scholarly journals Multi-omics analysis of m6A modification-related patterns based on m6A regulators and tumor microenvironment infiltration in lung adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xincheng Wu ◽  
Zhengping Bai

AbstractEpigenetic modifications, especially N6-methyladenosine (m6A) modification, play a key role in tumor microenvironment (TME) infiltration. However, the regulatory role of m6A modification in the TME of lung adenocarcinoma (LUAD) remains unclear. A total of 2506 patients with LUAD were included in the analysis and divided into different groups according to distinct m6A modification-related patterns based on 23 m6A regulators. A comprehensive analysis was performed to explore TME infiltration in different m6A modification-related patterns. Principal component analysis was performed to obtain the m6Ascore and to quantify m6A modification-related patterns in different individuals. Three distinct m6A modification-related patterns were identified by 23 m6A regulators. The pathway enrichment analysis showed that m6Acluster-A was associated with immune activation; m6Acluster-B was associated with carcinogenic activation; m6Acluster-C was prominently related to substance metabolism. M6Acluster-A was remarkably rich in TME-infiltrating immune cells and patients with this pattern showed a survival advantage. The m6Ascore could predict TME infiltration, tumor mutation burden (TMB), the effect of tumor immunotherapy, and the prognosis of patients in LUAD. High m6Ascore was characterized by increased TME infiltration, reduced TMB, and survival advantage. Patients with a high m6Ascore exhibited significantly improved clinical response to anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA4) immunotherapy. This study explored the regulatory mechanisms of TME infiltration in LUAD. The comprehensive analysis of m6A modification-related patterns may contribute to the development of individualized immunotherapy and the improvement of the overall effectiveness of immunotherapy for LUAD patients.

2021 ◽  
Vol 8 ◽  
Author(s):  
Sijin Sun ◽  
Wei Guo ◽  
Fang Lv ◽  
Guochao Zhang ◽  
Juhong Wang ◽  
...  

Ferroptosis is a newly discovered type of programmed cell death that differs from canonical apoptosis. However, the potential role of ferroptosis in lung adenocarcinoma (LUAD) has not been elaborated. In total, 1,328 samples from databases and 36 ferroptosis regulators were included in this study. By combining random survival forest and principal component analysis algorithms, a robust prognostic ferroptosis-related risk score (FRRS) was constructed, and the performance was validated in three independent datasets. Based on the median risk score, two subgroups were identified. Then, comparisons, including of mutational profiles, functional enrichment analyses and immune components, were conducted between subgroups. An immunotherapy cohort was applied to explore potential therapeutic-related biomarkers. Finally, the clinical utility of FRRS was validated in a proteomic cohort. In the TCGA-LUAD cohort, FRRS was calculated using the expression of 11 selected genes, and patients with high FRRS had a significantly (p < 0.001) worse prognosis than those with low FRRS. Multivariate regression suggested that FRRS was an independent prognostic factor. Functional enrichment analysis indicated that FRRS was mainly involved in cell cycle, metabolic and immune-related pathways. Furthermore, FRRS was shown to be significantly (p < 0.001) associated with the abundance of CD8 T cells and tumor mutation burden (TMB). The combination of TMB and FANCD2 expression, the main contributor to FRRS, substantially increased the precision of predicting the therapeutic response. In conclusion, the present study revealed the potential role of ferroptosis regulators in LUAD and identified ferroptosis-related biomarkers for prognostic and immunotherapeutic predictions.


2021 ◽  
Vol 22 (14) ◽  
pp. 7430
Author(s):  
Hiromi Sato ◽  
Ayaka Shimizu ◽  
Toya Okawa ◽  
Miaki Uzu ◽  
Momoko Goto ◽  
...  

The role of astrocytes in the periphery of metastatic brain tumors is unclear. Since astrocytes regulate central nervous metabolism, we hypothesized that changes in astrocytes induced by contact with cancer cells would appear in the metabolome of both cells and contribute to malignant transformation. Coculture of astrocytes with breast cancer cell supernatants altered glutamate (Glu)-centered arginine–proline metabolism. Similarly, the metabolome of cancer cells was also altered by astrocyte culture supernatants, and the changes were further amplified in astrocytes exposed to Glu. Inhibition of Glu uptake in astrocytes reduces the variability in cancer cells. Principal component analysis of the cancer cells revealed that all these changes were in the first principal component (PC1) axis, where the responsible metabolites were involved in the metabolism of the arginine–proline, pyrimidine, and pentose phosphate pathways. The contribution of these changes to the tumor microenvironment needs to be further pursued.


