LM22 matrix. Enrichment analysis was performed by GSVA. We used the ConsensusClusterPlus package for consistent cluster analysis. A prognostic model was constructed by Univariate Cox regression and Lasso regression analysis. Clinical specimens were detected their expression of genes in model by IHC. Results: Most lactate metabolism-associated gene were significantly differently expressed between normal and tumor samples. There was a strong correlation between the expression of lactate metabolism-associated gene and the abundance of immune cells. We divided them into two clusters (lactate.cluster A,B) with significantly different survival. The two clusters showed a difference in signal, immune cells, immune signatures, chemokines, and clinical features. We identified 162 differential genes from the two clusters, by which the samples were divided into three categories (gene.cluster A,B,C). They also showed a difference in OS and immune infiltration. Finally, a risk score model that was composed of six genes was constructed. There was significant difference in the survival between the high and low risk groups. ROC curves of 1,3, 5, and 10 years verified the model had good predictive efficiency. Gene expression were correlated with ORR and PFS in patients who received anti-PD-1/L1. Conclusion: The lactate metabolism-associated genes in LUAD were significantly associated with OS and immune signatures. The risk scoring model that was constructed by us was able to well identify and predict OS and were related with anti-PD-1/L1 therapy outcome.

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Section: Discussionmentioning

confidence: 99%

A Novel Risk Score Model of Lactate Metabolism for Predicting over Survival and Immune Signature in Lung Adenocarcinoma

Jiang

Luo

Zhang

et al. 2022

Cancers

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“…Furthermore, therapy response of patients with ‘low miR-142-3p’ to dimethyl fumarate (DMF), an established disease-modifying treatment (DMT), was superior to that of patients with ‘high miR-142-3p’ levels ( 37 ). In addition, study had shown that by screening and analyzing data from the CTRP and PRISM databases, the potential target gene CDC25C has been identified as being linked to the drugs oligomycin A and panobinostat, providing potential therapeutic options for treating patients with high-risk breast cancer ( 38 ). Our in vitro studies on the function of CDC25C in NSCLC cells showed that CDC25C downregulation efficiently inhibited NSCLC cell invasion, migration, and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Regulatory role of the miR-142-3p/CDC25C axis in modulating autophagy in non-small cell lung cancer

Meng,

Song,

Cong

et al. 2024

Transl Lung Cancer Res

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Background With its diverse genetic foundation and heterogeneous nature, non-small cell lung cancer (NSCLC) needs a better comprehension of prognostic evaluation and efficient treatment targeting. Methods Bioinformatics analysis was performed of The Cancer Genome Atlas (TCGA)-NSCLC and GSE68571 dataset. Overlapping differentially expressed genes (DEGs) were used for functional enrichment analysis and constructing the protein-protein interaction (PPI) network. In addition, key prognostic genes were identified through prognostic risk models, and their expression levels were verified. The phenotypic effects of cell division cycle 25C ( CDC25C ) regulation on NSCLC cell lines were assessed by in vitro experiments using various techniques such as flow cytometry, Transwell, and colony formation. Protein levels related to autophagy and apoptosis were assessed, specifically examining the impact of autophagy inhibition [3-methyladenine (3-MA)] and the miR-142-3p/ CDC25C axis on this regulatory system. Results CDC25C was identified as a key prognostic marker in NSCLC, showing high expression in tumor samples. In vitro experiments showed that CDC25C knockdown markedly reduced the capacity of cells to proliferate, migrate, invade, trigger apoptosis, and initiate cell cycle arrest. CDC25C and miR-142-3p displayed a reciprocal regulatory relationship. CDC25C reversed the inhibitory impacts of miR-142-3p on NSCLC cell cycle proliferation and progression. The synergy of miR-142-3p inhibition, CDC25C silencing, and 3-MA treatment was shown to regulate NSCLC cell processes including proliferation, apoptosis, and autophagy. Conclusions MiR-142-3p emerged as a key player in governing autophagy and apoptosis by directly targeting CDC25C expression. This emphasizes the pivotal role of the miR-142-3p/ CDC25C axis as a critical regulatory pathway in NSCLC.

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“…Our study demonstrates the clinical applications of compounds from the CTRP and PRISM databases provide effective strategies and circumstantial evidence for the screening of drugs targeting KRAS mutations. These databases offer opportunities for drug repurposing, identification of combination therapies, personalized medicine approaches, and biomarker discovery ( 58 ). As for other genes whose expression in cell lines was inconsistent with the model, we hope that further verification can be carried out by other means, such as organoid models, in which the sensitivity of candidate drugs can be further verified.…”

Section: Discussionmentioning

confidence: 99%

Exploring KRAS-mutant pancreatic ductal adenocarcinoma: a model validation study

Yang,

He,

et al. 2024

Front. Immunol.

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IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among all solid tumors. Tumorigenesis is promoted by the oncogene KRAS, and KRAS mutations are prevalent in patients with PDAC. Therefore, a comprehensive understanding of the interactions between KRAS mutations and PDAC may expediate the development of therapeutic strategies for reversing the progression of malignant tumors. Our study aims at establishing and validating a prediction model of KRAS mutations in patients with PDAC based on survival analysis and mRNA expression.MethodsA total of 184 and 412 patients with PDAC from The Cancer Genome Atlas (TCGA) database and the International Cancer Genome Consortium (ICGC), respectively, were included in the study.ResultsAfter tumor mutation profile and copy number variation (CNV) analyses, we established and validated a prediction model of KRAS mutations, based on survival analysis and mRNA expression, that contained seven genes: CSTF2, FAF2, KIF20B, AKR1A1, APOM, KRT6C, and CD70. We confirmed that the model has a good predictive ability for the prognosis of overall survival (OS) in patients with KRAS-mutated PDAC. Then, we analyzed differential biological pathways, especially the ferroptosis pathway, through principal component analysis, pathway enrichment analysis, Gene Ontology (GO) enrichment analysis, and gene set enrichment analysis (GSEA), with which patients were classified into low- or high-risk groups. Pathway enrichment results revealed enrichment in the cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450, and viral protein interaction with cytokine and cytokine receptor pathways. Most of the enriched pathways are metabolic pathways predominantly enriched by downregulated genes, suggesting numerous downregulated metabolic pathways in the high-risk group. Subsequent tumor immune infiltration analysis indicated that neutrophil infiltration, resting CD4 memory T cells, and resting natural killer (NK) cells correlated with the risk score. After verifying that the seven gene expression levels in different KRAS-mutated pancreatic cancer cell lines were similar to that in the model, we screened potential drugs related to the risk score.DiscussionThis study established, analyzed, and validated a model for predicting the prognosis of PDAC based on risk stratification according to KRAS mutations, and identified differential pathways and highly effective drugs.

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Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization

Cited by 11 publications

References 63 publications

A Novel Risk Score Model of Lactate Metabolism for Predicting over Survival and Immune Signature in Lung Adenocarcinoma

A Novel Risk Score Model of Lactate Metabolism for Predicting over Survival and Immune Signature in Lung Adenocarcinoma

Regulatory role of the miR-142-3p/CDC25C axis in modulating autophagy in non-small cell lung cancer

Exploring KRAS-mutant pancreatic ductal adenocarcinoma: a model validation study

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