scholarly journals Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuying Zhang ◽  
Baoyi Zhu ◽  
Yi Cai ◽  
Sihua Zhu ◽  
Hongjun Zhao ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cholesterol Synthesis ◽  
Immune Cell ◽  
Specific Treatment ◽  
Metabolic Reprogramming ◽  
Cancer Prognosis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Expression Levels ◽  
Significant Difference

Abstract Background Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa). Methods Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes. Results The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value< 0.05). Furthermore, aberrant PIK3CA expression level was significantly correlated with those of glycolytic and cholesterogenic genes. The quiescent subtype was associated with lower stemness indices and lower signature scores for gene sets involved in genomic instability, including DNA replication, DNA damage repair, mismatch repair, and homologous recombination genes. Moreover, quiescent tumors exhibited lower expression levels of pyruvate dehydrogenase kinases 1-3 (PDK1-3) than the other subtypes. In addition, distinct immune cell infiltration patterns were observed across the 4 metabolic subtypes, with greater infiltration of M0/M2 macrophages observed in glycolytic and mixed subtypes. However, no significant difference in immunotherapy response was observed across the 4 metabolic subtypes. Conclusion This study proposed a new metabolic subtyping method for BCa based on genes involved in glycolysis and cholesterol synthesis pathways. Our findings may provide novel insight for the development of personalized subtype-specific treatment strategies targeting metabolic vulnerabilities.

Identification of ncRNA-mediated prognostic Value and Immune Infiltration of MTHFD2 in Bladder Cancer

2021 ◽  
Author(s):  
Hao Zhang ◽  
Rui Li ◽  
Wanjun Deng ◽  
Huihua Xiong
Keyword(s):  
Bladder Cancer ◽  
Immune Cell ◽  
Tumor Development ◽  
Redox Balance ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Nucleic Acid Metabolism ◽  
Mitochondrial Enzymes ◽  
Immune Cell Infiltration ◽  
Cellular Mechanisms

Abstract Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), one of mitochondrial enzymes, is involved in folate and nucleic acid metabolism and maintains the cellular redox balance. However, the function of MTHFD2 in bladder cancer is still poorly characterized. This study was designed to elucidate the effect and regulatory mechanism of MTHFD2 on bladder cancer cells and explore the relationships between MTHFD2 and immune cell infiltration in tumor microenvironment (TME). Methods: The data from Oncomine, TIMER, The Cancer Genome Atlas (TCGA) and The Human Protein Atlas (HPA) database were extracted to evaluate the expression of MTHFD2 and its prognostic role in pan-cancer, especially in bladder cancer. Enrichment analyses, were utilized to explore the underlying cellular mechanisms. The ncRNA regulatory axis was established by Starbase database, and the PPI network was constructed by Cytoscape software. Ultimately, the relations between the expression of MTHFD2 and immune cell infiltration in bladder cancer was indicated by TCGA and TIMER databases.Results: Our results demonstrated that MTHFD2 expression was generally up-regulated in pan-cancers and its high expression was correlated with poor prognosis of patients with bladder cancer. Specifically, our study revealed that MTHFD2 was a powerful risk factor and involved in the tumor development of bladder cancer. Furthermore, hsa_circ_0046140 and hsa_circ_0006769/miR-383-5p/MTHFD2 axis could also play a significant role in tumorigenesis. Ultimately, a strong correlation was observed between MTHFD2 expression and various immune cell infiltration, which implied that MTHFD2 might serve as an agent in tumor immunotherapy. Conclusion: MTHFD2 is widely overexpressed in pan-cancers, and its expression is related with the prognosis of patients and the multiple immune cell infiltrates in TME. Besides, hsa_circ_0046140 and hsa_circ_0006769/miR-383-5p/MTHFD2 axis are implicated with the proliferation and invasion of tumors.

scholarly journals An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sia Viborg Lindskrog ◽  
Frederik Prip ◽  
Philippe Lamy ◽  
Ann Taber ◽  
Clarice S. Groeneveld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chromosomal Instability ◽  
Prognostic Value ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Invasive Bladder Cancer ◽  
Immune Cell Infiltration ◽  
Muscle Invasive Bladder Cancer ◽  
Omics Analysis ◽  
Muscle Invasive

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

scholarly journals Development and validation of a LRP1B mutation-associated prognostic model for hepatocellular carcinoma

2021 ◽  
Author(s):  
Jian Xu ◽  
Xiaomin Shen ◽  
Bo Zhang ◽  
Rui Su ◽  
Mingxuan Cui ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gene Mutation ◽  
Prognostic Model ◽  
Immune Cell ◽  
Low Risk ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Immune Cell Infiltration ◽  
Significant Difference ◽  
Patient Prognosis

