Integration of bulk RNA sequencing to reveal protein arginine methylation regulators have a good prognostic value in immunotherapy to treat lung adenocarcinoma
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ABSTRACT:
SUBMITTER: Yang Z
PROVIDER: S-EPMC10838759 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundEfferocytosis (ER) refers to the process of phagocytic clearance of programmed dead cells, and studies have shown that it is closely related to tumor immune escape.MethodsThis study was based on a comprehensive analysis of TCGA, GEO and CTRP databases. ER-related genes were collected from previous literature, univariate Cox regression was performed and consistent clustering was performed to categorize lung adenocarcinoma (LUAD) patients into two subgroups. Lasso regression and multivariate Cox regression analyses were used to construct ER-related prognostic features, and multiple immune infiltration algorithms were used to assess the correlation between the extracellular burial-related risk score (ERGRS) and tumor microenvironment (TME). And the key gene HAVCR1 was identified by deep learning, etc. Finally, pan-cancer analysis of the key genes was performed and in vitro experiments were conducted to verify the promotional effect of HAVCR1 on LUAD progression.ResultsA total of 33 ER-related genes associated with the prognosis of LUAD were identified, and the prognostic signature of ERGRS was successfully constructed to predict the overall survival (OS) and treatment response of LUAD patients. The high-risk group was highly enriched in some oncogenic pathways, while the low-ERGRS group was highly enriched in some immune-related pathways. In addition, the high ERGRS group had higher TMB, TNB and TIDE scores and lower immune scores. The low-risk group had better immunotherapeutic response and less likelihood of immune escape. Drug sensitivity analysis revealed that BRD-K92856060, monensin and hexaminolevulinate may be potential therapeutic agents for the high-risk group. And ERGRS was validated in several cohorts. In addition, HAVCR1 is one of the key genes, and knockdown of HAVCR1 in vitro significantly reduced the proliferation, migration and invasion ability of lung adenocarcinoma cells.ConclusionOur study developed a novel prognostic signature of efferocytosis-related genes. This prognostic signature accurately predicted survival prognosis as well as treatment outcome in LUAD patients and explored the role of HAVCR1 in lung adenocarcinoma progression.
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Project description:N6-methyladenosine (m6A) RNA modification is the most abundant modification method in mRNA, and it plays an important role in the occurrence and development of many cancers. This paper mainly discusses the role of m6A RNA methylation regulators in lung adenocarcinoma (LUAD) to identify novel prognostic biomarkers. The gene expression data of 19 m6A methylation regulators in LUAD patients and its relevant clinical parameters were extracted from The Cancer Genome Atlas (TCGA) database. We selected three significantly differentially expressed m6A regulators in LUAD to construct the risk signature, and evaluated its prognostic prediction efficiency using the receiver operating characteristic (ROC) curve. Kaplan-Meier survival analysis and Cox regression analysis were used to identify the independent prognostic significance of the risk signature. The ROC curve indicated that the area under the curve (AUC) was 0.659, which means that the risk signature had a good prediction efficiency. The results of the Kaplan-Meier survival analysis and Cox regression analysis showed that the risk score can be used as an independent prognostic factor for LUAD. In addition, we explored the differential signaling pathways and cellular processes related to m6A methylation regulators in LUAD.
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Project description:Tumoral heterogeneity has proven to be a leading cause of difference in prognosis and acquired drug resistance. High intratumor heterogeneity often means poor clinical response and prognosis. Histopathological subtypes suggest tumor heterogeneity evolved during the progression of lung adenocarcinoma, but the exploration of its molecular mechanisms remains limited. In this work, we first verified that transcriptional patterns of a set of differentially expressed genes profoundly revealed the histologic progression of lung adenocarcinoma. Next, a predictive model based on the transcriptional patterns was established to accurately distinguish histologic subtypes. Two crucial genes were identified and used to construct a tumor heterogeneous scoring model (L2SITH) to stratify patients, and we found that patients with low heterogeneity score had better prognosis. Low L2SITH scores implied low tumor purity and beneficial tumor microenvironment. Moreover, L2SITH effectively identified cohorts with better responses to anti-PD-1 immunotherapy.
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Project description:BackgroundThe N6-methyladenosine (m6A) RNA modification is the most prevalent and abundant type found in eukaryotic cells. It plays a crucial role in the initiation and progression of cancers. In this study, we aimed to comprehensively investigate the landscape of m6A regulators and their association with tumor microenvironment (TME), immunotherapeutic strategies in colon adenocarcinoma (COAD).ResultsThe differential expression, mutation, CNV frequency and prognostic value of 27 m6A regulators were systematically analyzed in COAD. Patients were classified into two clusters based on m6A regulators through consistent clustering analysis, with cluster A showing significant survival benefits. Most of the m6A regulators were negatively correlated with immune cells, except for WTAP, IGF2BP3, FTO, ALKBH5, which showed a positive correlation. We developed an m6A scoring system to calculate the m6Ascore for each patient. Patients with a high-m6Ascore had a better outcome, with the AUC of 0.775. An independent cohort of 416 COAD patients acquired from GSE38832 database was used to validate the prognosis prediction ability of m6Ascore. Moreover, the m6Ascore was negatively correlated with infiltration of anti-tumor immune cells. Additionally, patients with a high-m6Ascore responded better to anti-PD1 and anti-CTLA4 therapies, and those with MSI-H had a higher m6Ascore. Finally, we investigated the value of m6Ascore in predicting the response of patients to 15 commonly used drugs.ConclusionsWe comprehensively analyzed m6A regulators in COAD, including RNA expression, CNV changes, mutations and their correlation with TME. Our results showed that the m6A scoring system had significant predictive power for the prognosis of COAD patients, potentially leading to new personalized immunotherapy strategies.
