scholarly journals The Detection and Bioinformatic Analysis of Alternative 3′ UTR Isoforms as Potential Cancer Biomarkers

2021 ◽  
Vol 22 (10) ◽  
pp. 5322
Author(s):  
Nitika Kandhari ◽  
Calvin A. Kraupner-Taylor ◽  
Paul F. Harrison ◽  
David R. Powell ◽  
Traude H. Beilharz
Keyword(s):  
Gene Expression ◽  
Cell Transformation ◽  
Alternative Polyadenylation ◽  
Cancer Biomarkers ◽  
Bioinformatic Analysis ◽  
Alternative Transcript ◽  
Clinical Parameters ◽  
Transcript Cleavage ◽  
Cleavage And Polyadenylation ◽  
Potential Cancer

Alternative transcript cleavage and polyadenylation is linked to cancer cell transformation, proliferation and outcome. This has led researchers to develop methods to detect and bioinformatically analyse alternative polyadenylation as potential cancer biomarkers. If incorporated into standard prognostic measures such as gene expression and clinical parameters, these could advance cancer prognostic testing and possibly guide therapy. In this review, we focus on the existing methodologies, both experimental and computational, that have been applied to support the use of alternative polyadenylation as cancer biomarkers.

scholarly journals Precise gene models using long-read sequencing reveal a unique poly(A) signal in Giardia lamblia

2021 ◽  
Author(s):  
Danielle Y Bilodeau ◽  
Ryan M Sheridan ◽  
Balu Balan ◽  
Aaron R Jex ◽  
Olivia S Rissland
Keyword(s):  
Gene Expression ◽  
Protein Complex ◽  
Giardia Lamblia ◽  
Alternative Polyadenylation ◽  
Mrna Processing ◽  
Cleavage Sites ◽  
Nascent Transcript ◽  
Long Read ◽  
Show Evidence ◽  
Cleavage And Polyadenylation

During pre-mRNA processing, the poly(A) signal is recognized by a protein complex that ensures precise cleavage and polyadenylation of the nascent transcript. The location of this cleavage event establishes the length and sequence of the 3' UTR of an mRNA, thus determining much of its post-transcriptional fate. Here, using long-read sequencing, we characterize the polyadenylation signal and related sequences surrounding Giardia lamblia cleavage sites for over 2600 genes. We find that G. lamblia uses a AGURAA poly(A) signal, which differs from the mammalian AAUAAA. We also describe how G. lamblia lacks common auxiliary elements found in other eukaryotes, along with the proteins that recognize them. Further, we identify 133 genes that show evidence of alternative polyadenylation. These results suggest that despite pared down cleavage and polyadenylation machinery, 3' end formation still appears to be an important regulatory step for gene expression in G. lamblia.

scholarly journals Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 621
Author(s):  
Maria Grazia Muoio ◽  
Marianna Talia ◽  
Rosamaria Lappano ◽  
Andrew H. Sims ◽  
Veronica Vella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Bioinformatic Analysis ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Diabetic Patients ◽  
Obesity And Diabetes ◽  
Er Positive

Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.

Global expression analysis of ECL cells in Mastomys natalensis gastric mucosa identifies alterations in the AP-1 pathway induced by gastrin-mediated transformation

2004 ◽  
Vol 20 (1) ◽  
pp. 131-142 ◽  
Author(s):  
M. Kidd ◽  
T. Hinoue ◽  
G. Eick ◽  
K. D. Lye ◽  
S. M. Mane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Mucosa ◽  
Western Blot ◽  
Cell Transformation ◽  
Mastomys Natalensis ◽  
Rt Pcr ◽  
Cell Hyperplasia ◽  
Ecl Cells ◽  
Ecl Cell ◽  
Gene Expression Alterations