Abstract Purpose: To develop a LRP1B gene mutation based prognostic model for hepatocellular carcinoma (HCC) patients risk prediction. Methods: The LRP1B gene mutation rate was calculated from HCC patient samples. Meanwhile, differentially expressed genes according to LRP1B mutant were screened out for prognostic model establishment. Based on this innovative model, HCC patients were categoried into high and low-risk group. The immune status including immune cell infiltration ratio and checkpoints have been explored in two groups. Results: It can be shown here 11 genes demonstrate significant differences according to LRP1B status, which can better predict HCC patient prognosis. The accuracy of the model prediction is evaluated and approved by the AUC value. From the immune cell infiltration ratio analysis, there is a significant difference in the infiltration degree of 7 types of immune cells and 2 immune checkpoints between high and low-risk HCC patients. Meanwhile, LRP1B was tested as a prognostic marker in clinic to predict different stages for HCC with satisfied accurancy. Conclusion: This study has explored a potential prognostic biomarker and developed a novel LRP1B mutation-associated prognostic model for hepatocellular carcinoma, which provides a systematic reference for future better understanding of clinical research.

scholarly journals Transcriptional expression of ZICs as an independent indicator of survival in gliomas

2020 ◽  
Author(s):  
Zhao cheng Han ◽  
Jingnan Jia ◽  
Yangting Lv ◽  
Rongyanqi Wang ◽  
Kegang Cao
Keyword(s):  
Immune Cell ◽  
Cox Regression ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Cell Infiltration ◽  
Low Grade ◽  
Immune Cell Infiltration ◽  
Expression Levels ◽  
Ppi Networks

Abstract Background: The functional significance of the zinc-finger of the cerebellum (ZIC) gene family in gliomas remains to be elucidated. Methods: Clinical data from patients with gliomas, containing expression levels of ZIC genes, were extracted from CCLE, GEPIA2 and The Human Protein Atlas(HPA). Univariate survival analysis adjusted by Cox regression via OncoLnc was used to determine the prognostic significance of ZIC expression. We used cBioPortal to explore the correlation between gene mutations and overall survival (OS). ZIC expression was found to be related to immune cell infiltration in gliomas via TIMER analysis. GO term and KEGG pathway enrichment analyses were performed with Metascape. PPI networks were constructed using STRING. Result: The expression levels of ZIC1/2/4 in gliomas were significantly different from those in normal samples. High expression levels of ZIC1/2/5 were associated with poor OS in brain low-grade glioma (LGG) patients, while low ZIC3 expression combined with high ZIC4 expression was related to favourable OS in glioblastoma multiforme (GBM). ZIC mutations were associated with poor prognosis in LGG patients and related to favourable prognosis in GBM patients. We observed that the expression of ZICs was related to immune cell infiltration in glioma patients. ZICs were enriched in several pathways and biological processes involving arrhythmogenic right ventricular cardiomyopathy (ARVC) and tissue morphogenesis. The PPI network revealed that some coexpressed proteins of ZICs played a role in the pathogenesis of gliomas. Conclusions: Differences in the expression levels of ZIC genes could provide a significant marker for predicting prognosis in gliomas.

scholarly journals Tumor-Infiltrating CD8+ T Cells Driven by the Immune Checkpoint-Associated Gene IDO1 Are Associated With Cervical Cancer Prognosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Shun Zhang ◽  
Junhui Wan ◽  
Minjie Chen ◽  
Desheng Cai ◽  
Junlan Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
T Cells ◽  
Immune Cell ◽  
Expression Profiles ◽  
Differentially Expressed Gene ◽  
Cancer Prognosis ◽  
Cell Infiltration ◽  
Positive Correlation ◽  
Significant Difference

Tumor-infiltrating immune cells, associated with tumor progression, are promising prognostic biomarkers. However, the relationship between levels of gene expression and that of immune cell infiltration in cervical cancer prognosis is unknown. In this study, three cervical cancer gene expression microarrays (GSE6791, GSE63678 and GSE55940) were obtained from the GEO database. The IDO1 gene was identified by differentially expressed gene screening. The gene expression profiles of TCGA and GTEx databases along with comprehensive bioinformatics analysis identified that the IDO1 gene was upregulated in cervical cancer with significant difference in expression at different N stages. In addition, it was also upregulated in HPV16 positive sample. The pan-cancer analysis identified that IDO1 was highly expressed in most cancers. TIMER analysis revealed that the expression of IDO1 in CESC shows positive correlation with CD8+ T cells, CD4+ T cells, neutrophils, dendritic cells. IDO1 expression showed remarkable positive correlation with all immune cell markers except M1 macrophages. CD8+ T cell infiltration GSEA results showed that IDO1 was mainly associated with tumor immune-related signaling pathways.

