scholarly journals Oncogenic Activation of Nrf2, Though as a Master Antioxidant Transcription Factor, Liberated by Specific Knockout of the Full-Length Nrf1α that Acts as a Dominant Tumor Repressor

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 520 ◽  
Author(s):  
Lu Qiu ◽  
Meng Wang ◽  
Shaofan Hu ◽  
Xufang Ru ◽  
Yonggang Ren ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
A Priori ◽  
Xenograft Model ◽  
Underlying Mechanism ◽  
Suppressive Effect ◽  
Tumor Promoter ◽  
Transcriptomic Sequencing ◽  
Pathological Model ◽  
Multiple Signaling

Liver-specific knockout of Nrf1 in the mouse leads to spontaneous development of non- alcoholic steatohepatitis with dyslipidemia, and then its deterioration results in hepatoma, but the underlying mechanism remains elusive to date. A similar pathological model is reconstructed here by using human Nrf1α-specific knockout cell lines. Our evidence has demonstrated that a marked increase of the inflammation marker COX2 definitely occurs in Nrf1α−/− cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in Keap1, PTEN and most of 26S proteasomal subunits in Nrf1α−/− cells. Further investigation of xenograft model mice showed that malignant growth of Nrf1α−/−-derived tumors is almost abolished by silencing of Nrf2, while Nrf1α+/+-tumor is markedly repressed by an inactive mutant (i.e., Nrf2−/−ΔTA), but largely unaffected by a priori constitutive activator (i.e., caNrf2ΔN). Mechanistic studies, combined with transcriptomic sequencing, unraveled a panoramic view of opposing and unifying inter-regulatory cross-talks between Nrf1α and Nrf2 at different layers of the endogenous regulatory networks from multiple signaling towards differential expression profiling of target genes. Collectively, Nrf1α manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity. Though as a tumor promoter, Nrf2 can also, in turn, directly activate the transcriptional expression of Nrf1 to form a negative feedback loop. In view of such mutual inter-regulation by between Nrf1α and Nrf2, it should thus be taken severe cautions to interpret the experimental results from loss of Nrf1α, Nrf2 or both.

scholarly journals Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

2018 ◽  
Author(s):  
Lu Qiu ◽  
Meng Wang ◽  
Shaofan Hu ◽  
Xufang Ru ◽  
Yonggang Ren ◽  
...  
Keyword(s):  
Feedback Loop ◽  
A Priori ◽  
Underlying Mechanism ◽  
Suppressive Effect ◽  
List Type ◽  
Inflammation Marker ◽  
Malignant Growth ◽  
Pathological Model ◽  
Xenograft Mice ◽  
Tumor Suppressive Effect

SUMMARYLiver-specific knockout of Nrf1 in mice leads to non-alcoholic steatohepatitis with dyslipidemia, and its deterioration results in spontaneous hepatoma, but the underlying mechanism remains elusive. A similar pathological model is herein reconstructed by using human Nrf1α-specific knockout cell lines. We demonstrated that a marked increase of the inflammation marker COX2 in Nrf1α−/− cells. Loss of Nrf1α leads to hyperactivation of Nrf2, which results from substantial decreases in both Keap1 and PTEN in Nrf1α−/− cells. Further investigation of xenograft mice showed that malignant growth of Nrf1α−/−-derived tumor is almost abolished by silencing Nrf2, while Nrf1α+/+-tumor is markedly repressed by inactive Nrf2−/−ΔTA, but unaffected by a priori constitutive activator of caNrf2ΔN. Mechanistic studies unraveled there exist opposing and unifying inter-regulatory cross-talks between Nrf1 and Nrf2. Collectively, Nrf1α manifests a dominant tumor-suppressive effect by confining Nrf2 oncogenicity, while Nrf2 can directly activate the transcriptional expression of Nrf1 to form a negative feedback loop.HIGHLIGHTSOpposing and unifying inter-regulatory cross-talks between Nrf1α and Nrf2Malignant growth of Nrf1α−/−-derived tumor is prevented by silencing Nrf2Hyper-activation of Nrf2 by Nrf1α−/− results from decreased Keap1 and PTENNrf1α+/+-tumor is repressed by Nrf2−/−ΔTA, but unaltered by its active caNrf2ΔN

scholarly journals Identification of differentially expressed genes in asthma by bioinformatics analysis