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Project description:BackgroundHeart failure (HF) represents one of healthcare's biggest challenges. Although rarely noticed, aging is a crucial risk factor for cardiovascular disease. Our study aims to reveal aging's role in HF by integrating single-cell RNA-sequencing (scRNA-seq) and bulk RNA-sequencing databases.MethodsWe collected HF heart sample data from the Gene Expression Omnibus database and senescence gene data from CellAge. The FindCluster () package was used for cell cluster analysis. Differentially expressed genes (DEG) were identified operating the FindMarkers function. Cell activity score calculation was performed using the AUCell package. UpSetR plotted the intersection between DEGs of active cell types, bulk data DEGs, and genes associated with aging. Using the DGIdb database gene-drug interaction data, we search for potential targeted therapeutics based on common senescence genes.ResultsThe scRNA-seq data revealed myocardial heterogeneity in HF tissues. A series of crucial common senescence genes were found. The senescence gene expression profile hints at an intriguing connection between monocytes and HF. After analyzing the DEGs in the bulk dataset, the DEGs in scRNA-seq, the DEGs in each active cell type, and senescence genes, we identified ten genes as common senescence genes present in HF. Correlation analysis of transcriptomics, proteomics, and ceRNA was performed to provide ideas for future studies individually. Moreover, we discovered that common senescence genes and potential therapeutic drugs interact among different cell types. Further research is needed on the expression pattern of senescence genes and molecular regulation in HF.ConclusionsIn summary, we identified the functional significance of the senescence gene in HF using integrated data. It is possible that this more profound understanding of how senescence contributes to the development of HF will aid in unraveling the mechanisms that promote the disease and provide hints for developing therapeutics.
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Project description:The present study explored the prognosis and biological function roles of chromatin regulators (CRs) in patients with lung adenocarcinoma (LUAD). Using transcriptome profile and clinical follow-up data of LUAD dataset, we explored the molecular classification, developed, and validated a CR prognostic model, built an individual risk scoring system in LUAD, and compared the clinical and molecular characteristics between different subtypes and risk stratifications. We investigated the chemotherapy sensitivity and predicted potential immunotherapy response. Lastly, we collected the clinical samples and validated the prognosis and potential function role of NAPS2. Our study indicated that LUAD patients could be classified into two subtypes that had obviously different clinical background and molecular features. We constructed a prognostic model with eight CR genes, which was well validated in several other population cohort. We built high- and low-risk stratifications for LUAD patients. Patients from high-risk group were totally different from low-risk groups in clinical, biological function, gene mutation, microenvironment, and immune infiltration levels. We idented several potential molecular compounds for high-risk group treatment. We predicted that high-risk group may have poor immunotherapy response. We finally found that Neuronal PAS Domain Protein 2 (NPAS2) involved in the progression of LUAD via regulating cell adhesion. Our study indicated that CR involved in the progression of LUAD and affect their prognosis. Different therapeutic strategies should be developed for different molecular subtypes and risk stratifications. Our comprehensive analyses uncover specific determinants of CRs in LUAD and provides implications for investigating disease-associated CRs.
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| S-EPMC5722492 | biostudies-literature
Project description:N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.
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Project description:BackgroundThe distinction between right-sided and left-sided colon adenocarcinoma has recently received considerable. This study aims to identify key MicroRNA (miRNA) and mRNAs in right-sided colon adenocarcinoma (RSCOAD) and left-sided colon adenocarcinoma (LSCOAD) by TCGA integration analysis.MethodsThe miRNA and mRNA expression profiles of a large group of patients with RSCOAD and LSCOAD were obtained from TCGA. The differentially expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) were identified by TCGA integration analysis. The optimal diagnostic miRNA biomarkers for RSCOAD and LSCOAD were identified by Boruta algorithm. We established classification models to distinguish RSCOAD and LSCOAD. Protein-protein interaction (PPI) network analysis, DEmiRNA-DEmRNA interaction analysis, and functional annotation were performed. The expression of selected DEmiRNAs and DEmRNAs was validated by qRT-PCR.ResultsA total of 2534 DEmRNAs (940 downregulated and 1594 upregulated mRNAs) and 54 DEmiRNAs (22 downregulated and 32 upregulated miRNAs) between RSCOAD and LSCOAD were identified. The feature selection procedure was to obtain 22 optimal diagnostic miRNAs biomarkers in RSCOAD compared to LSCOAD. The AUC of the random forests model was 0.869 and the specificity and sensitivity of this model were 79% and 84.6%, respectively. Three DEmiRNAs (hsa-miR-224-5p, hsa-miR-155-5p, and hsa-miR-31-5p) and five DEmRNAs (CXCR4, SMAD4, KRAS, FITM2, and PLAGL2) were identified key DEmiRNAs and DEmRNAs in RSCOAD compared to LSCOAD. The qRT-PCR results of CXCR4, FITM2, TFAP2A, ULBP2, hsa-miR-224-5p, and hsa-miR-155-5p were consistent with our integrated analysis.ConclusionA total of three DEmiRNAs (hsa-miR-224-5p, hsa-miR-155-5p, and hsa-miR-31-5p) and five DEmRNAs (CXCR4, SMAD4, KRAS, FITM2, and PLAGL2) may be involved in the pathogenesis of RSCOAD and LSCOAD which may make a contribution for understanding mechanisms and developing therapeutic strategies for RSCOAD and LSCOAD.
| S-EPMC6470432 | biostudies-literature