scholarly journals Integrated analysis reveals five potential ceRNA biomarkers in human lung adenocarcinoma

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6694 ◽  
Author(s):  
Yu Liu ◽  
Deyao Xie ◽  
Zhifeng He ◽  
Liangcheng Zheng
Keyword(s):  
Gene Expression ◽  
Functional Analysis ◽  
Transcription Factor ◽  
Early Diagnosis ◽  
Lung Adenocarcinoma ◽  
Integrated Analysis ◽  
Aberrant Expression ◽  
Ontology Term ◽  
Tumor Stages ◽  
Potential Biomarkers

Background Competing endogenous RNAs (ceRNAs) are a newly identified type of regulatory RNA. Accumulating evidence suggests that ceRNAs play an important role in the pathogenesis of diseases such as cancer. Thus, ceRNA dysregulation may represent an important molecular mechanism underlying cancer progression and poor prognosis. In this study, we aimed to identify ceRNAs that may serve as potential biomarkers for early diagnosis of lung adenocarcinoma (LUAD). Methods We performed differential gene expression analysis on TCGA-LUAD datasets to identify differentially expressed (DE) mRNAs, lncRNAs, and miRNAs at different tumor stages. Based on the ceRNA hypothesis and considering the synergistic or feedback regulation of ceRNAs, a lncRNA–miRNA–mRNA network was constructed. Functional analysis was performed using gene ontology term and KEGG pathway enrichment analysis and KOBAS 2.0 software. Transcription factor (TF) analysis was carried out to identify direct targets of the TFs associated with LUAD prognosis. Identified DE genes were validated using gene expression omnibus (GEO) datasets. Results Based on analysis of TCGA-LUAD datasets, we obtained 2,610 DE mRNAs, 915 lncRNAs, and 125 miRNAs that were common to different tumor stages (|log2(Fold change)| ≥ 1, false discovery rate < 0.01), respectively. Functional analysis showed that the aberrantly expressed mRNAs were closely related to tumor development. Survival analyses of the constructed ceRNA network modules demonstrated that five of them exhibit prognostic significance. The five ceRNA interaction modules contained one lncRNA (FENDRR), three mRNAs (EPAS1, FOXF1, and EDNRB), and four miRNAs (hsa-miR-148a, hsa-miR-195, hsa-miR-196b, and hsa-miR-301b). The aberrant expression of one lncRNA and three mRNAs was verified in the LUAD GEO dataset. Transcription factor analysis demonstrated that EPAS1 directly targeted 13 DE mRNAs. Conclusion Our observations indicate that lncRNA-related ceRNAs and TFs play an important role in LUAD. The present study provides novel insights into the molecular mechanisms underlying LUAD pathogenesis. Furthermore, our study facilitates the identification of potential biomarkers for the early diagnosis and prognosis of LUAD and therapeutic targets for its treatment.

scholarly journals Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells

2020 ◽  
Vol 117 (48) ◽  
pp. 30639-30648
Author(s):  
Dan Hu ◽  
Emily C. Tjon ◽  
Karin M. Andersson ◽  
Gabriela M. Molica ◽  
Minh C. Pham ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
Proinflammatory Cytokines ◽  
Th17 Cells ◽  
Gene Set Enrichment Analysis ◽  
Aberrant Expression ◽  
Signature Genes ◽  
The Impact

IL-17–producing Th17 cells are implicated in the pathogenesis of rheumatoid arthritis (RA) and TNF-α, a proinflammatory cytokine in the rheumatoid joint, facilitates Th17 differentiation. Anti-TNF therapy ameliorates disease in many patients with rheumatoid arthritis (RA). However, a significant proportion of patients do not respond to this therapy. The impact of anti-TNF therapy on Th17 responses in RA is not well understood. We conducted high-throughput gene expression analysis of Th17-enriched CCR6+CXCR3−CD45RA−CD4+T (CCR6+T) cells isolated from anti-TNF–treated RA patients classified as responders or nonresponders to therapy. CCR6+T cells from responders and nonresponders had distinct gene expression profiles. Proinflammatory signaling was elevated in the CCR6+T cells of nonresponders, and pathogenic Th17 signature genes were up-regulated in these cells. Gene set enrichment analysis on these signature genes identified transcription factor USF2 as their upstream regulator, which was also increased in nonresponders. Importantly, short hairpin RNA targetingUSF2in pathogenic Th17 cells led to reduced expression of proinflammatory cytokines IL-17A, IFN-γ, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as transcription factor T-bet. Together, our results revealed inadequate suppression of Th17 responses by anti-TNF in nonresponders, and direct targeting of the USF2-signaling pathway may be a potential therapeutic approach in the anti-TNF refractory RA.