2021 ◽  
Vol 3 (2) ◽  
pp. 28-36
Author(s):  
Zhaojun Wang ◽  
Zhifeng Mo ◽  
Hongsen Liang ◽  
Qiwei Zhang ◽  
Wei Li ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Microarray Dataset ◽  
Underlying Mechanism ◽  
Gene Expression Omnibus ◽  
The Novel ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Healthy Donors

Objective Asthma is a common inflammatory disease of the airway, and its underlying mechanism is complex. The role of microRNAs (miRNAs) in asthma is unclear. The present study aimed to investigate miRNA-mRNA regulatory networks underlying asthma. Methods One microarray dataset was downloaded from the Gene Expression Omnibus (GEO) database. Differential expression of miRNAs (DEMs) was identified in bronchial epithelial cells (BECs) isolated from healthy donors and patients with asthma. MiRTarBase, mirDIP, and miRDB were used to predict target genes, followed by protein-protein interaction (PPI) network analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Ontology (GO) analysis; cytoHubba was used to predict the important nodes in the network. The miRNA-hub genes sub-network of interest was determined. Results This study constructed an asthma-associated miRNA-mRNA network, in which seven key miRNAs and 10 hub genes were identified. Conclusions The novel miRNAs and hub genes identified in the present study could be potential diagnostic and treatment biomarkers for asthma.

scholarly journals EPEN-21. IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION IN PEDIATRIC EPENDYMOMA REVEALED BY SINGLE-CELL RNA-SEQ

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii311-iii312
Author(s):  
Bernhard Englinger ◽  
Johannes Gojo ◽  
Li Jiang ◽  
Jens M Hübner ◽  
McKenzie L Shaw ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Regulatory Networks ◽  
Target Genes ◽  
Target Identification ◽  
Rna Seq ◽  
Cell Models ◽  
Pediatric Ependymoma ◽  
Glial Fate ◽  
Anatomic Locations

Abstract Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, the intratumoral heterogeneity and developmental origins of these groups are only partially understood, and effective treatments are still lacking for about 50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/nucleus RNA-sequencing to analyze 24 tumor specimens across major molecular subgroups and anatomic locations. We additionally analyzed ten patient-derived ependymoma cell models and two patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating from undifferentiated neural stem cell-like populations towards different degrees of impaired differentiation states comprising neuronal precursor-like, astro-glial-like, and ependymal-like tumor cells. While prognostically favorable ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations. Projection of transcriptomic signatures onto an independent bulk RNA-seq cohort stratified patient survival even within known molecular groups, thus refining the prognostic power of DNA methylation-based profiling. Furthermore, we identified novel potentially druggable targets including IGF- and FGF-signaling within poorly prognostic transcriptional programs. Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate identified target genes in functional follow-up analyses. Taken together, our analyses reveal a developmental hierarchy and transcriptomic context underlying the biologically and clinically distinct behavior of ependymoma groups. The newly characterized cellular states and underlying regulatory networks could serve as basis for future therapeutic target identification and reveal biomarkers for clinical trials.

scholarly journals Sulforaphane Inhibits the Expression of Long Noncoding RNA H19 and Its Target APOBEC3G and Thereby Pancreatic Cancer Progression

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 827
Author(s):  
Yiqiao Luo ◽  
Bin Yan ◽  
Li Liu ◽  
Libo Yin ◽  
Huihui Ji ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Colony Formation ◽  
Noncoding Rna ◽  
Target Genes ◽  
Gene Array ◽  
New Drugs ◽  
Tumor Promoter ◽  
Ductal Adenocarcinoma ◽  
Pilot Studies

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and the therapeutic options available usually have little impact on survival. Great hope is placed on new therapeutic targets, including long noncoding RNAs (lncRNAs), and on the development of new drugs, based on e.g., broccoli-derived sulforaphane, which meanwhile has shown promise in pilot studies in patients. We examined whether sulforaphane interferes with lncRNA signaling and analyzed five PDAC and two nonmalignant cell lines, patient tissues (n = 30), and online patient data (n = 350). RT-qPCR, Western blotting, MTT, colony formation, transwell and wound healing assays; gene array analysis; bioinformatics; in situ hybridization; immunohistochemistry and xenotransplantation were used. Sulforaphane regulated the expression of all of five examined lncRNAs, but basal expression, biological function and inhibition of H19 were of highest significance. H19 siRNA prevented colony formation, migration, invasion and Smad2 phosphorylation. We identified 103 common sulforaphane- and H19-related target genes and focused to the virus-induced tumor promoter APOBEC3G. APOBEC3G siRNA mimicked the previously observed H19 and sulforaphane effects. In vivo, sulforaphane- or H19 or APOBEC3G siRNAs led to significantly smaller tumor xenografts with reduced expression of Ki67, APOBEC3G and phospho-Smad2. Together, we identified APOBEC3G as H19 target, and both are inhibited by sulforaphane in prevention of PDAC progression.

