STEM-24. INTERFERON SIGNALING REGULATES THE PROLIFERATION AND MESENCHYMAL PHENOTYPE OF GLIOBLASTOMA STEM CELLS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi26-vi26
Author(s):  
Sabbir Khan ◽  
Rajasekaran Mahalingam ◽  
Shayak Sen ◽  
Kaitlin Gandy ◽  
Kristin Alfaro-Munoz ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Single Cell ◽  
In Silico ◽  
The Cancer Genome Atlas ◽  
Cytokine Signaling ◽  
Rna Seq ◽  
Mesenchymal Phenotype ◽  
Cancer Genome Atlas ◽  
Stat1 Signaling

Abstract Interferon (IFN) signaling contributes to stemness, cell proliferation, cell death, and cytokine signaling in cancer and immune cells; however, the role of IFN signaling in glioblastoma (GBM) and GBM stem-like cells (GSCs) is unclear. This study aimed to investigate the cancer cell-intrinsic IFN signaling in tumorigenesis and malignant phenotype of GBM. We characterized cell-intrinsic IFN signaling in The Cancer Genome Atlas, patient-derived cohorts of GSCs, and published single-cell RNA sequencing datasets by in-silico analyses. The in-silico findings were further validated by evaluating the cytokine secretion and using pharmacological activators and blockers of IFN/transducer and activator of transcription 1 (STAT1) signaling. We found that GSCs and GBM tumors exhibited differential cell-intrinsic IFN signaling, and high IFN/STAT1 signaling is associated with mesenchymal phenotype and poor survival outcomes. Ruxolitinib, a pharmacological inhibitor of IFN/STAT1, abolished the IFN/STAT1 signaling in GSCs with intrinsically high IFN signaling. IFN-γ treatment for 1 week promotes the mesenchymal phenotype in GSCs with low IFN signature. In addition, chronic inhibition of IFN/STAT1 signaling with ruxolitinib decreased cell proliferation and mesenchymal signatures (CD44, YKL40, and TIMP1) in GSCs with intrinsically active IFN/STAT1 signaling. Publicly available human glioma single-cell RNA-seq (scRNA-seq) datasets analyses showed that both tumor and nontumor cells expressed IFN signaling genes, and the mesenchymal signature was highly expressed in the same cluster where IFN signaling genes were upregulated. We demonstrated that cell-intrinsic IFN signaling in GSCs and GBM tumors is associated with mesenchymal signatures and cell proliferation. Our study provides evidence for the possibility of targeting IFN signaling in a specific group of GBM patients.

Hypoxia-induced RNASEH2A limits activation of cGAS-STING signaling in HCC and predicts poor prognosis

2021 ◽  
pp. 030089162110260
Author(s):  
Fengbo Zhao ◽  
Aifen Liu ◽  
Xiu Gong ◽  
Hao Chen ◽  
Jinhuan Wei ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Poor Prognosis ◽  
Quantitative Polymerase Chain Reaction ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Genome Atlas

Background: Hypoxia is a hallmark of solid cancers, including hepatocellular carcinoma (HCC). There is scarce information about how hypoxia avoids immunologic stress and maintains a cancer-promoting microenvironment. Methods: The Cancer Genome Atlas, RNA-seq data, and Oncomine database were used to discover the correlation of RNASEH2A with tumor progression; then expression of RNASEH2A mRNA and protein were detected in HCC tissues and cells subjected to hypoxia or with the treatment of CoCl2 via real-time quantitative polymerase chain reaction and immunochemistry assays. Finally, the effect of RNASEH2A on cell proliferation and the involved signaling pathway was explored further. Results: RNASEH2A was positively correlated with tumor grade, size, vascular invasion, and poor prognosis. The expression of RNASEH2A mRNA and protein were increased and dependent on hypoxia-inducible factor 2α in HCC tissues and cell lines. Knockout of RNASEH2A in HCC cells greatly reduced cell proliferation and induced the transcription of multiple cGAS-STING (cyclic GMP–AMP synthase–stimulator of interferon genes) targeted type 1 interferon-related genes, including IFIT1, USP18, and CXCL10, which suggests knockout of RNASEH2A may produce immunologic stress and tumor suppressive effects. Conclusions: RNASEH2A plays a critical role and potentially predicts patient outcomes in HCC, which uncovers a new mechanism that RNASEH2A contributes to limit immunologic stress of cancer cells in the context of hypoxia.

scholarly journals Scaling concepts in 'omics: nuclear lamin-B scales with tumor growth and predicts poor prognosis, whereas fibrosis can be pro-survival

