scholarly journals Pan-Cancer analysis of clinical significance and associated molecular features of glycolysis

2021 ◽  
Author(s):  
Yi-chen Liu ◽  
Peng Lin ◽  
Yu-jia Zhao ◽  
Lin-yong Wu ◽  
Yu-quan Wu ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Cancer Progression ◽  
Mammalian Target Of Rapamycin ◽  
Prognostic Significance ◽  
Gene Expression Signature ◽  
The Cancer Genome Atlas ◽  
Molecular Features ◽  
Dopamine Receptor Antagonists ◽  
Tumor Glycolysis ◽  
Pan Cancer

Abstract Background Tumor glycolysis acts as a major promoter of carcinogenesis and cancer progression. Given its complex mechanisms and interactions, a comprehensive analysis to reveal its clinical significance and molecular features is urgent. Materials and Methods Based on a well-established glycolysis gene expression signature, we quantified 8633 patients across different cancer types from The Cancer Genome Atlas (TCGA) and evaluated their prognostic associations. High tumor glycolytic activity correlated with inferior overall survival in pan-cancer patients (hazard ratio: 1.70, 95% confidence interval: 1.20–2.40, P = 0.003). The prognostic value of glycolysis was stable regardless of clinical parameters and correlated with molecular subtypes. The prognostic significance of glycolysis was validated using another three independent datasets. In addition, genome, transcriptome, and proteome profiles were utilized to characterize distinctive molecular features associated with glycolysis.Results Mechanistically, glycolysis fulfilled the fundamental needs of tumor proliferation in multiple ways. Exploration of the relationships between glycolysis and tumor infiltrating immune cells showed that glycolysis enabled immune evasion of tumor cells. Mammalian target of rapamycin inhibitors and dopamine receptor antagonists represent classes of compounds that can effectively reverse the glycolytic status of cancers.Conclusion Our study provides an in-depth molecular understanding of tumor glycolysis and may have practical implications for clinical cancer therapy.

scholarly journals Characterization of Glycolysis-Associated Molecules in the Tumor Microenvironment Revealed by Pan-Cancer Tissues and Lung Cancer Single Cell Data

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1788
Author(s):  
Jinfen Wei ◽  
Kaitang Huang ◽  
Zixi Chen ◽  
Meiling Hu ◽  
Yunmeng Bai ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Single Cells ◽  
Gene Expression Signature ◽  
Human Lung Cancer ◽  
Driver Genes ◽  
Molecular Features ◽  
Cancer Types ◽  
Cancer Tissues ◽  
Pan Cancer

Altered metabolism is a hallmark of cancer and glycolysis is one of the important factors promoting tumor development. There is however still a lack of molecular characterization glycolysis and comprehensive studies related to tumor glycolysis in the pan-cancer landscape. Here, we applied a gene expression signature to quantify glycolysis in 9229 tumors across 25 cancer types and 7875 human lung cancer single cells and verified the robustness of signature using defined glycolysis samples from previous studies. We classified tumors and cells into glycolysis score-high and -low groups, demonstrated their prognostic associations, and identified genome and transcriptome molecular features associated with glycolysis activity. We observed that glycolysis score-high tumors were associated with worse prognosis across cancer types. High glycolysis tumors exhibited specific driver genes altered by copy number aberrations (CNAs) in most cancer types. Tricarboxylic acid (TCA) cycle, DNA replication, tumor proliferation and other cancer hallmarks were more active in glycolysis-high tumors. Glycolysis signature was strongly correlated with hypoxia signature in all 25 cancer tissues (r > 0.7) and cancer single cells (r > 0.8). In addition, HSPA8 and P4HA1 were screened out as the potential modulating factors to glycolysis as their expression were highly correlated with glycolysis score and glycolysis genes, which enables future efforts for therapeutic options to block the glycolysis and control tumor progression. Our study provides a comprehensive molecular-level understanding of glycolysis with a large sample data and demonstrates the hypoxia pressure, growth signals, oncogene mutation and other potential signals could activate glycolysis, thereby to regulate cell cycle, energy material synthesis, cell proliferation and cancer progression.

