scholarly journals A Comprehensive Bioinformatic Analysis of NOTCH Pathway Involvement in Stomach Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Dongyun Xue ◽  
Dong Li ◽  
Cong Dou ◽  
Junshan Li

Background. Activation of NOTCH signaling pathways, which are key regulators of multiple cellular functions, has been frequently implicated in cancer pathogenesis, and NOTCH inhibitors have received much recent focus in the context of cancer therapeutics. However, the role and possible involvement of NOTCH pathways in stomach adenocarcinoma (STAD) are unclear. Here, putative regulatory mechanisms and functions of NOTCH pathways in STAD were investigated. Methods. Publicly available data from the TCGA-STAD database were utilized to explore the involvement of canonical NOTCH pathways in STAD by analyzing RNA expression levels of NOTCH receptors, ligands, and downstream genes. Statistical analysis of the data pertaining to cancer and noncancerous samples was performed using R software packages and public databases/webservers. Results. Significant differential gene expression between control and STAD samples was noted for all NOTCH receptors (NOTCH1, 2, 3, and 4), the delta-like NOTCH ligands (DLL-3 and 4), and typical downstream genes (HES1 and HEY1). Four genes (NOTCH1, NOTCH2, NOTCH3, and HEY1) presented prognostic values for the STAD outcome in terms of overall survival. Functional enrichment analysis indicated that NOTCH family genes-strongly correlated genes were mainly enriched in several KEGG signaling pathways such as the PI3K-Akt signaling pathway, human papillomavirus infection, focal adhesion, Rap1 signaling pathway, and ECM-receptor interaction. Gene set enrichment analysis (GSEA) results showed that NOTCH family genes-significantly correlated genes were mainly enriched in four signaling pathways, ECM (extracellular matrix), tumor angiogenesis, inflammatory response, and immune regulation. Conclusions. NOTCH family genes may play an essential role in the progression of STAD by modulating immune cells and mediating ECM synthesis, angiogenesis, focal adhesion, and PI3K-Akt signaling. Multiple NOTCH family genes are valuable candidate biomarkers or therapeutic targets for the management of STAD.

2021 ◽  
Vol 12 ◽  
Author(s):  
Yani Dong ◽  
Likang Lyu ◽  
Daiqiang Zhang ◽  
Jing Li ◽  
Haishen Wen ◽  
...  

Long non-coding RNAs (lncRNAs) have been reported to be involved in multiple biological processes. However, the roles of lncRNAs in the reproduction of half-smooth tongue sole (Cynoglossus semilaevis) are unclear, especially in the molecular regulatory mechanism driving ovarian development and ovulation. Thus, to explore the mRNA and lncRNA mechanisms regulating reproduction, we collected tongue sole ovaries in three stages for RNA sequencing. In stage IV vs. V, we identified 312 differentially expressed (DE) mRNAs and 58 DE lncRNAs. In stage V vs. VI, we identified 1,059 DE mRNAs and 187 DE lncRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DE mRNAs were enriched in ECM-receptor interaction, oocyte meiosis and steroid hormone biosynthesis pathways. Furthermore, we carried out gene set enrichment analysis (GSEA) to identify potential reproduction related-pathways additionally, such as fatty metabolism and retinol metabolism. Based on enrichment analysis, DE mRNAs with a potential role in reproduction were selected and classified into six categories, including signal transduction, cell growth and death, immune response, metabolism, transport and catabolism, and cell junction. The interactions of DE lncRNAs and mRNAs were predicted according to antisense, cis-, and trans-regulatory mechanisms. We constructed a competing endogenous RNA (ceRNA) network. Several lncRNAs were predicted to regulate genes related to reproduction including cyp17a1, cyp19a1, mmp14, pgr, and hsd17b1. The functional enrichment analysis of these target genes of lncRNAs revealed that they were involved in several signaling pathways, such as the TGF-beta, Wnt signaling, and MAPK signaling pathways and reproduction related-pathways such as the progesterone-mediated oocyte maturation, oocyte meiosis, and GnRH signaling pathway. RT-qPCR analysis showed that two lncRNAs (XR_522278.2 and XR_522171.2) were mainly expressed in the ovary. Dual-fluorescence in situ hybridization experiments showed that both XR_522278.2 and XR_522171.2 colocalized with their target genes cyp17a1 and cyp19a1, respectively, in the follicular cell layer. The results further demonstrated that lncRNAs might be involved in the biological processes by modulating gene expression. Taken together, this study provides lncRNA profiles in the ovary of tongue sole and further insight into the role of lncRNA involvement in regulating reproduction in tongue sole.