2021 ◽  
Author(s):  
Manasvita Vashisth ◽  
Dennis Discher ◽  
Sangkyun Cho ◽  
Jerome Irianto ◽  
Yuntao Xia ◽  
...  
Keyword(s):  
Single Cell ◽  
Power Laws ◽  
The Cancer Genome Atlas ◽  
Structural Factors ◽  
Rna Seq ◽  
Lamin B ◽  
Nuclear Lamin ◽  
Cancer Genome Atlas ◽  
Tumor Types ◽  
Pan Cancer

Spatiotemporal relationships between genes expressed in tissues likely reflect physicochemical principles that range from stoichiometric interactions to co-organized fractals with characteristic scaling. For key structural factors within the nucleus and extracellular matrix (ECM), gene-gene power laws are found to be characteristic across several tumor types in The Cancer Genome Atlas (TCGA) and across single-cell RNA-seq data. The nuclear filament LMNB1 scales with many tumor-elevated proliferation genes that predict poor survival in liver cancer, and cell line experiments show LMNB1 regulates cancer cell cycle. Also high in the liver, lung, and breast tumors studied here are the main fibrosis-associated collagens, COL1A1 and COL1A2, that scale stoichiometrically with each other and superstoichiometrically with a pan-cancer fibrosis gene set. However, high fibrosis predicts prolonged survival of patients undergoing therapy and does not correlate with LMNB1. Single-cell RNA-seq data also reveal scaling consistent with the pan-cancer power laws obtained from bulk tissue, allowing new power law relations to be predicted. Lastly, although noisy data frustrate weak scaling, concepts such as stoichiometric scaling highlight a simple, internal consistency check to qualify expression data.

scholarly journals STEM-09. INTRINSIC INTERFERON SIGNALING REGULATES THE CELL DEATH OF GLIOBLASTOMA STEM CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii198-ii198
Author(s):  
Sabbi Khan Khan ◽  
Emmanuel Martinez-Ledesma ◽  
Sandeep Mittal ◽  
Kaitlin Gandy ◽  
Kristin Alfaro-Munoz ◽  
...  
Keyword(s):  
Cell Death ◽  
Treatment Resistance ◽  
Primary Brain Tumor ◽  
The Cancer Genome Atlas ◽  
Cytokine Signaling ◽  
Type I ◽  
Type Ii ◽  
Mechanistic Investigation ◽  
Differential Cell ◽  
Stat1 Signaling

Abstract Glioblastoma (GBM) is the most common, highly aggressive, and lethal primary brain tumor in adults. Interferon (IFN)-mediated signal transducer and activator of transcription 1 (STAT1) signaling contributes to various aspects of stemness, cell death, cytokine signaling in immune and non-immune cells. However, the role of IFN/STAT1 signaling in stemness, cell death and treatment resistance in GBM is unclear. This study aimed to investigate the cancer cell-intrinsic IFN/STAT1 signaling and its role in cell proliferation, stemness, and apoptosis. By using the metagene scores for type I and type II IFN-responsive genes, we evaluated basal IFN/STAT1 signaling in The Cancer Genome Atlas (TCGA) and in patient-derived cohorts of stem-like cells (GSCs) RNA expression datasets. In-silico analyses were further validated for the constitutive IFN signaling in a subset of GSCs using qPCR, WB and ELISA assays. We employed pharmacological activators and/or inhibitors of IFN/STAT1 signaling in GSCs to study its role in stemness and cell death. We found differential cell-intrinsic type I and type II IFN-signaling markers in GSCs and GBM tumors. High IFN-signaling is associated with mesenchymal phenotype and poor survival outcomes. Acute and chronic GSC exposure to recombinant IFNs reversibly activated both type I and II IFN-signaling in GSCs. IFN-β exposure induced apoptosis in intrinsically high IFN/STAT1-signaling GSCs, but not in the low IFN/STAT1-signaling GSCs. In summary, our findings demonstrate that GBM exhibit differential cell-intrinsic IFN-signaling, and basal IFN/STAT1 is a key factor for IFN-β-mediated cell death in GSCs. However, further mechanistic investigation of intrinsic IFN signaling in GBM, particularly in the stem cell compartment is needed.