scholarly journals Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2046 ◽  
Author(s):  
Valerio Izzi ◽  
Martin N. Davis ◽  
Alexandra Naba
Keyword(s):  
Cancer Progression ◽  
Protein Function ◽  
The Cancer Genome Atlas ◽  
Copy Number Alterations ◽  
Cellular Functions ◽  
Genomic Alterations ◽  
Genes Encoding ◽  
Cancer Genome Atlas ◽  
Biomechanical Changes ◽  
Pan Cancer

The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the “matrisome” as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome. We also found that these alterations are predicted to significantly impact gene expression and protein function. Moreover, we identified matrisome genes whose mutational burden is an independent predictor of survival. We propose that studying genomic alterations of matrisome genes will further our understanding of the roles of this compartment in cancer progression and will lead to the development of innovative therapeutic strategies targeting the ECM.

scholarly journals MicroRNA-7 as a Potential Biomarker for Prognosis in Pancreatic Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Zhi-qiang Ye ◽  
Chang-lin Zou ◽  
Han-bin Chen ◽  
Ming-jie Jiang ◽  
Zhu Mei ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Progression ◽  
Clinical Significance ◽  
Cancer Progression ◽  
Cox Proportional Hazards Model ◽  
The Cancer Genome Atlas ◽  
Cancer Tissue ◽  
Advanced Tumor ◽  
Potential Biomarker ◽  
Tumor Stages

MicroRNAs play critical roles in tumor progression. Our recent study has indicated that microRNA-7 (miR-7) impairs autophagy-derived pools of glucose to suppress the glycolysis in pancreatic cancer progression. However, the roles of miR-7 in clinical significance and chemoresistance of pancreatic cancer remain unexplored. The aim of this study was to assess the expression of miR-7 in patients with pancreatic cancer and to evaluate the possibility of its usage as a prognostic molecular biomarker. MicroRNA array-based quantification analysis of 372 miRNAs was compared in serum between pancreatic cancer and healthy individuals, gemcitabine-sensitive and gemcitabine-resistance patients. We identified miR-7 showed the potential predictive power for gemcitabine-sensitive patients with pancreatic cancer. Then, the results were validated in pancreatic tissue microarray and The Cancer Genome Atlas (TCGA) dataset, demonstrating that lower miR-7 expression was correlated with more advanced tumor stages and worse prognosis in pancreatic cancer. The Cox proportional-hazards model analysis identified miR-7 to be an independent variable for prediction of the survival. Furthermore, the mechanistic exploration suggested the clinical significance of miR-7 involved its interference effect on autophagy and glycolysis in pancreatic cancer using pancreatic cancer tissue microarrays and TCGA data. Therefore, the results of the present study provide evidences that low microRNA-7 expression may contribute to tumor progression and poor prognosis in pancreatic cancer.

scholarly journals Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

2020 ◽  
Author(s):  
Haitang Yang ◽  
Liang Zhao ◽  
Feng Yao ◽  
Yanyun Gao ◽  
Thomas M. Marti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Gene Networks ◽  
Gene Expression Signature ◽  
The Cancer Genome Atlas ◽  
P Value ◽  
Solid Cancer ◽  
Cancer Drugs ◽  
Pan Cancer

Abstract Background: Ferroptosis is an apoptosis-independent cell death program implicated in various diseases including cancer. Emerging evidence has demonstrated the promise of pharmacological induction of ferroptosis as a novel anti-cancer approach, but the molecular underpinnings of ferroptosis regulation and biomarkers associated with sensitivity to ferroptosis indcuers has been poorly defined. Methods: By implementing integrated pharmacogenomic analysis, we correlated the sensitivity of small-molecule compounds (n=481) against the transcriptomes of solid cancer cell lines (n=659). The potential of a drug compound to modulate ferroptosis was determined by significant (empirical p-value < 0.01) association of drug effectiveness with SLC7A11 expression. To establish generalized gene signatures for ferroptosis sensitivity and resistance, we interrogated drug effects of multiple ferroptosis inducers (n=7) with transcriptomic data of pan-solid cancer cells. Finally, the ferroptosis gene signature was applied to The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) project to identify cancer patients and cells that likely benefit from ferroptosis-based therapeutics. Results: We report, for the first time, the comprehensive identification of cancer drugs with the potential to induce ferroptosis and a generalized gene expression signature predicting ferroptosis response in pan-cancer. Informed by the findings, we reveal an unanticipated role for class I histone deacetylase (HDAC) in regulating ferroptosis and show that targeting HDAC significantly enhances the ferroptosis-promoting effect of Erastin in lung cancer cells. Moreover, our data indicate that small cell lung cancer (SCLC) and isocitrate dehydrogenase ( IDH )-mutant brain tumors are highly primed for ferroptosis, suggesting that relaunching ferroptosis might be an innovative strategy to target these malignancies. Conclusions: Expanding arsenal targeting aberrant ferroptosis and deciphering gene networks dictating ferroptosis sensitivity shed light on ferroptosis regulatory networks and may facilitate biomarker-guided stratification for ferroptosis-based therapy.

