scholarly journals Chromosome 1q amplification perturbs a ceRNA network to promote melanoma metastasis

2021 ◽  
Author(s):  
Xiaonan Xu ◽  
Kaizhen Wang ◽  
Olga Vera ◽  
Akanksha Verma ◽  
Olivier Elemento ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Target Genes ◽  
Melanoma Metastasis ◽  
Dependent Manner ◽  
Suppressor Activity ◽  
Protein Coding ◽  
Chromosome 1Q ◽  
Cerna Network ◽  
Melanoma Progression

Deregulated gene expression through epigenetic, transcriptional, and copy number alterations is a major driver of melanoma progression and metastasis. In addition to serving as blueprints for translation, some mRNAs post-transcriptionally regulate gene expression by competitively sequestering miRNAs they share with other targets. Here we report that such mRNAs, termed competitive endogenous RNAs (ceRNAs), contribute to melanoma progression and metastasis. ceRNA predictions identified multiple candidate genes on chromosome 1q, which is recurrently amplified in melanoma. Genetic studies reveal that three of these mRNAs, CEP170, NUCKS1, and ZC3H11A, promote melanoma migration, invasion, and metastasis in a protein coding-independent and miRNA binding site-dependent manner. Interestingly, CEP170, NUCKS1, and ZC3H11A cooperate to elicit oncogenic effects by collectively impairing the tumor suppressor activity of 8 miRNAs on several pro-metastatic target genes. Finally, this complex chromosome 1q ceRNA network is evident in other cancer types, suggesting ceRNA network deregulation is a common driver of cancer progression.

scholarly journals Gene Expression and Transcriptome Profiling of Changes in a Cancer Cell Line Post-Exposure to Cadmium Telluride Quantum Dots: Possible Implications in Oncogenesis

Dose-Response ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 155932582110198
Author(s):  
Mohammed S. Aldughaim ◽  
Mashael R. Al-Anazi ◽  
Marie Fe F. Bohol ◽  
Dilek Colak ◽  
Hani Alothaid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantum Dots ◽  
Cancer Cells ◽  
Cadmium Telluride ◽  
Cancer Progression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dependent Manner ◽  
Cdte Qds ◽  
Cadmium Telluride Quantum Dots

Cadmium telluride quantum dots (CdTe-QDs) are acquiring great interest in terms of their applications in biomedical sciences. Despite earlier sporadic studies on possible oncogenic roles and anticancer properties of CdTe-QDs, there is limited information regarding the oncogenic potential of CdTe-QDs in cancer progression. Here, we investigated the oncogenic effects of CdTe-QDs on the gene expression profiles of Chang cancer cells. Chang cancer cells were treated with 2 different doses of CdTe-QDs (10 and 25 μg/ml) at different time intervals (6, 12, and 24 h). Functional annotations helped identify the gene expression profile in terms of its biological process, canonical pathways, and gene interaction networks activated. It was found that the gene expression profiles varied in a time and dose-dependent manner. Validation of transcriptional changes of several genes through quantitative PCR showed that several genes upregulated by CdTe-QD exposure were somewhat linked with oncogenesis. CdTe-QD-triggered functional pathways that appear to associate with gene expression, cell proliferation, migration, adhesion, cell-cycle progression, signal transduction, and metabolism. Overall, CdTe-QD exposure led to changes in the gene expression profiles of the Chang cancer cells, highlighting that this nanoparticle can further drive oncogenesis and cancer progression, a finding that indicates the merit of immediate in vivo investigation.