2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Taijie Lin ◽  
Jinping Gu ◽  
Caihua Huang ◽  
Suli Zheng ◽  
Xu Lin ◽  
...  

Aims. To study the changes of the metabolic profile during the pathogenesis in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH).Methods. Forty male Sprague-Dawley (SD) rats were randomly divided into 5 groups (n=8, each). PAH rats were induced by a single dose intraperitoneal injection of 60 mg/kg MCT, while 8 rats given intraperitoneal injection of 1 ml normal saline and scarified in the same day (W0) served as control. Mean pulmonary arterial pressure (mPAP) was measured through catherization. The degree of right ventricular hypertrophy and pulmonary hyperplasia were determined at the end of first to fourth weeks; nuclear magnetic resonance (NMR) spectra of sera were then acquired for the analysis of metabolites. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to discriminate different metabolic profiles.Results. The prominent changes of metabolic profiles were seen during these four weeks. Twenty specific metabolites were identified, which were mainly involved in lipid metabolism, glycolysis, energy metabolism, ketogenesis, and methionine metabolism. Profiles of correlation between these metabolites in each stage changed markedly, especially in the fourth week. Highly activated methionine and betaine metabolism pathways were selected by the pathway enrichment analysis.Conclusions. Metabolic dysfunction is involved in the development and progression of PAH.


2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Ningyang Gao ◽  
Li Ding ◽  
Jian Pang ◽  
Yuxin Zheng ◽  
Yuelong Cao ◽  
...  

Purpose. This study is aimed at exploring the potential metabolite/gene biomarkers, as well as the differences between the molecular mechanisms, of osteoarthritis (OA) and rheumatoid arthritis (RA). Methods. Transcriptome dataset GSE100786 was downloaded to explore the differentially expressed genes (DEGs) between OA samples and RA samples. Meanwhile, metabolomic dataset MTBLS564 was downloaded and preprocessed to obtain metabolites. Then, the principal component analysis (PCA) and linear models were used to reveal DEG-metabolite relations. Finally, metabolic pathway enrichment analysis was performed to investigate the differences between the molecular mechanisms of OA and RA. Results. A total of 976 DEGs and 171 metabolites were explored between OA samples and RA samples. The PCA and linear module analysis investigated 186 DEG-metabolite interactions including Glycogenin 1- (GYG1-) asparagine_54, hedgehog acyltransferase- (HHAT-) glucose_70, and TNF receptor-associated factor 3- (TRAF3-) acetoacetate_35. Finally, the KEGG pathway analysis showed that these metabolites were mainly enriched in pathways like gap junction, phagosome, NF-kappa B, and IL-17 pathway. Conclusions. Genes such as HHAT, GYG1, and TRAF3, as well as metabolites including glucose, asparagine, and acetoacetate, might be implicated in the pathogenesis of OA and RA. Metabolites like ethanol and tyrosine might participate differentially in OA and RA progression via the gap junction pathway and phagosome pathway, respectively. TRAF3-acetoacetate interaction may be involved in regulating inflammation in OA and RA by the NF-kappa B and IL-17 pathway.


2021 ◽  
Author(s):  
Yaqin Wang ◽  
Wenchao Chen ◽  
Kun Li ◽  
Gang Wu ◽  
Wei Zhang ◽  
...  

Abstract Purpose This study was aimed to screen differential metabolites between gastric cancer (GC) and paracancerous (PC) tissues and find new biomarkers of GC. Methods GC (n = 28) and matched PC (n = 28) tissues were collected and LC-MS/MS analyses were performed to detect metabolites of GC and PC tissues in positive and negative models. Principal component analysis (PCA) and orthogonal projections to latent structures-discriminate analysis (OPLS-DA) were conducted to describe distribution of origin data and general separation and estimate the robustness and the predictive ability of our mode. Differential metabolites were screened based on criterion of variables with p value < 0.05 and VIP (variable importance in the projection) > 1.0. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic power of differential metabolites. Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to search for metabolite pathways and MetaboAnalyst was used for pathway enrichment analysis. Results Several metabolites were significantly changed in GC group compared with PC group. Thirteen metabolites with high VIP were chose and among which 1-methylnicotinamide, dodecanoic acid and sphinganine possessed high AUC values (AUC > 0.8) indicating an excellent discriminatory ability on GC. Pathways such as pentose phosphate pathway and histidine metabolism were focused based on differential metabolites demonstrating their effects on progress of GC. Conclusions In conclusion, we investigated the tissue-based metabolomics profile of GC and several differential metabolites and signaling pathways were focused. Further study is needed to verify those results.