Enterochromaffin-like (ECL) cell hyperplasia and then irreversible neoplasia can be generated in the African rodent Mastomys natalensis using the H2 receptor blocker, loxtidine, for 8–16 wk. We used a GeneChip approach complemented by standard technologies to identify gene expression alterations in the gastric mucosa during gastrin-mediated ECL cell transformation. Gastric mucosa (mucosal scrapping) and ECL cell-enriched fractions were obtained from untreated Mastomys (controls) and from animals treated with loxtidine for 8 wk (hyperplasia). Tumor ECL cells were obtained by hand-dissection of gastric ECL cell nodules from animals treated with loxtidine for >16 wk and from a spontaneously developed ECL cell tumor. RNA was isolated, examined on rat U34A GeneChips, and comparison analysis was performed to identify altered gene expression. Alterations in gene expressions were examined further by immunohistochemistry, quantitative RT-PCR (Q-RT-PCR), sequencing and Western blot. GeneSpring analysis demonstrated alterations in few genes (<20) in hyperplastic and tumor mucosa. The histamine H1 receptor was consistently increased in proliferating mucosa. This gene change was confirmed by Q-RT-PCR. Other genes showing alterations included neural-(chromogranin A and somatostatin), cell-cycle-, and AP-1-associated genes. Immunostaining confirmed alterations in neural markers. Cluster analysis of ECL cell-enriched samples demonstrated that c- fos and junD were differently regulated. Q-RT-PCR and Western blot in prospectively collected gastric mucosal samples confirmed the differential expression of Fos and Jun. The negative regulators of AP-1, JunD, and Menin were decreased in tumor mucosa. A missense of unknown function was noted in the menin gene. Hypergastrinemia in an animal model of gastric carcinoids differentially altered the histamine type 1 receptor and gene expression and protein composition of AP-1. These results suggest that expression of this receptor and an altered composition of AP-1 with a loss of inhibition play a role in ECL cell transformation.

scholarly journals Human cell transformation by combined lineage conversion and oncogene expression

Oncogene ◽  
2021 ◽  
Author(s):  
Biswajyoti Sahu ◽  
Päivi Pihlajamaa ◽  
Kaiyang Zhang ◽  
Kimmo Palin ◽  
Saija Ahonen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Cancer ◽  
Human Cell ◽  
Genetic Disease ◽  
Cell Transformation ◽  
Human Fibroblasts ◽  
Driver Mutations ◽  
Primary Hepatocytes ◽  
Direct Support

AbstractCancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.

MAAPER: model-based analysis of alternative polyadenylation using 3' end-linked reads

2021 ◽  
Author(s):  
Wei Vivian Li ◽  
Dinghai Zheng ◽  
Ruijia Wang ◽  
Bin Tian
Keyword(s):  
Single Cell ◽  
Robust Statistics ◽  
Single Cell Analysis ◽  
Alternative Polyadenylation ◽  
Computational Method ◽  
Model Based ◽  
Eukaryotic Genes ◽  
Counting Strategy ◽  
Cleavage And Polyadenylation ◽  
Model Based Analysis

Most eukaryotic genes harbor multiple cleavage and polyadenylation sites (PASs), leading to expression of alternative polyadenylation (APA) isoforms. APA regulation has been implicated in a diverse array of physiological and pathological conditions. While RNA sequencing tools that generate reads containing the PAS, named onSite reads, have been instrumental in identifying PASs, they have not been widely used. By contrast, a growing number of methods generate reads that are close to the PAS, named nearSite reads, including the 3' end counting strategy commonly used in single cell analysis. How these nearSite reads can be used for APA analysis, however, is poorly studied. Here, we present a computational method, named model-based analysis of alternative polyadenylation using 3' end-linked reads (MAAPER), to examine APA using nearSite reads. MAAPER uses a probabilistic model to predict PASs for nearSite reads with high accuracy and sensitivity, and examines different types of APA events, including those in 3'UTRs and introns, with robust statistics. We show MAAPER's accuracy with data from both bulk and single cell RNA samples and its applicability in unpaired or paired experimental designs. Our result also highlights the importance of using well annotated PASs for nearSite read analysis.