Role of MicroRNAs and Long Non-Coding RNAs in Regulating Angiogenesis in Human Breast Cancer- A Molecular Medicine Perspective

2021 ◽  
Vol 22 ◽  
Author(s):  
Vandana Golhani ◽  
Suman Kumar Ray ◽  
Sukhes Mukherjee
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathways ◽  
Cancer Therapeutics ◽  
Molecular Medicine ◽  
Dependent Manner ◽  
Protein Coding ◽  
Controlled Systems ◽  
Expression Of Genes ◽  
Non Coding Rnas

: MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are proficient in regulating gene expression post-transcriptionally. Considering the recent trend in exploiting non-coding RNAs (ncRNAs) as cancer therapeutics, the potential use of miRNAs and lncRNAs as biomarkers and novel therapeutic agents against angiogenesis is an important scientific aspect. An estimated 70% of the genome is actively transcribed, only 2% of which codes for known protein-coding genes. Long noncoding RNAs (lncRNAs) are a large and diverse class of RNAs > 200 nucleotides in length, and not translated into protein, and are of utmost importance and it governs the expression of genes in a temporal, spatial, and cell context-dependent manner. Angiogenesis is an essential process for organ morphogenesis and growth during development, and it is relevant during the repair of wounded tissue in adults. It is coordinated by an equilibrium of pro-and anti-angiogenic factors; nevertheless, when affected, it promotes several diseases, including breast cancer. Signaling pathways involved here are tightly controlled systems that regulate the appropriate timing of gene expression required for the differentiation of cells down a particular lineage essential for proper tissue development. Lately, scientific reports are indicating that ncRNAs, such as miRNAs, and lncRNAs, play critical roles in angiogenesis related to breast cancer. The specific roles of various miRNAs and lncRNAs in regulating angiogenesis in breast cancer, with particular focus on the downstream targets and signaling pathways regulated by these ncRNAs with molecular medicine perspective, are highlighted in this write-up.

scholarly journals Maximal STAT5-Induced Proliferation and Self-Renewal at Intermediate STAT5 Activity Levels

2008 ◽  
Vol 28 (21) ◽  
pp. 6668-6680 ◽  
Author(s):  
Albertus T. J. Wierenga ◽  
Edo Vellenga ◽  
Jan Jacob Schuringa
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Target Genes ◽  
Expression Patterns ◽  
Activity Levels ◽  
Dependent Manner ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

ABSTRACT The level of transcription factor activity critically regulates cell fate decisions, such as hematopoietic stem cell (HSC) self-renewal and differentiation. We introduced STAT5A transcriptional activity into human HSCs/progenitor cells in a dose-dependent manner by overexpression of a tamoxifen-inducible STAT5A(1*6)-estrogen receptor fusion protein. Induction of STAT5A activity in CD34+ cells resulted in impaired myelopoiesis and induction of erythropoiesis, which was most pronounced at the highest STAT5A transactivation levels. In contrast, intermediate STAT5A activity levels resulted in the most pronounced proliferative advantage of CD34+ cells. This coincided with increased cobblestone area-forming cell and long-term-culture-initiating cell frequencies, which were predominantly elevated at intermediate STAT5A activity levels but not at high STAT5A levels. Self-renewal of progenitors was addressed by serial replating of CFU, and only progenitors containing intermediate STAT5A activity levels contained self-renewal capacity. By extensive gene expression profiling we could identify gene expression patterns of STAT5 target genes that predominantly associated with a self-renewal and long-term expansion phenotype versus those that identified a predominant differentiation phenotype.

scholarly journals The TEA Transcription Factor Tec1 Confers Promoter-Specific Gene Regulation by Ste12-Dependent and -Independent Mechanisms

2010 ◽  
Vol 9 (4) ◽  
pp. 514-531 ◽  
Author(s):  
Barbara Heise ◽  
Julia van der Felden ◽  
Sandra Kern ◽  
Mario Malcher ◽  
Stefan Brückner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Target Genes ◽  
Specific Gene ◽  
Dependent Manner ◽  
A Genome ◽  
Regulated Gene Expression