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.


2021 ◽  
Author(s):  
Ying Luo ◽  
Ying Zhang ◽  
Shuang-yi Yin ◽  
Yue Luo ◽  
Xiao-jie Ding ◽  
...  

Abstract Background: Taodan granules (TDGs), traditional Chinese herbals, are effective in treating psoriasis. However, mechanisms of TDGs remain indistinct. The current study aims to indicate the molecular mechanisms of TDGs in treating psoriasis.Methods: Primarily, transcriptional profiling was applied to identify differentially expression genes (DEGs). The following was that we used Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analysis for functional enrichment analysis. Eventually, RT-PCR was performed to validation. Results: The results revealed that TDGs could regulated the Wnt signaling pathway to ameliorate skin lesions of imiquimod (IMQ)-induced psoriatic mouse models. IPA core network associated with Wnt signaling pathways in TDGs for psoriasis was established. Thereinto zeste homolog (EZH) 2, CTNNB1, TP63, and WD repeat domain (WDR) 5 could be considered as upstream genes in the Wnt signaling pathway.Conclusions: The Wnt signaling pathway with these above upstream genes might be potential therapeutic targets of TDGs for psoriasis.


2020 ◽  
Author(s):  
Jianjun Wu ◽  
Peian Cai ◽  
Zhenhui Lu ◽  
Zhi Zhang ◽  
Xixi He ◽  
...  

Abstract Background: The differentiation of bone mesenchymal stem cells (BMSCs) into adipogenesis (AD) rather than osteogenesis (OS) is an important pathological feature of osteoporosis. Illuminating the detailed mechanisms of the differentiation of BMSCs into OS and AD would contribute to the interpretation of osteoporosis pathology.Methods: To identify the regulated mechanism in lineage commitment of the BMSCs into OS and AD in the early-stages, the gene expression profiles with temporal series were downloaded to reveal the distinct fates when BMSCs adopt a committed lineage. For both OS and AD lineages, the profiles of day 2–4 were compared with day 0 to screen the differentially expressed genes (DEGs), respectively. Next, the functional enrichment analysis was utilized to find out the biological function, and Protein-Protein Interaction network to predict the central genes. Finally, experiments were performed to verify our finding.Results: FoxO signaling pathway with central genes like FoxO3, IL6 and CAT, is the crucial mechanism of OS, while Rap1 signaling pathway of VEGFA and FGF2 enrichment is more significant for AD. Besides, PI3K-Akt signaling pathway might serves as the latent mechanism about the initiation of differentiation of BMSCs into multiple lineages.Conclusion: Above hub genes and early-responder signaling pathways control osteogenic and adipogenic fates of BMSCs, which maybe mechanistic models clarifying the changes of bone metabolism in the clinical progress of osteoporosis. The findings provide a crucial reference for the prevention and therapy of osteoporosis.


2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jianjun Wu ◽  
Peian Cai ◽  
Zhenhui Lu ◽  
Zhi Zhang ◽  
Xixi He ◽  
...  

Abstract Background The differentiation of bone mesenchymal stem cells (BMSCs) into adipogenesis (AD) rather than osteogenesis (OS) is an important pathological feature of osteoporosis. Illuminating the detailed mechanisms of the differentiation of BMSCs into OS and AD would contribute to the interpretation of osteoporosis pathology. Methods To identify the regulated mechanism in lineage commitment of the BMSCs into OS and AD in the early stages, the gene expression profiles with temporal series were downloaded to reveal the distinct fates when BMSCs adopt a committed lineage. For both OS and AD lineages, the profiles of days 2–4 were compared with day 0 to screen the differentially expressed genes (DEGs), respectively. Next, the functional enrichment analysis was utilized to find out the biological function, and protein-protein interaction network to predict the central genes. Finally, experiments were performed to verify our finding. Results FoxO signaling pathway with central genes like FoxO3, IL6, and CAT is the crucial mechanism of OS, while Rap1 signaling pathway of VEGFA and FGF2 enrichment is more significant for AD. Besides, PI3K-Akt signaling pathway might serve as the latent mechanism about the initiation of differentiation of BMSCs into multiple lineages. Conclusion Above hub genes and early-responder signaling pathways control osteogenic and adipogenic fates of BMSCs, which maybe mechanistic models clarifying the changes of bone metabolism in the clinical progress of osteoporosis. The findings provide a crucial reference for the prevention and therapy of osteoporosis.


2021 ◽  
Author(s):  
XinJie Yang ◽  
Sha Niu ◽  
JiaQiang Liu ◽  
ZeYu Wu ◽  
Shizhang Ling ◽  
...  