Knockdown of PGM1 Synergistically Enhances Anticancer Effects of Orlistat in Gastric Cancer Under Glucose Deprivation

2021 ◽  
Author(s):  
Bo Cao ◽  
Huan Deng ◽  
Hao Cui ◽  
Ruiyang Zhao ◽  
Hanghang Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Enrichment Analysis ◽  
Glucose Deprivation ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas

Abstract Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. MethodsCorrelation and enrichment analysis of PGM1 was conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan-Meier Plotter database were analyzed for correlations between PGM1 expression and survival time of GC patients. CCK-8, EdU, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and detection of lipid regulators levels by western blot were used to reflect on the cell lipid metabolism. ResultsCorrelation and enrichment analysis suggested that PGM1 was closely associated with cell proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients, which was also correlated with some clinicopathological features, including T stage and TNM stage. Under low glucose conditions, knockdown of PGM1 significantly suppressed cell proliferation and glycolysis levels, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity for obesity treatment, effectively induced apoptosis, suppressed FASN activity. However, orlistat conversely increased glycolytic levels in GC cells. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism. ConclusionsDownregulation of PGM1 expression under glucose deprivation synergistically enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

scholarly journals PR/SET Domain Family and Cancer: Novel Insights from the Cancer Genome Atlas

2018 ◽  
Vol 19 (10) ◽  
pp. 3250 ◽  
Author(s):  
Anna Sorrentino ◽  
Antonio Federico ◽  
Monica Rienzo ◽  
Patrizia Gazzerro ◽  
Maurizio Bifulco ◽  
...  
Keyword(s):  
Family Members ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Driver Gene ◽  
Rna Seq ◽  
Set Domain ◽  
Primary Tumors ◽  
Cancer Genome Atlas ◽  
Pan Cancer ◽  
Genome Atlas

The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein–protein, protein–RNA, or protein–DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of PRDM genes, we reanalyzed the Exome- and RNA-Seq public datasets available at The Cancer Genome Atlas portal. Overall, PRDM2, PRDM3/MECOM, PRDM9, PRDM16 and ZFPM2/FOG2 were the most mutated genes with pan-cancer frequencies of protein-affecting mutations higher than 1%. Moreover, we observed heterogeneity in the mutation frequencies of these genes across tumors, with cancer types also reaching a value of about 20% of mutated samples for a specific PRDM gene. Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region. These findings, together with OncodriveCLUST results, suggest it could be putatively considered a cancer driver gene in this malignancy. Finally, transcriptome analysis from RNA-Seq data of paired samples revealed that transcription of PRDMs was significantly altered in several tumors. Specifically, PRDM12 and PRDM13 were largely overexpressed in many cancers whereas PRDM16 and ZFPM2/FOG2 were often downregulated. Some of these findings were also confirmed by real-time-PCR on primary tumors.

scholarly journals Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer

2018 ◽  
Vol 111 (7) ◽  
pp. 664-674 ◽  
Author(s):  
Rongqiang Yang ◽  
Steven W Li ◽  
Zirong Chen ◽  
Xin Zhou ◽  
Wei Ni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptome Profiling ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Growth And Survival ◽  
Cancer Genome Atlas ◽  
Lung Adenocarcinomas ◽  
Genome Atlas

Abstract Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.

scholarly journals Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3126
Author(s):  
Dominik Saul ◽  
Robyn Laura Kosinsky
Keyword(s):  
Single Cell ◽  
Myelogenous Leukemia ◽  
Ductal Adenocarcinoma ◽  
Cell Populations ◽  
Rna Seq ◽  
Healthy Control ◽  
Transcriptional Changes ◽  
The Relationship ◽  
Senescence Associated Genes

The human aging process is associated with molecular changes and cellular degeneration, resulting in a significant increase in cancer incidence with age. Despite their potential correlation, the relationship between cancer- and ageing-related transcriptional changes is largely unknown. In this study, we aimed to analyze aging-associated transcriptional patterns in publicly available bulk mRNA-seq and single-cell RNA-seq (scRNA-seq) datasets for chronic myelogenous leukemia (CML), colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer (LC), and pancreatic ductal adenocarcinoma (PDAC). Indeed, we detected that various aging/senescence-induced genes (ASIGs) were upregulated in malignant diseases compared to healthy control samples. To elucidate the importance of ASIGs during cell development, pseudotime analyses were performed, which revealed a late enrichment of distinct cancer-specific ASIG signatures. Notably, we were able to demonstrate that all cancer entities analyzed in this study comprised cell populations expressing ASIGs. While only minor correlations were detected between ASIGs and transcriptome-wide changes in PDAC, a high proportion of ASIGs was induced in CML, CRC, HCC, and LC samples. These unique cellular subpopulations could serve as a basis for future studies on the role of aging and senescence in human malignancies.