scholarly journals Clinical significance of a microRNA signature for the identification and predicting prognosis in colorectal cancers with mucinous differentiation

2020 ◽  
Vol 41 (11) ◽  
pp. 1498-1506
Author(s):  
Juan Ruiz-Bañobre ◽  
Roshni Roy ◽  
Miren Alustiza Fernández ◽  
Óscar Murcia ◽  
Rodrigo Jover ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Prognostic Significance ◽  
Mucinous Carcinoma ◽  
Tnm Staging ◽  
Assessment Model ◽  
Risk Scores ◽  
Risk Assessment Model ◽  
Molecular Features ◽  
Novel Mirna ◽  
Mere Presence

Abstract Accumulating evidence supports the fact that the mere presence of mucinous differentiation in colorectal cancer (CRC), rather than its proportion, is a more accurate representative of a particular CRC subtype with distinct clinical and molecular features. In addition, the prognostic significance of the mucinous carcinoma (MC) subtype remains poorly understood and biomarkers have been barely explored in this disease. Herein, we have performed a systematic and comprehensive analysis in MCs and non-MCs and identified a panel of microRNAs (miRNAs) that are differentially expressed between these two subtypes of CRC. Next, we interrogated their clinical significance and demonstrated their robust diagnostic and prognostic clinical ability in CRCs with mucinous differentiation. Finally, we established an integrative risk-assessment model by combining the miRNA-based risk scores together with TNM staging, which was a superior predictor of prognosis in mucinous CRC patients. Collectively, we report a novel miRNA biomarker panel for the identification and predicting survival in CRC patients with mucinous differentiation.

scholarly journals Pan-cancer characterization of metabolism-related biomarkers identifies potential therapeutic targets

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guoshu Bi ◽  
Yunyi Bian ◽  
Jiaqi Liang ◽  
Jiacheng Yin ◽  
Runmei Li ◽  
...  
Keyword(s):  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Score System ◽  
Molecular Features ◽  
Cancer Genome Atlas ◽  
Metabolic Heterogeneity ◽  
Tumor Types ◽  
Pan Cancer ◽  
Worse Prognosis

Abstract Background Generally, cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. However, the mutual relationship between two critical metabolic pathways, glycolysis and oxidative phosphorylation (OXPHOS), remains poorly defined. Methods We developed a “double-score” system to quantify glycolysis and OXPHOS in 9668 patients across 33 tumor types from The Cancer Genome Atlas and classified them into four metabolic subtypes. Multi-omics bioinformatical analyses was conducted to detect metabolism-related molecular features. Results Compared with patients with low glycolysis and high OXPHOS (LGHO), those with high glycolysis and low OXPHOS (HGLO) were consistently associated with worse prognosis. We identified common dysregulated molecular features between different metabolic subgroups across multiple cancers, including gene, miRNA, transcription factor, methylation, and somatic alteration, as well as investigated their mutual interfering relationships. Conclusion Overall, this work provides a comprehensive atlas of metabolic heterogeneity on a pan-cancer scale and identified several potential drivers of metabolic rewiring, suggesting corresponding prognostic and therapeutic utility.

scholarly journals A Comprehensive Prognostic and Immune Analysis of SLC41A3 in Pan-Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Jun Liu ◽  
Shanqiang Zhang ◽  
Wenjie Dai ◽  
Chongwei Xie ◽  
Ji-Cheng Li
Keyword(s):  
Overall Survival ◽  
Immune Cells ◽  
Cox Regression ◽  
Expression Profiles ◽  
Prognostic Significance ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Cancer Prognosis ◽  
Cox Regression Analysis ◽  
Pan Cancer