Abstract 117: MicroRNA-138 regulates S100A1 in Endothelial Cells

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Anagha Sen ◽  
Shumei Ren ◽  
Jianxin Sun ◽  
Patrick Most ◽  
Karsten Peppel
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Reporter Gene ◽  
Recombinant Adenovirus ◽  
Limb Ischemia ◽  
Bioinformatic Analysis ◽  
Reporter Gene Expression ◽  
Luciferase Reporter ◽  
C2c12 Myotubes ◽  
Luciferase Reporter Construct

Rationale: The EF-hand Ca2+ sensor S100A1 is essential for proper endothelial nitric oxide (NO) synthase (eNOS) activation. S100A1 levels are greatly reduced in endothelial cells (ECs) subjected to hypoxia, rendering them dysfunctional. Objective: To determine if the 3’UTR mediates the rapid hypoxia-induced downregulation of S100A1 in ECs. Methods and Results: ECs transfected with a S100A1 - 3’ untranslated region (UTR) luciferase reporter construct displayed significantly reduced gene expression when subjected to gas or chemical hypoxia. Bioinformatic analysis suggested that microRNA -138 (miR-138) could target the 3’UTR of S100A1. Hypoxia greatly increased miR-138 levels in ECs, but not in skeletal muscle C2C12 myotubes. Consistent with this finding, patients with critical limb ischemia (CLI) or mice subjected to femoral artery resection (FAR) displayed increased miR-138 levels. Transfection of a miR-138 mimic into ECs reduced S100A1 - 3 ‘UTR reporter gene expression, while transfection of an anti miR-138 (antagomir) prevented the hypoxia-induced downregulation of the reporter gene. The increased levels of miR-138 are dependent on Hif1-α activation as treatment with siRNA against Hif1-α prevented S100A1 reporter gene downregulation after hypoxia. Conversely, specific activation of Hif1-α by a selective prolyl-hydroxylase inhibitor (IOX2) reduced reporter gene expression. Finally, ECs transfected with miR-138 mimic displayed reduced tube formation when plated onto Matrigel matrix and expressed less NO when stimulated with VEGF. These effects were reversed by gene transfer of S100A1 using recombinant adenovirus. Conclusions: Our study shows that miR-138 is an essential mediator of EC dysfunction via its ability to target the 3’UTR of S100A1 in a hypoxia-induced manner. MiR-138 might thus be an attractive target for the treatment of pathologies that are linked to endothelial dysfunction.

Systematic pan-cancer characterization of nuclear receptors identifies potential cancer biomarkers and therapeutic targets

2021 ◽  
pp. canres.3458.2020
Author(s):  
Junjie Jiang ◽  
Jiao Yuan ◽  
Zhongyi Hu ◽  
Mu Xu ◽  
Youyou Zhang ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Therapeutic Targets ◽  
Cancer Biomarkers ◽  
Pan Cancer ◽  
Potential Cancer

Alternative translation and alternative RNA processing mechanism in parvovirus RNA processing

2014 ◽  
Author(s):  
◽  
Olufemi Fasina
Keyword(s):  
Gene Expression ◽  
Rna Processing ◽  
Viral Genome ◽  
Transcription Initiation ◽  
Alternative Polyadenylation ◽  
Open Reading Frames ◽  
Genome Replication ◽  
University Of Missouri ◽  
Diverse Range ◽  
Viral Genome Replication

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Viruses as obligate intracellular metabolic parasite require the capacity to orchestrate and modulate the host environment either in the nucleus or cytoplasm for their efficient reproductive life cycle. This warrants the use of diverse range of proteins expressed from the viral genome with the ability of regulating viral genome replication, transcription and translation, in addition antagonizing host factors inhibitory to the virus. Therefore, in order to achieve these goals, viruses utilizes gene expression strategies to expand their coding capacity. Gene expression mechanism such as transcription initiation, capping, splicing and 3�-end processing afford viruses the opportunities to utilize the eukaryotic metabolic machineries for generating proteome diversity. Parvoviruses and other DNA viruses effectively capitalize on their use of nuclear eukaryotic metabolic machineries to co-opt host cell factors for optimal replication and gene expression. Parvoviruses with small genome size and overlapping open reading frames utilize alternative transcription initiation, alternative splicing and alternative polyadenylation to co-ordinate the expression of its non-structural and structural proteins. In this work, we have characterized how two parvoviruses; Dependovirus AAV5 and Bocavirus Minute virus of canine (MVC) utilize alternative gene expression mechanisms and strategies to optimize expression of viral proteins from their genome.

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