scholarly journals C3aR1 Correlates With Immune Cell Infiltration and Serves as Prognostic and Therapeutic Biomarker in Gastric Cancer

2021 ◽  
Author(s):  
weifeng liu ◽  
Zhijie Chu ◽  
Cheng Yang ◽  
Tianbao Yang ◽  
Yanhui Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Differentially Expressed Genes ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Expression Levels

Abstract As the fourth most common malignancy worldwide, gastric cancer can lead more than 720 000 patient death every year. Precisely therapeutic intervention can significantly improve patients’ survival status underlying the precise clarification by molecular indexes. Identifying the biomarkers highly associated with disease prognosis will be helpful to guide the clinical therapy. C3ar1 is an essential receptor in the complement system, and participates in various biological processes associated with immunological responses. To identify the crucial roles of C3AR1 in gastric cancer tmorigenesis, we determined the mRNA profile, protein expression levels and the clinicopathological indexes using cBioportal, Kaplan-Meier plotter and the Human Protein Atlas databases. To identify the molecular network in C3AR1-expressed gastric cancer, we obtained the differentially expressed genes using the GEPIA database compared with normal stomach tissues. Furthermore, we analyzed the biological impact of these differentially expressed genes using protein-protein interaction network and gene set enrichment analysis, in which we identified the hub genes and critical pathways influenced by over-expressed C3AR1 in gastric cancer. Finally, we evaluated the correlation between the C3AR1 expression levels and immune cell infiltration levels utilizing the Tumor Immunoassay Resource database. Our results revealed that the higher expression level of C3AR1 can lead higher infiltration of T cell CD8+, T cell CD4+, macrophage, neutrophil, B cell and myeloid dendritic cells into tumor tissue. Moreover, we also found that higher infiltration of macrophage cells into tumor tissue can worsen the survival of patients with gastric cancer, which may be highly associated with the polarization states of macrophages (TAM and M2 status). Our investigation suggest that C3AR1 can be as an efficient diagnostic biomarkers for gastric cancer therapy.

scholarly journals Therapeutic Targets of Fingolimod (FTY720) in the Brains of Alzheimer's Disease Patients and the Associated Biological Mechanisms: a Network Pharmacology Study

2020 ◽  
Author(s):  
Pengqi Yin ◽  
Yang Xue ◽  
Guozhong Li ◽  
Di Zhong
Keyword(s):  
Alzheimer’S Disease ◽  
Immune Cell ◽  
Calcium Signalling ◽  
Cell Infiltration ◽  
Network Pharmacology ◽  
Immune Cell Infiltration ◽  
Expression Levels ◽  
The Core ◽  
Cholinergic Synapses ◽  
Cortical Regions

Abstract BackgroundThe sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720), which is commonly used as an immunomodulator in multiple sclerosis treatment, was recently reported to be effective in the treatment of Alzheimer’s disease (AD), but its mechanism of action remains elusive. In this study, network pharmacology methods were applied to detect the potential pharmacological mechanisms of fingolimod in the brains of these patients. MethodsThe pharmacological macromolecular targets of fingolimod and fingolimod phosphate were downloaded from Swisstarget. Systematic intersection analysis of the expression profiles of brain tissues (709 AD tissues and 534 control tissues) was performed, and AD-associated fingolimod targets (F-ADGs) in the frontal, temporal and entorhinal cortices were analysed. The Minimal Common Oncology Data Elements method was used to detect core F-ADGs. Gene function enrichment analyses of the core F-ADGs were performed. Correlation analyses were performed to identify core F-ADGs with expression levels that were associated with the severity of AD. CIBERSORTx (https://cibersortx.stanford.edu/) was used to estimate the percentages of various immune cell populations in the cortex of each AD patient. ResultsWe found the fingolimod targets S1PR1, GNG3, GNG11 and GABBR2 were simultaneously detected in all three cortical regions. The core F-ADGs in all three cortical regions were enriched in similar biological processes, such as the G protein-coupled receptor signalling pathway, synaptic transmission, and pathways related to the function of synapses, especially GABAergic synapses. Core F-ADGs in the temporal and entorhinal cortices were also enriched in functions related to calcium signalling and cholinergic synapses. Correlation analysis showed that the expression levels of 7 core F-ADGs (S1PR1, NPY, NPY2R, GNAI1, GNG5, FPR1 and GPR183) in the frontal cortex were correlated with the severity of AD. No differences in immune cell infiltration between AD patients and normal controls were observed in any of the three cortical regions. ConclusionsThe pharmacological macromolecular targets of fingolimod and fingolimod phosphate, including S1PR1, were abnormally expressed in the cortices of multiple AD patients. The pharmacological effect of fingolimod on AD may be attributed to its ability to regulate GABA synapses, calcium signalling, and cholinergic synapses, other than regulating immune cell infiltration.

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