SLC41A3, as a member of the 41st family of solute carriers, participates in the transport of magnesium. The role of SLC41A3 in cancer prognosis and immune regulation has rarely been reported. This study was designed to analyze the expression status and prognostic significance of SLC41A3 in pan-cancers. The mRNA expression profiles of SLC41A3 were obtained from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx), the Broad Institute Cancer Cell Line Encyclopedia (CCLE), and the International Cancer Genome Consortium (ICGC). The Cox regression and Kaplan-Meier analyses were used to evaluate the prognostic value of SLC41A3 in pan-cancer. Furthermore, the correlation between SLC41A3 expression and immune cells infiltration, immune checkpoint, mismatch repair (MMR), DNA methyltransferase (DNMT), tumor mutation burden (TMB), and microsatellite instability (MSI) were calculated using data form TCGA database. The results showed that the expression of SLC41A3 was down-regulated in kidney renal clear cell carcinoma (KIRC), and was associated with poor overall survival and tumor-specific mortality. Whereas, the expression of SLC41A3 was up-regulated in liver hepatocellular carcinoma (LIHC), and the results of Cox regression analysis revealed that SLC41A3 was an independent factor for LIHC prognosis. Meanwhile, a nomogram including SLC41A3 and stage was built and exhibited good predictive power for the overall survival of LIHC patients. Additionally, correlation analysis suggested a significant correlation between SLC41A3 and TMB, MSI, MMR, DNMT, and immune cells infiltration in various cancers. The overall survival and disease-specific survival analysis revealed that the combined SLC41A3 expression and immune cell score, TMB, and MSI were significantly associated with clinical outcomes in ACC, LIHC, and UVM patients. Therefore, we proposed that SLC41A3 may serve as a potential prognostic biomarker for cancer.

scholarly journals Genome-Wide Profiling and Clinical Significance of Alternative Splicing Events in Glioblastoma

2020 ◽  
Author(s):  
Xiufang Ren ◽  
Tianqi Liu ◽  
Xin Chen ◽  
Gefei Guan ◽  
Cunyi Zou ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Clinical Significance ◽  
Immune Cell ◽  
Sequence Data ◽  
Prognostic Significance ◽  
Interaction Network ◽  
Clinical Information ◽  
The Cancer Genome Atlas ◽  
Genome Wide ◽  
Alternative Splicing Events

Abstract Aims: The purpose of this study was to depict alternative splicing (AS) profiles in GBM and identify their clinical significance in the progression of GBM. Materials and Methods: RNA sequence data and clinical information were downloaded from The Cancer Genome Atlas portal (https://portal.gdc.cancer.gov/projects). Genome-wide alternative splicing events were obtained using SpliceSeq tool. Analyses were performed using GraphPad Prism 7 and R software. Key findings: Univariate Cox analysis identified 2406 AS events with prognostic significance. We built an interaction network based on these survival-related AS events. Unsupervised clustering analysis showed that patients in cluster 2 had a better prognosis than those in other clusters. The prognostic splicing factors and AS events were used to generate a splicing network. Seven prognostic signatures, developed based on the top three survival-related AS events, predicted the survival risk and may serve as independent indicators of unfavorable prognosis. Among these risk signatures, only the alternate promoter (AP) signature was upregulated in the mesenchymal subtype, which is characterized by a complex immune microenvironment. A high AP risk score indicated an overloaded local immune response and enriched immune cell infiltration, which may accelerate the progression of GBM.Significance: AS-related signatures may serve as predictors of prognosis as well as provide treatment targets and guidance for GBM patients.

scholarly journals TBX5-AS1, an enhancer RNA, is a potential novel prognostic biomarker for lung adenocarcinoma

2021 ◽  
Author(s):  
Lin Cheng ◽  
Tong Han ◽  
Bolin Chen ◽  
Kechao Nie ◽  
Weijun Peng
Keyword(s):  
Correlation Analysis ◽  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Prognostic Biomarker ◽  
Lung Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Pcr Analysis ◽  
Qrt Pcr ◽  
Pan Cancer