scholarly journals Functional Analysis of an Arabidopsis Transcription Factor, DREB2A, Involved in Drought-Responsive Gene Expression

2006 ◽  
Vol 18 (5) ◽  
pp. 1292-1309 ◽  
Author(s):  
Yoh Sakuma ◽  
Kyonoshin Maruyama ◽  
Yuriko Osakabe ◽  
Feng Qin ◽  
Motoaki Seki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Functional Analysis ◽  
Transcription Factor ◽  
Responsive Gene

scholarly journals Aberrant Expression of the Tyrosine Kinase Receptor EphA4 and the Transcription Factor Twist in Sézary Syndrome Identified by Gene Expression Analysis

2004 ◽  
Vol 64 (16) ◽  
pp. 5578-5586 ◽  
Author(s):  
Remco van Doorn ◽  
Remco Dijkman ◽  
Maarten H. Vermeer ◽  
Jacoba J. Out-Luiting ◽  
Elisabeth M. H. van der Raaij-Helmer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Tyrosine Kinase ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Tyrosine Kinase Receptor ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Aberrant Expression

scholarly journals Functional analysis of a NAC-type transcription factor OsNAC6 involved in abiotic and biotic stress-responsive gene expression in rice

2007 ◽  
Vol 51 (4) ◽  
pp. 617-630 ◽  
Author(s):  
Kazuo Nakashima ◽  
Lam-Son P. Tran ◽  
Dong Van Nguyen ◽  
Miki Fujita ◽  
Kyonoshin Maruyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Functional Analysis ◽  
Transcription Factor ◽  
Biotic Stress ◽  
Abiotic And Biotic Stress ◽  
Responsive Gene

scholarly journals Members of the CREB/ATF and AP1 family of transcription factors are involved in the regulation of SOX18 gene expression

2011 ◽  
Vol 63 (3) ◽  
pp. 517-525 ◽  
Author(s):  
Isidora Petrovic ◽  
Natasa Kovacevic-Grujicic ◽  
Jelena Popovic ◽  
A. Krstic ◽  
Milena Milivojevic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Functional Analysis ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Endothelial Cell ◽  
Promoter Region ◽  
Promoter Activity ◽  
Cell Specification ◽  
Factor Interactions

The SOX18 transcription factor plays an important role in endothelial cell specification, angiogenesis and atherogenesis. By profiling transcription factor interactions (TranSignal TM TF Protein Array) we identified several transcription factors implicated in angiogenesis that have the ability to bind to the SOX18 optimal promoter region in vitro. In this report we focused our attention on distinct transcription factors identified by the array as belonging to AP-1 and CREB/ATF protein families. In particular, we analyzed the effects of CREB, JunB, c-Jun and ATF3 on SOX18 gene expression. Functional analysis revealed that CREB acts as a repressor, while JunB, c-Jun and ATF3 act as activators of SOX18 promoter activity. Our findings indicate that a transcriptional network that includes CREB, JunB, c-Jun and ATF3 could be involved in angiogenesis-related transcriptional regulation of the SOX18 gene.

The HOX11/TLX1 Transcription Factor Oncogene Induces Chromosomal Aneuploidy in T-ALL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 142-142 ◽  
Author(s):  
Kim De Keersmaecker ◽  
Pedro Jose Real Luna ◽  
Giusy Della Gatta ◽  
Teresa Palomero ◽  
Mireia Castillo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
T Cell ◽  
Transgenic Mice ◽  
Target Genes ◽  
Cell Transformation ◽  
Double Positive ◽  
Aberrant Expression ◽  
On Chip ◽  
Gains And Losses