scholarly journals TMOD-15. EFFICACY OF THE MDM2 INHIBITOR KRT-232 IN GLIOBLASTOMA PATIENT-DERIVED XENOGRAFT MODELS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii231-ii231
Author(s):  
Rachael Vaubel ◽  
Ann Mladek ◽  
Yu Zhao ◽  
Shiv K Gupta ◽  
Minjee Kim ◽  
...  
Keyword(s):  
Target Genes ◽  
Xenograft Model ◽  
Culture Conditions ◽  
Patient Derived Xenograft ◽  
Fold Induction ◽  
Extended Survival ◽  
Mdm2 Amplification ◽  
Mdm2 Inhibitor

Abstract Non-genotoxic reactivation of p53 by MDM2 inhibitors represents a promising therapeutic strategy for tumors with wild-type TP53, particularly tumors harboring MDM2 amplification. MDM2 controls p53 levels by targeting it for degradation, while disruption of the MDM2-p53 interaction causes rapid accumulation of p53 and activation of the p53 pathway. We examined the efficacy of the small molecule MDM2 inhibitor KRT-232, alone and in combination with radiation therapy (RT), in MDM2-amplified and/or p53 wildtype patient-derived xenograft (PDX) models of glioblastoma in vitro and in vivo. In vitro, glioblastoma PDX explant cultures showed sensitivity to KRT-232, both tumors with MDM2 amplification (GBM108 and G148) and non-amplified but TP53-wildtype lines (GBM10, GBM14, and GBM39), with IC50s ranging from 300-800 nM in FBS culture conditions. A TP53 p.F270C mutant PDX (GBM43) was inherently resistant, with IC50 >3000 nM. In the MDM2-amplified GBM108 line, KRT-232 led to a robust (5-6 fold) induction of p53-target genes p21, PUMA, and NOXA, with initiation of both apoptosis and senescence. Expression of p21 and PUMA was greater with KRT-232 in combination with RT (25-35 fold induction), while stable knock-down of p53 in GBM108 led to complete resistance to KRT-232. In contrast, GBM10 showed lower induction of p21 and PUMA (2-3 fold) and was more resistant to KRT-232. In an orthotopic GBM108 xenograft model, treatment with KRT-232 +/- RT for one week extended survival from 22 days (placebo) to 46 days (KRT-232 alone); combination KRT-232 + RT further extended survival (77 days) over RT alone (31 days). KRT-232 is an effective treatment in a subset of glioblastoma pre-clinical models alone and in combination with RT. Further studies are underway to understand the mechanisms conferring innate sensitivity or resistance to KRT-232.

scholarly journals Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julia M. Kempf ◽  
Sabrina Weser ◽  
Michael D. Bartoschek ◽  
Klaus H. Metzeler ◽  
Binje Vick ◽  
...  
Keyword(s):  
Target Genes ◽  
Chemotherapeutic Agent ◽  
Chemotherapy Resistance ◽  
Xenograft Model ◽  
Histone Methyltransferase ◽  
Loss Of Function ◽  
Resistance Development ◽  
Selective Growth Advantage ◽  
Patient Derived Xenograft ◽  
Transmembrane Transporter

AbstractChemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms inducing resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicate that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.

scholarly journals Rs56288038 (C/G) in 3'UTR of IRF-1 Regulated by MiR-502-5p Promotes Gastric Cancer Development

2016 ◽  
Vol 40 (1-2) ◽  
pp. 391-399 ◽  
Author(s):  
Bo Wang ◽  
Huan Yang ◽  
Liqin Shen ◽  
Ji Wang ◽  
Wangyang Pu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Survival Rate ◽  
Target Genes ◽  
Diagnostic Value ◽  
Tumor Promoter ◽  
Luciferase Reporter ◽  
Nucleotide Polymorphisms ◽  
Susceptible Population ◽  
Poor Differentiation ◽  
Regulatory Capacity