Abstract Background: Enhancer RNAs (eRNAs) are demonstrated to be closely associated with tumourigenesis and cancer progression. However, the role of eRNAs in lung adenocarcinoma (LUAD) remains largely unclear. Thus, a comprehensive analysis was constructed to identify the key eRNAs, and to explore the clinical utility of the identified eRNAs in LUAD.Methods: First, LUAD expression profile data from the Cancer Genome Atlas (TCGA) dataset and eRNA-relevant information were integrated for Kaplan-Meier survival analysis and Spearman’s correlation analysis to filtered the key candidate eRNAs that was associated with survival rate and their target genes in LUAD. Then, the key eRNA was selected for subsequent clinical correlation analysis. KEGG pathway enrichment analyses were undertaken to explore the potential signaling pathways of the key eRNA. Data from the human protein atlas (HPA) database were used to validate the outcomes and the quantitative real time-polymerase chain reaction (qRT-PCR) analysis was conducted to measure eRNA expression levels in tumour tissues and paired normal adjacent tissues from LUAD patients. Finally, the eRNAs were validated in pan-cancer.Results: As a result, TBX5-AS1 was identified as the key eRNA, which has T-box transcription factor 5 (TBX5) as its regulatory target. KEGG analysis indicated that TBX5-AS1 may exert a vital role via the PI3K/AKT pathway. Additionally, the qRT-PCR results and the HPA database indicated that TBX5-AS1 and TBX5 were significantly downregulated in tumour samples compared to matched-adjacent pairs. The pan-cancer validation results showed that TBX5-AS1 was associated with survival in four tumours, namely, adrenocortical carcinoma (ACC), LUAD, lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC). Correlations were found between TBX5-AS1 and its target gene, TBX5, in 26 tumour types.Conclusion: Collectively, we supposed that TBX5-AS1 is a tumor suppressor, and could be a new prognostic biomarker for LUAD patients and promote the targeted therapy of LUAD.

scholarly journals Pan-Cancer Analysis Shows Enrichment of Macrophages, Overexpression of Checkpoint Molecules, Inhibitory Cytokines, and Immune Exhaustion Signatures in EMT-High Tumors

2022 ◽  
Vol 11 ◽  
Author(s):  
Jayesh Kumar Tiwari ◽  
Shloka Negi ◽  
Manju Kashyap ◽  
Sheikh Nizamuddin ◽  
Amar Singh ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Escape ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Gene Signatures ◽  
Immune Exhaustion ◽  
Cancer Types ◽  
Tcga Dataset ◽  
Pan Cancer

Epithelial–mesenchymal transition (EMT) is a highly dynamic process that occurs under normal circumstances; however, EMT is also known to play a central role in tumor progression and metastasis. Furthermore, role of tumor immune microenvironment (TIME) in shaping anticancer immunity and inducing the EMT is also well recognized. Understanding the key features of EMT is critical for the development of effective therapeutic interventions. Given the central role of EMT in immune escape and cancer progression and treatment, we have carried out a pan-cancer TIME analysis of The Cancer Genome Atlas (TCGA) dataset in context to EMT. We have analyzed infiltration of various immune cells, expression of multiple checkpoint molecules and cytokines, and inflammatory and immune exhaustion gene signatures in 22 cancer types from TCGA dataset. A total of 16 cancer types showed a significantly increased (p &lt; 0.001) infiltration of macrophages in EMT-high tumors (mesenchymal samples). Furthermore, out of the 17 checkpoint molecules we analyzed, 11 showed a significant overexpression (p &lt; 0.001) in EMT-high samples of at least 10 cancer types. Analysis of cytokines showed significant enrichment of immunosuppressive cytokines—TGFB1 and IL10—in the EMT-high group of almost all cancer types. Analysis of various gene signatures showed enrichment of inflammation, exhausted CD8+ T cells, and activated stroma signatures in EMT-high tumors. In summary, our pan-cancer EMT analysis of TCGA dataset shows that the TIME of EMT-high tumors is highly immunosuppressive compared to the EMT-low (epithelial) tumors. The distinctive features of EMT-high tumors are as follows: (i) the enrichment of tumor-associated macrophages, (ii) overexpression of immune checkpoint molecules, (iii) upregulation of immune inhibitory cytokines TGFB1 and IL10, and (iv) enrichment of inflammatory and exhausted CD8+ T-cell signatures. Our study shows that TIMEs of different EMT groups differ significantly, and this would pave the way for future studies analyzing and targeting the TIME regulators for anticancer immunotherapy.

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