Abstract Purpose: Glioblastoma (GBM) is a class of strikingly heterogeneous and lethal brain tumor with very poor prognosis. LncRNAs play critical roles in the tumorigenesis and progression of GBM through regulation of various cancer-related genes and signaling pathways. Here, we aimed to establish an epithelial-mesenchymal transition (EMT)-related lncRNA signature for GBM and explore its underlying mechanisms. Methods: Differential expression analysis and Gene set enrichment analysis (GSEA) were performed to explore key genes and signaling pathways associated with GBM. Spearman correlation analysis, Univariate and multivariate Cox regression analyses were used to construct a lncRNA prognostic signature for GBM patients. Kaplan-Meier analysis and receiver-operating-characteristic (ROC) analysis were applied to assess the performance of the prognostic signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) enrichment analyses were performed to explore the underlying mechanisms of the signature. Single-sample GSEA (ssGSEA) was employed to explore the relationship of the signature and immune activities in GBM.Results: We focused on the essential role of EMT in GBM and identified 78 upregulated EMT-related genes in GBM. A total of 301 EMT-related lncRNAs were confirmed in GBM and a prognostic signature consisting of seven EMT-related lncRNAs (AC012615.1, H19, LINC00609, LINC00634, POM121L9P, SNHG11, and USP32P3) was established, which could divide GBM patients into low- and high-risk subgroups. The accuracy and efficiency of the signature were validated to be satisfactory. Functional enrichment analysis revealed multiple EMT and metastasis-related pathways were associated with the EMT-related lncRNA prognostic signature. In addition, we found the degree of immune cell infiltration and immune responses were significantly increased in high-risk subgroup compared with low-risk subgroup. Conclusion: we established an effective and robust EMT-related lncRNA signature which is expected to predict the prognosis and immunotherapy response for GBM patients.


2021 ◽  
Author(s):  
Long-Jiang Chen ◽  
Lu-Lu Zhai ◽  
Wei Wang ◽  
Lun Wu ◽  
Li-Chao Yao ◽  
...  

Abstract While previous studies have suggested that B3GNT3 is associated with tumorigenesis and progression of several tumors, its expression level and clinical significance in pancreatic adenocarcinoma (PAAD) remains unclear. Our study aimed to investigate the role of B3GNT3 in PAAD. B3GNT3 RNA sequencing and clinicopathological data were collected from the TCGA, GEO and GTEx databases. We assessed the expression and prognostic value of B3GNT3 in PAAD using R program and attached packages. Additionally, we investigate the correlation between B3GNT3 expression and tumor-infiltrating immune cells using CIBERSORT and the “correlation” module of GEPIA. Finally, gene set enrichment analysis (GSEA) was used to elucidate B3GNT3 related signaling pathways in PAAD. Results showed that B3GNT3 expression was significantly higher in tumor tissues compared to normal tissues (P <0.05). Increased B3GNT3 expression was correlated with advanced histologic grade and stage (Ⅰ Vs Ⅱ). Patients with high B3GNT3 expression had a worse OS (HR = 1.713, P = 0.0005). Moreover, a negative correlation between increased B3GNT3 expression and immune infiltrating level of naive B cells, CD8 T cells, and CD4 memory activated T cells was revealed by CIBERSORT analysis. Then, further analysis verified the correlation using the “correlation” module of GEPIA. Finally, GSEA suggested that functional enrichment of B3GNT3 was mainly involved in pathways in cancer, p53 signaling pathway, TGF beta signaling pathway, catabolic and transport processes of proteins, etc. Collectively, these results suggested that overexpression of B3GNT3 might affect the infiltration of immune cells and could act as a potential prognostic biomarker of PAAD.