Abstract Abstract 142 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with the activation of transcription factor oncogenes. TLX1/HOX11 was originally isolated from the recurrent t(10;14)(q24;q11) in T-ALL and is aberrantly expressed in 5% to 10% of pediatric and up to 30% of adult T-ALL cases. Tlx1 plays an important role during embryonic development and acts as a master transcriptional regulator necessary for the genesis of the spleen. TLX1 positive T-ALLs have a distinct gene expression profile resembling that of thymocytes blocked at the early double positive stage of development. This observation supports the hypothesis that aberrant expression of TLX1 contributes to the pathogenesis of T-ALL by interfering with critical transcriptional regulatory networks involved in cell proliferation, differentiation and survival during T-cell development. However, the identity of such oncogenic pathways and the mechanisms though which they operate are still largely unknown. In order to gain further insight into the mechanisms of transformation induced by TLX1, we generated a transgenic model of TLX1 induced T-ALL. In this model, a human TLX1 cDNA was expressed in developing thymocytes under the control of the proximal LCK promoter. TLX1 transgenic mice displayed a specific defect in T-cell development characterized by reduced thymic size and cellularity with increased apoptosis and a differentiation arrest at the CD4/CD8 double negative, CD25/CD44 double positive stage of differentiation (DN2 thymocytes). Long term follow up revealed that TLX1 transgenic mice develop tumors with a median latency of 29 weeks. TLX1 induced leukemias are characterized by increased thymic size and diffuse infiltration of bone marrow, spleen and peripheral organs by lymphoblasts expressing T-cell markers. Analysis of TCRβ expression and transplantation into isogenic recipients demonstrated that TLX1 tumors are clonal and transplantable. Microarray gene expression profiling of mouse and human T-ALLs showed that tumors from TLX1 transgenic mice have a gene expression signature that is highly related to that of human T-ALLs with aberrant expression of TLX1. Moreover, ChIP-on-chip analysis of promoters bound by TLX1 showed this genetic program is dominated by the downregulation of TLX1 direct target genes. Mutation profiling of T-cell oncogenes and array CGH analysis in mouse TLX1 tumors demonstrated the presence of cooperative mutations including Pten deletions, activating mutations in Notch1 and loss of Bcl11b. Strikingly, SKY analysis and array CGH revealed that 80% of TLX1 induced tumors had numerical chromosomal abnormalities including a high frequency of trisomy 15. Analysis of gene expression of ChIP-on-chip TLX1 direct target genes in double negative thymocytes from preleukemic mice showed downregulation of genes primarily involved in the control of chromosomal segregation during mitosis such as Bub1, Brca2, Chek1, Kntc1, Kif23, CenpE and Plk1. These data suggest that aberrant TLX1 expression directly promotes aneuploidy and contributes to T-cell transformation by interfering with the expression of genes responsible for chromosomal segregation during mitosis. Importantly, T-cell lymphoblasts from TLX1 transgenic mice failed to undergo a mitotic cell cycle arrest after treatment with taxol, a cell cycle inhibitor that interferes with microtubule remodeling during mitosis. Strikingly, karyotype analysis of a series of 59 pediatric T-ALLs demonstrated a high frequency of chromosomal gains and losses in TLX1 and TLX3 positive human T-cell tumors compared with other genetic subgroups of T-ALL (P <0.001). Thus, aberrant expression of TLX1 in T-cell precursors seems to impair the function of the mitotic checkpoint and facilitate the acquisition of chromosomal gains and losses during T-cell transformation. These results establish for the first time a mechanistic link between the activity of a leukemogenic transcription factor oncogene and the development of chromosomal aneuploidy in the pathogenesis of human leukemia. Disclosures: Ferrando: Merck, Pfizer: Research Funding.

scholarly journals Transcription factor abundance controlled by an auto-regulatory mechanism involving a transcription start site switch

2013 ◽  
Vol 42 (4) ◽  
pp. 2171-2184 ◽  
Author(s):  
Richard Patryk Ngondo ◽  
Philippe Carbon
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Start Site ◽  
Regulatory Mechanism ◽  
Start Site ◽  
Transcription Start ◽  
Aberrant Expression ◽  
Alternative Transcription ◽  
Activating Transcription Factor

Abstract A transcriptional feedback loop is the simplest and most direct means for a transcription factor to provide an increased stability of gene expression. In this work performed in human cells, we reveal a new negative auto-regulatory mechanism involving an alternative transcription start site (TSS) usage. Using the activating transcription factor ZNF143 as a model, we show that the ZNF143 low-affinity binding sites, located downstream of its canonical TSS, play the role of protein sensors to induce the up- or down-regulation of ZNF143 gene expression. We uncovered that the TSS switch that mediates this regulation implies the differential expression of two transcripts with an opposite protein production ability due to their different 5′ untranslated regions. Moreover, our analysis of the ENCODE data suggests that this mechanism could be used by other transcription factors to rapidly respond to their own aberrant expression level.

scholarly journals Identification of microbial markers across populations in early detection of colorectal cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuanqi Wu ◽  
Na Jiao ◽  
Ruixin Zhu ◽  
Yida Zhang ◽  
Dingfeng Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Functional Analysis ◽  
Random Forest ◽  
Early Detection ◽  
Early Diagnosis ◽  
Gut Microbiota ◽  
Early Stage ◽  
Control Area ◽  
Integrated Analysis ◽  
Quantitative Real Time Pcr

AbstractAssociations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-l-glycero-beta-d-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.

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