ABSTRACT In Saccharomyces cerevisiae, the TEA transcription factor Tec1 is known to regulate target genes together with a second transcription factor, Ste12. Tec1-Ste12 complexes can activate transcription through Tec1 binding sites (TCSs), which can be further combined with Ste12 binding sites (PREs) for cooperative DNA binding. However, previous studies have hinted that Tec1 might regulate transcription also without Ste12. Here, we show that in vivo, physiological amounts of Tec1 are sufficient to stimulate TCS-mediated gene expression and transcription of the FLO11 gene in the absence of Ste12. In vitro, Tec1 is able to bind TCS elements with high affinity and specificity without Ste12. Furthermore, Tec1 contains a C-terminal transcriptional activation domain that confers Ste12-independent activation of TCS-regulated gene expression. On a genome-wide scale, we identified 302 Tec1 target genes that constitute two distinct classes. A first class of 254 genes is regulated by Tec1 in a Ste12-dependent manner and is enriched for genes that are bound by Tec1 and Ste12 in vivo. In contrast, a second class of 48 genes can be regulated by Tec1 independently of Ste12 and is enriched for genes that are bound by the stress transcription factors Yap6, Nrg1, Cin5, Skn7, Hsf1, and Msn4. Finally, we find that combinatorial control by Tec1-Ste12 complexes stabilizes Tec1 against degradation. Our study suggests that Tec1 is able to regulate TCS-mediated gene expression by Ste12-dependent and Ste12-independent mechanisms that enable promoter-specific transcriptional control.

scholarly journals Candidate cancer driver mutations in superenhancers and long-range chromatin interaction networks

2017 ◽  
Author(s):  
Lina Wadi ◽  
Liis Uusküla-Reimand ◽  
Keren Isaev ◽  
Shimin Shuai ◽  
Vincent Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Target Genes ◽  
Tumor Biology ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Driver Mutations ◽  
Regulatory Regions ◽  
Protein Coding ◽  
Primary Tumors

AbstractA comprehensive catalogue of the mutations that drive tumorigenesis and progression is essential to understanding tumor biology and developing therapies. Protein-coding driver mutations have been well-characterized by large exome-sequencing studies, however many tumors have no mutations in protein-coding driver genes. Non-coding mutations are thought to explain many of these cases, however few non-coding drivers besides TERT promoter are known. To fill this gap, we analyzed 150,000 cis-regulatory regions in 1,844 whole cancer genomes from the ICGC-TCGA PCAWG project. Using our new method, ActiveDriverWGS, we found 41 frequently mutated regulatory elements (FMREs) enriched in non-coding SNVs and indels (FDR<0.05) characterized by aging-associated mutation signatures and frequent structural variants. Most FMREs are distal from genes, reported here for the first time and also recovered by additional driver discovery methods. FMREs were enriched in super-enhancers, H3K27ac enhancer marks of primary tumors and long-range chromatin interactions, suggesting that the mutations drive cancer by distally controlling gene expression through threedimensional genome organization. In support of this hypothesis, the chromatin interaction network of FMREs and target genes revealed associations of mutations and differential gene expression of known and novel cancer genes (e.g., CNNB1IP1, RCC1), activation of immune response pathways and altered enhancer marks. Thus distal genomic regions may include additional, infrequently mutated drivers that act on target genes via chromatin loops. Our study is an important step towards finding such regulatory regions and deciphering the somatic mutation landscape of the non-coding genome.

Construction of Novel mRNA-miRNA-lncRNA Regulatory Networks Associated with Prognosis of HCV Related HCC

2021 ◽  
Author(s):  
YiQun Ma ◽  
LISHI SHAO ◽  
CHEN SHI ◽  
JIAPING WANG
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Gene Expression Omnibus ◽  
Functional Enrichment ◽  
Protein Protein Interaction ◽  
Cerna Network ◽  
Prognostic Relevance ◽  
Bioinformatics Databases ◽  
Geo Dataset