scholarly journals Comprehensive Analysis of The Significance of Hypoxia-Related Genes in Ovarian Cancer

2021 ◽  
Author(s):  
Wancheng Zhao ◽  
Lili Yin
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Principal Component ◽  
Vital Role ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas ◽  
Pca Algorithm

Abstract Background: Hypoxia-related genes have been reported to play important roles in a variety of cancers. However, their roles in ovarian cancer (OC) have remained unknown. The aim of our research was to explore the significance of hypoxia-related genes in OC patients.Methods: In this study, 15 hypoxia-related genes were screened from The Cancer Genome Atlas (TCGA) database to group the ovarian cancer patients using the consensus clustering method. Principal component analysis (PCA) was performed to calculate the hypoxia score for each patient to quantify the hypoxic status. Results: The OC patients from TCGA-OV dataset were divided into two distinct hypoxia statuses (cluster.A and cluster.B) based on the expression level of the 15 hypoxia-related genes. Most hypoxia-related genes were expressed more highly in the cluster.A group than in the cluster.B group. We also found that patients in the cluster.A group exhibited higher expression of immune checkpoint-related genes, epithelial-mesenchymal transition-related genes, and immune activation-related genes, as well as elevated immune infiltrates. PCA algorithm indicated that patients in the cluster.A group had higher hypoxia scores than that in in the cluster.B group.Conclusions: In summary, our research elucidated the vital role of hypoxia-related genes in immune infiltrates of OC. Our investigation of hypoxic status may be able to improve the efficacy of immunotherapy for OC.

scholarly journals Molecular basis of distinct oestrogen responses in endometrial and breast cancer

2019 ◽  
Vol 26 (1) ◽  
pp. 31-46 ◽  
Author(s):  
Eva Baxter ◽  
Karolina Windloch ◽  
Greg Kelly ◽  
Jason S Lee ◽  
Frank Gannon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Activation ◽  
The Cancer Genome Atlas ◽  
Breast Cancers ◽  
Oestrogen Receptor Alpha ◽  
Limited Success ◽  
Cancer Genome Atlas ◽  
Using Data ◽  
Oestrogen Signalling

Up to 80% of endometrial and breast cancers express oestrogen receptor alpha (ERα). Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in both cancers. We investigated the role of oestrogen in endometrial and breast cancers using data from The Cancer Genome Atlas (TCGA) in conjunction with cell line studies. Using phosphorylation of ERα (ERα-pSer118) as a marker of transcriptional activation of ERα in TCGA datasets, we found that genes associated with ERα-pSer118 were predominantly unique between tumour types and have distinct regulators. We present data on the alternative and novel roles played by SMAD3, CREB-pSer133 and particularly XBP1 in oestrogen signalling in endometrial and breast cancer.

scholarly journals Visual Display of 5p-arm and 3p-arm miRNA Expression with a Mobile Application

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Chao-Yu Pan ◽  
Wei-Ting Kuo ◽  
Chien-Yuan Chiu ◽  
Wen-chang Lin
Keyword(s):  
Mirna Expression ◽  
Expression Patterns ◽  
Mirna Gene ◽  
Visual Display ◽  
Mature Mirnas ◽  
Mobile App ◽  
The Cancer Genome Atlas ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
User Friendly

MicroRNAs (miRNAs) play important roles in human cancers. In previous studies, we have demonstrated that both 5p-arm and 3p-arm of mature miRNAs could be expressed from the same precursor and we further interrogated the 5p-arm and 3p-arm miRNA expression with a comprehensive arm feature annotation list. To assist biologists to visualize the differential 5p-arm and 3p-arm miRNA expression patterns, we utilized a user-friendly mobile App to display. The Cancer Genome Atlas (TCGA) miRNA-Seq expression information. We have collected over 4,500 miRNA-Seq datasets from 15 TCGA cancer types and further processed them with the 5p-arm and 3p-arm annotation analysis pipeline. In order to be displayed with the RNA-Seq Viewer App, annotated 5p-arm and 3p-arm miRNA expression information and miRNA gene loci information were converted into SQLite tables. In this distinct application, for any given miRNA gene, 5p-arm miRNA is illustrated on the top of chromosome ideogram and 3p-arm miRNA is illustrated on the bottom of chromosome ideogram. Users can then easily interrogate the differentially 5p-arm/3p-arm expressed miRNAs with their mobile devices. This study demonstrates the feasibility and utility of RNA-Seq Viewer App in addition to mRNA-Seq data visualization.

Sign in / Sign up

Export Citation Format

Share Document