2019 ◽  
Author(s):  
rui kong ◽  
Nan Wang ◽  
Wei Han ◽  
Yuejuan Zheng ◽  
Jie Lu

Abstract Background: In recent years, long non-coding RNAs (lncRNAs) are emerging as crucial regulators in the immunological process of liver hepatocellular carcinoma (LIHC). Increasing studies have found that some lncRNAs could be used as a diagnostic or therapeutic target for clinical management, but little research has investigated the role of immune-related lncRNA in tumor prognosis. In this study, we aimed to develop an immune lncRNA signature for the precise diagnosis and prognosis of liver hepatocellular carcinoma. Methods: Gene expression profiles of LIHC samples obtained from TCGA were screened for immune-related genes using two reference gene sets. The optimal immune-related lncRNA signature was built via correlational analysis, univariate and multivariate cox analysis. Then the Kaplan-Meier plot, ROC curve, clinical analysis, gene set enrichment analysis, and principal component analysis were carried out to evaluate the capability of immune lncRNA signature as a prognostic indicator. Results: Six long non-coding RNA MSC−AS1, AC009005.1, AL117336.3, AL031985.3, AL365203.2, AC099850.3 were identified via correlation analysis and cox regression analysis considering their interactions with immune genes. Next, tumor samples were separated into two risk groups by the signature with different clinical outcomes. Stratification analysis showed the prognostic ability of this signature acted as an independent factor. The AUC value of ROC curve was 0.779. The Kaplan-Meier method was used in survival analysis and results showed a statistical difference between the two risk groups. The predictive performance of this signature was validated by principal component analysis (PCA). Data from gene set enrichment analysis (GSEA) further unveiled several potential biological processes of these biomarkers may involve in. Conclusion: In summary, the study demonstrated the potential role of the six-lncRNA signature served as an independent prognostic factor for LIHC patients.


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10560
Author(s):  
Mingrui Shao ◽  
Shize Yang ◽  
Siyuan Dong

Backgrounds Lung adenocarcinoma is a complex disease that results in over 1.8 million deaths a year. Recent advancements in treating and managing lung adenocarcinoma have led to modest decreases in associated mortality rates, owing in part to the multifactorial etiology of the disease. Novel prognostic biomarkers are needed to accurately stage the disease and act as the basis of adjuvant treatments. Material and Methods The microarray datasets GSE75037, GSE31210 and GSE32863 were downloaded from the Gene Expression Omnibus (GEO) database to identify prognostic biomarkers for lung adenocarcinoma and therapy. The differentially expressed genes (DEGs) were identified by GEO2R. Functional and pathway enrichment analysis were performed by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). Validation was performed based on 72 pairs of lung adenocarcinoma and adjacent normal lung tissues. Results Results showed that the DEGs were mainly focused on cell cycle and DNA replication initiation. Forty-one hub genes were identified and further analyzed by CytoScape. Here, we provide evidence which suggests MCM10 is a potential target with prognostic, diagnostic and therapeutic value. We base this on an integrated approach of comprehensive bioinformatics analysis and in vitro validation using the A549 lung adenocarcinoma cell line. We show that MCM10 overexpression correlates with a poor prognosis, while silencing of this gene decreases aberrant growth by 2-fold. Finally, evaluation of 72 clinical biopsy samples suggests that overexpression of MCM10 in the lung adenocarcinoma highly correlates with larger tumor size. Together, this work suggests that MCM10 may be a clinically relevant gene with both predictive and therapeutic value in lung adenocarcinoma.


Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 429 ◽  
Author(s):  
Zou ◽  
Zheng ◽  
Deng ◽  
Yang ◽  
Xie ◽  
...  