Abstract Background: Infection with hepatitis C virus (HCV) can cause hepatic fibrosis and cirrhosis, thereby significantly increasing the risk of HCC development. Many prior studies have shown that oncogenesis and cancer progression are governed by competing endogenous RNA (ceRNA) networks composed of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs. As such, we herein sought to identify and evaluate the prognostic relevance of novel ceRNA network related to HCC associated with HCV. Methods: Differentially expressed genes (DEGs) in the GSE140845 Gene Expression Omnibus (GEO) dataset were identified using NetworkAnalyst, and were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Gene, Genome (KEGG) pathway, and Reactome analyses. In addition, a protein-protein interaction (PPI) network was generated, and key hub genes were detected. Hub gene expression levels, as well as those of their upstream lncRNAs and miRNAs and associated survival analyses were conducted using appropriate bioinformatics databases. Predicted target relationships were additionally used to establish putative ceRNA networks for HCV-related HCC. Results: 372 and 360 upregulated and downregulated significant DEGs were identified, respectively. Functional enrichment analyses suggested that DE-mRNAs were associated with nuclear division, the cell cycle, and ATPase activity. The top 11 genes with the greatest degree of connectivity among these DE-mRNAs were selected for subsequent prognostic evaluation. The differential expression of six of these candidate mRNAs (BUB1, BUB1B, CDC20, CDC45, CDK1, NDC80) in liver tissue was validated. After further analyses of the expression and prognostic relevance of the miRNAs and lncRNAs predicted to lie upstream of these DE-mRNAs, we identified 22 miRNAs and 4 lncRNAs significantly associated with poorer-HCV-related HCC prognosis. By combining the results of these analyses, we also identified the BUB1-hsa-miR-193a-3p-MALAT1 ceRNA sub-network as being related to the survival of these patients. Conclusion: This study providing novel insights into the mRNA-miRNA-lncRNA ceRNA network and reveals potential lncRNA biomarkers in HCV related HCC.

scholarly journals Regulation of Breast Cancer and Bone Metastasis by MicroRNAs

2013 ◽  
Vol 35 ◽  
pp. 369-387 ◽  
Author(s):  
S. Vimalraj ◽  
P. J. Miranda ◽  
B. Ramyakrishna ◽  
N. Selvamurugan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Bone Metastasis ◽  
Cancer Progression ◽  
Human Breast ◽  
Protein Coding ◽  
Regulate Gene Expression ◽  
Complex Process ◽  
And Function

Breast cancer progression including bone metastasis is a complex process involving numerous changes in gene expression and function. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs posttranscriptionally, often affecting a number of gene targets simultaneously. Alteration in expression of miRNAs is common in human breast cancer, possessing with either oncogenic or tumor suppressive activity. The expression and the functional role of several miRNAs (miR-206, miR-31, miR-27a/b, miR-21, miR-92a, miR-205, miR-125a/b, miR-10b, miR-155, miR-146a/b, miR-335, miR-204, miR-211, miR-7, miR-22, miR-126, and miR-17) in breast cancer has been identified. In this review we summarize the experimentally validated targets of up- and downregulated miRNAs and their regulation in breast cancer and bone metastasis for diagnostic and therapeutic purposes.

scholarly journals Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingyi Chen ◽  
Yuxuan Song ◽  
Mei Li ◽  
Yu Zhang ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Target Genes ◽  
Immune Cell ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cerna Network

Abstract Background Competing endogenous RNA (ceRNA) represents a class of RNAs (e.g., long noncoding RNAs [lncRNAs]) with microRNA (miRNA) binding sites, which can competitively bind miRNA and inhibit its regulation of target genes. Increasing evidence has underscored the involvement of dysregulated ceRNA networks in the occurrence and progression of colorectal cancer (CRC). The purpose of this study was to construct a ceRNA network related to the prognosis of CRC and further explore the potential mechanisms that affect this prognosis. Methods RNA-Seq and miRNA-Seq data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed lncRNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs), and a prognosis-related ceRNA network was constructed based on DElncRNA survival analysis. Subsequently, pathway enrichment, Pearson correlation, and Gene Set Enrichment Analysis (GSEA) were performed to determine the function of the genes in the ceRNA network. Gene Expression Profiling Interactive Analysis (GEPIA) and immunohistochemistry (IHC) were also used to validate differential gene expression. Finally, the correlation between lncRNA and immune cell infiltration in the tumor microenvironment was evaluated based on the CIBERSORT algorithm. Results A prognostic ceRNA network was constructed with eleven key survival-related DElncRNAs (MIR4435-2HG, NKILA, AFAP1-AS1, ELFN1-AS1, AC005520.2, AC245884.8, AL354836.1, AL355987.4, AL591845.1, LINC02038, and AC104823.1), 54 DEmiRNAs, and 308 DEmRNAs. The MIR4435-2HG- and ELFN1-AS1-associated ceRNA subnetworks affected and regulated the expression of the COL5A2, LOX, OSBPL3, PLAU, VCAN, SRM, and E2F1 target genes and were found to be related to prognosis and tumor-infiltrating immune cell types. Conclusions MIR4435-2HG and ELFN1-AS1 are associated with prognosis and tumor-infiltrating immune cell types and could represent potential prognostic biomarkers or therapeutic targets in colorectal carcinoma.