Background/Aims: Interferon regulatory factor 1 (IRF-1) has been shown to function as a transcriptional activator or repressor of a variety of target genes. However, its upstream, non-coding RNA-related regulatory capacity remains unknown. In this study, we focus on the miRNA-associated single nucleotide polymorphisms (SNPs) in the 3′untranslated region (UTR) of IRF-1 to further investigate the functional relationship and potential diagnostic value of the SNPs and miRNAs among Chinese gastric cancer (GC) patients. Methods: We performed a case-control study with 819 GC patients and 756 cancer-free controls. Genotyping by realtime PCR assay, cell transfection, and the dual luciferase reporter assay were used in our study, and the 5-year overall survival rate and relapse-free survival rate in different groups were investigated. Results: We found that patients suffering from Helicobacter pylori (Hp) infection were the susceptible population compared to controls. SNP rs56288038 (C/G) in IRF-1 3′UTR was involved in the occurrence of GC by acting as a tumor promoter factor. SNP rs56288038 (C/G) could be up-regulated by miR-502-5p, which caused a down-regulation of IRF-1 in cell lines and decreased apoptosis induced by IFN-γ. Carrying the G genotype was related to significantly low expression of IRF-1 and Hp infection, poor differentiation, big tumor size, invasion depth, as well as the high probability of metastasis, and moreover, the C/G SNP was associated with shorter survival of GC patients with five years of follow-up study. Conclusions: our findings have shown that the SNP rs56288038 (C/G) in IRF-1 3′UTR acted as a promotion factor in GC development through enhancing the regulatory role of miR-502-5p in IRF-1 expression.

scholarly journals Novel Serine 176 Phosphorylation of YBX1 Activates NF-κB in Colon Cancer

2017 ◽  
Vol 292 (8) ◽  
pp. 3433-3444 ◽  
Author(s):  
Matthew Martin ◽  
Laiqing Hua ◽  
Benlian Wang ◽  
Han Wei ◽  
Lakshmi Prabhu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Target Genes ◽  
Phosphorylation Site ◽  
Tumor Promoter ◽  
Mass Spectrometry Analysis ◽  
Hek293 Cells ◽  
Spectrometry Analysis ◽  
Ht29 Cells ◽  
Therapy Strategy ◽  
Attractive Therapeutic Target

Y box protein 1 (YBX1) is a well known oncoprotein that has tumor-promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. To develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Previously, we have shown that YBX1 could function as a tumor promoter through phosphorylation of its Ser-165 residue, leading to the activation of the NF-κB signaling pathway (1). In this study, using mass spectrometry analysis, we discovered a distinct phosphorylation site, Ser-176, on YBX1. Overexpression of the YBX1-S176A (serine-to-alanine) mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB-activating ability compared with that of WT-YBX1, confirming that Ser-176 phosphorylation is critical for the activation of NF-κB by YBX1. Importantly, the mutant of Ser-176 and the previously reported Ser-165 sites regulate distinct groups of NF-κB target genes, suggesting the unique and irreplaceable function of each of these two phosphorylated serine residues. Our important findings could provide a novel cancer therapy strategy by blocking either Ser-176 or Ser-165 phosphorylation or both of YBX1 in colon cancer.

scholarly journals Gene Expression Networks in the Drosophila Genetic Reference Panel

2019 ◽  
Author(s):  
Logan J. Everett ◽  
Wen Huang ◽  
Shanshan Zhou ◽  
Mary Anna Carbone ◽  
Richard F. Lyman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Dna Sequences ◽  
Quantitative Trait ◽  
Regulatory Networks ◽  
Target Genes ◽  
Reference Panel ◽  
Modern Biology ◽  
Specific Expression ◽  
Drosophila Genetic Reference Panel

SummaryA major challenge in modern biology is to understand how naturally occurring variation in DNA sequences affects complex organismal traits through networks of intermediate molecular phenotypes. Here, we performed deep RNA sequencing of 200 Drosophila Genetic Reference Panel inbred lines with complete genome sequences, and mapped expression quantitative trait loci for annotated genes, novel transcribed regions (most of which are long noncoding RNAs), transposable elements and microbial species. We identified host variants that affect expression of transposable elements, independent of their copy number, as well as microbiome composition. We constructed sex-specific expression quantitative trait locus regulatory networks. These networks are enriched for novel transcribed regions and target genes in heterochromatin and euchromatic regions of reduced recombination, and genes regulating transposable element expression. This study provides new insights regarding the role of natural genetic variation in regulating gene expression and generates testable hypotheses for future functional analyses.

scholarly journals NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

2020 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Yan He ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Xenograft Model ◽  
Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

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