2020 ◽  
Author(s):  
Ben Ke ◽  
Wen Shen ◽  
Zhibing Duan

Abstract Backround: PLA2R-associated IMN covers 70% of IMN, which is one of the main types of chronic kidney disease in adults and one of the most common causes of end‑stage renal disease. Vascular endothelial growth factor A (VEGFA), a homodimeric vasoactive glycoprotein, is the key mediator of angiogenesis, which lead to numerous kidney diseases, including TSHD7A-associated IMN. However, the role of VEGFA in PLA2R-associated IMN is still poorly understood.Methods: We downloaded the microarray data GSE115857 from GEO. The DEGs were identified with R software, and the functional and pathway enrichment analysis of DEGs was performed utilizing the DAVID and Cytoscape ClueGo plug-in. A comprehensive list of interacting DEGs was constructed using the STRING database and visualized by Cytoscape software. The Cytoscape MCODE and cytoHubba plug-in were used to identify clustered sub-networks, and hub genes from the protein-protein interaction network. Gene set enrichment analysis (GSEA) was used to identify signaling pathway in IMN. Results: There were 1422 genes (952 up-regulated genes and 470 down-regulated genes) were identified as DEGs in GSE115857. The BP of DEGs in GSE115857 was clustered in regulation of transcription from RNA polymerase II promoter, positive regulation of nuclear-transcribed mRNA poly(A) tail shortening, cell adhesion et al. The KEGG pathway of DEGs in GSE115857 was clustered in Rheumatoid arthritis, ABC transporters, PI3K/AKT signaling pathway et al. Then we got a huge PPI network from STRING. 6 modules were screen out to study the functional changes in IMN. The KEGG pathway of module 3 was enriched in soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) interactions in vesicular transport. There were 3 hub genes screened out, namely, VEGFA, JUN,and FOS. Following the random walk, all genes were ranked and GSEA analysis showed that the signaling pathway of DEGs in GSE115857 was focused on angiogenesis, in which VEGFA acts as a core gene. CONCLUSION: In summary, this study reveals VEGFA promotes PLA2R-associated IMN by stimulating angiogenesis via PI3K/AKT signaling. Moreover, SNARE interactions in vesicular transport was involved in the development of PLA2R-associated IMN, which may offer a novel therapeutic strategy in treatment of IMN.


2020 ◽  
Author(s):  
jianjun wu ◽  
Peian Cai ◽  
Zhenhui Lu ◽  
Zhi Zhang ◽  
Xixi He ◽  
...  

Abstract Background: The differentiation of bone mesenchymal stem cells (BMSCs) into adipogenesis (AD) rather than osteogenesis (OS) is an important pathological feature of osteoporosis. Illuminating the detailed mechanisms of the differentiation of BMSCs into OS and AD would contribute to the interpretation of osteoporosis pathology. Methods: To identify the regulated mechanism in lineage commitment of the BMSCs into OS and AD in the early-stages, the gene expression profiles with temporal series were downloaded to reveal the distinct fates when BMSCs adopt a committed lineage. For both OS and AD lineages, the profiles of day 2-4 were compared with day 0 to screen the differentially expressed genes (DEGs), respectively. Next, the functional enrichment analysis was utilized to find out the biological function, and Protein-Protein Interaction network to predict the central genes. Finally, experiments were performed to verify our finding. Results: FoxO signaling pathway with central genes like FoxO3, IL6 and CAT, is the crucial mechanism of OS, while Rap1 signaling pathway of VEGFA and FGF2 enrichment is more significant for AD. Besides, PI3K-Akt signaling pathway might serves as the latent mechanism about the initiation of differentiation of BMSCs into multiple lineages. Conclusion: Above hub genes and early-responder signaling pathways control osteogenic and adipogenic fates of BMSCs, which maybe mechanistic models clarifying the changes of bone metabolism in the clinical progress of osteoporosis. The findings provide a crucial reference for the prevention and therapy of osteoporosis.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yankai Dong ◽  
Bo Tao ◽  
Xing Xue ◽  
Caixia Feng ◽  
Yating Ren ◽  
...  

Abstract Background Increasing attention has been paid to the effect of Epimedium on the nervous system, particularly anti-depression function. In the present study, we applied network pharmacology to introduce a testable hypothesis on the multi-target mechanisms of Epicedium against depression. Methods By reconstructing the network of protein–protein interaction and drug–component–target, we predicted the key protein targets of Epicedium for the treatment of depression. Then, through molecular docking, the interaction of the main active components of Epicedium and predicted candidate targets were verified. Results Nineteen active compounds were selected from Epicedium. There were 200 targets associated with Epicedium and 537 targets related to depression. The key targets of Epicedium for treating depression were IL6, VEGFA, AKT1, and EGF. According to gene ontology functional enrichment analysis, 22 items of biological process (BP), 13 items of cell composition (CC) and 9 items of molecular function (MF) were obtained. A total of 56 signaling pathways (P < 0.05) were identified by Kyoto Encyclopedia of Genes and Genomes analysis, mainly involving depression-related pathways such as dopaminergic synapse, TNF signaling pathway, and prolactin signaling pathway. The results of molecular docking showed that the most important activity components, including luteoklin, quercetin and kaempferol, were well combined with the key targets. Conclusions Luteoklin, quercetin, kaempferol and other active compounds in Epicedium can regulate multiple signaling pathways and targets such as IL6, AKT1, and EGF, therefore playing therapeutic roles in depression.


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