Circular RNA CDR1as/ciRS-7 functions as an oncogenic regulator in various cancers. However, there has been a lack of systematic and comprehensive analysis to further elucidate its underlying role in cancer. In the current study, we firstly performed a bioinformatics analysis of CDR1as among 868 cancer samples by using RNA-seq datasets of the MiOncoCirc database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), CIBERSORT, Estimating the Proportion of Immune and Cancer cells (EPIC), and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were applied to investigate the underlying functions and pathways. Functional enrichment analysis suggested that CDR1as has roles associated with angiogenesis, extracellular matrix (ECM) organization, integrin binding, and collagen binding. Moreover, pathway analysis indicated that it may regulate the TGF-β signaling pathway and ECM-receptor interaction. Therefore, we used CIBERSORT, EPIC, and the ESTIMATE algorithm to investigate the association between CDR1as expression and the tumor microenvironment. Our data strongly suggest that CDR1as may play a specific role in immune and stromal cell infiltration in tumor tissue, especially those of CD8+ T cells, activated NK cells, M2 macrophages, cancer-associated fibroblasts (CAFs) and endothelial cells. Generally, systematic and comprehensive analyses of CDR1as were conducted to shed light on its underlying pro-cancerous mechanism. CDR1as regulates the TGF-β signaling pathway and ECM-receptor interaction to serve as a mediator in alteration of the tumor microenvironment.


PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Min Zhao ◽  
Xiaoyang Li ◽  
Yunxiang Zhang ◽  
Hongming Zhu ◽  
Zhaoqing Han ◽  
...  

Previous studies showed that low PPARG expression was associated with poor prognosis of lung adenocarcinoma (LA) with limited mechanisms identified. We first conducted a large-scale literature-based data mining to identify potential molecular pathways where PPARG could exert influence on the pathological development of LA. Then a mega-analysis using 13 independent LA expression datasets and a Pathway Enrichment Analysis (PEA) was conducted to study the gene expression levels and the functionalities of PPARG and the PPARG-driven triggers within the molecular pathways. Finally, a protein-protein interaction (PPI) network was established to reveal the functional connection between PPARG and its driven molecules. We identified 25 PPARG-driven molecule triggers forming multiple LA-regulatory pathways. Mega-analysis using 13 LA datasets supported these pathways and confirmed the downregulation of PPARG in the case of LA (p=1.07e−05). Results from the PEA and PPI analysis suggested that PPARG might inhibit the development of LA through the regulation of tumor cell proliferation and transmission-related molecules, including an LA tumor cell suppressor MIR145. Our results suggested that increased expression of PPARG could drive multiple molecular triggers against the pathologic development and prognosis of LA, indicating PPARG as a valuable therapeutic target for LA treatment.


2021 ◽  
Author(s):  
Nan Hong ◽  
Bo Jiang ◽  
Lei Gu ◽  
Si-Yi Chen ◽  
Jian-Ping Tong

Background: Myopia (nearsightedness) is currently the most common human eye disorder worldwide. In the recent years, several studies have addressed the role of microRNAs (miRNAs) in the pathogenesis of myopia. Objectives: The aim of this study was to perform a meta-analysis on the miRNA expression profiling studies in myopia to identify commonly dysregulated miRNAs in myopic tissues. Method: Seven independent studies were included in the meta-analysis. A vote-counting strategy were employed as the meta-analysis method. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Ontology (GO) functional enrichment analysis were performed to identify the pathways most strongly affected by the dysregulated mouse miRNAs. Results: According to the vote-counting method, eighteen miRNAs were reported in at least two studies with the consistent direction, of which 13 miRNAs were commonly up-regulated in myopic samples compared with control samples and five miRNAs were commonly down-regulated. Subgroup analyses divided and compared the differentially expressed miRNAs according to species (human and animal) and ocular tissue types. The KEGG analysis showed that the dysregulated mouse miRNAs were most enriched in extracellular matrix (ECM)-receptor interaction signal pathway. The most enriched GO processes regulated by the dysregulated mouse miRNAs was cellular protein modification process. Conclusions. Our meta-analysis recommends several miRNAs may provide some clues of the potential biomarkers in myopia. Further mechanistic studies are warranted to elucidate the biological role of the dysregulated miRNAs in the development of myopia.


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