scholarly journals VDR/RXR and TCF4/β-Catenin Cistromes in Colonic Cells of Colorectal Tumor Origin: Impact on c-FOS and c-MYC Gene Expression

2012 ◽  
Vol 26 (1) ◽  
pp. 37-51 ◽  
Author(s):  
Mark B. Meyer ◽  
Paul D. Goetsch ◽  
J. Wesley Pike
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Target Genes ◽  
Direct Action ◽  
Transcriptional Start Site ◽  
Dependent Manner ◽  
Distal Enhancer ◽  
Dihydroxyvitamin D3 ◽  
Regulatory Complex ◽  
Myc Gene

Abstract Many of the transcriptional and growth regulating activities of 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in the intestine and colon are recapitulated in the human colorectal cancer cell LS180. We therefore used this line together with chromatin immunoprecipitation-seq and gene expression analyses to identify the vitamin D receptor (VDR)/retinoid X receptor (RXR) and transcription factor 7-like 2 (TCF7L2/TCF4)/β-catenin cistromes and the genes that they regulate. VDR and RXR colocalized to predominantly promoter distal, vitamin D response element-containing sites in a largely ligand-dependent manner. These regulatory sites control the expression of both known as well as novel 1,25-(OH)2D3 target genes. TCF4 and β-catenin cistromes partially overlapped, contained TCF/lymphoid enhancer-binding factor consensus elements, and were only modestly influenced by 1,25-(OH)2D3. However, the two heterodimer complexes colocalized at sites near a limited set of genes that included c-FOS and c-MYC; the expression of both genes was modulated by 1,25-(OH)2D3. At the c-FOS gene, both VDR/RXR and TCF4/β-catenin bound to a single distal enhancer located 24 kb upstream of the transcriptional start site. At the c-MYC locus, however, binding was noted at a cluster of sites between −139 and −165 kb and at a site located −335 kb upstream. Examined as isolated enhancer fragments, these regions exhibited basal and 1,25-(OH)2D3-inducible activities that were interlinked to both VDR and β-catenin activation. These data reveal additional complexity in the regulation of target genes by 1,25-(OH)2D3 and support a direct action of both VDR and the TCF4/β-catenin regulatory complex at c-FOS and c-MYC.

scholarly journals MINDY1 promotes bladder cancer progression by stabilizing YAP

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yongwen Luo ◽  
Jun Zhou ◽  
Jianing Tang ◽  
Fengfang Zhou ◽  
Zhiwen He ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Tumor Model ◽  
Dependent Manner ◽  
Interaction Domain ◽  
Bona Fide ◽  
The Hippo Pathway

Abstract Background Bladder cancer is one of the most commonly diagnosed urological malignant tumor. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in bladder cancer remains to be characterized. Methods Western blot was used to measure the expression of MINDY1 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect the cell viability. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between MINDY1 and YAP. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results In the present study, we identified MINDY1, a DUB enzyme in the motif interacting with ubiquitin-containing novel DUB family, as a bona fide deubiquitylase of YAP in bladder cancer. MINDY1 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. MINDY1 depletion significantly decreased bladder cancer cell proliferation. The effects induced by MINDY1 depletion could be rescued by further YAP overexpression. Depletion of MINDY1 decreased the YAP protein level and the expression of YAP/TEAD target genes in bladder cancer, including CTGF, ANKRD1 and CYR61. Conclusion In general, our findings establish a previously undocumented catalytic role for MINDY1 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of bladder cancer.

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