scholarly journals A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation

2018 ◽  
Vol 29 (14) ◽  
pp. 1682-1692 ◽  
Author(s):  
Marc A. Vittoria ◽  
Elizabeth M. Shenk ◽  
Kevin P. O’Rourke ◽  
Amanda F. Bolgioni ◽  
Sanghee Lim ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Proliferative Capacity ◽  
Tetraploid Cell ◽  
Genome Doubling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Studies

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, nontransformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-of-function genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

scholarly journals A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation

2018 ◽  
Author(s):  
Marc A. Vittoria ◽  
Elizabeth M. Shenk ◽  
Kevin P. O’Rourke ◽  
Amanda F. Bolgioni ◽  
Sanghee Lim ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Proliferative Capacity ◽  
Tetraploid Cell ◽  
Genome Doubling ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Studies

AbstractTetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these anti-proliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive, gain-of-function genome-wide screen to identify miRNAs that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g. miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g. miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via downregulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

scholarly journals Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (8) ◽  
pp. 3937
Author(s):  
Colin F. Davenport ◽  
Tobias Scheithauer ◽  
Alessia Dunst ◽  
Frauke Sophie Bahr ◽  
Marie Dorda ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Nanopore Sequencing ◽  
Sequencing Technology ◽  
Suppressor Genes ◽  
Genome Wide ◽  
A Genome

Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, we mapped 5-methylcytosine signal at a genome-wide scale using nanopore sequencing technology to identify novel TSGs. Integration of methylation data with gene transcription profile of regenerated liver and primary HCCs allowed us to identify 10 potential tumor suppressor gene candidates. Subsequent validation led us to focus on functionally characterizing one candidate—glucokinase (GCK). We show here that overexpression of GCK inhibits the proliferation of HCC cells via induction of intracellular lactate accumulation and subsequently causes energy crisis due to NAD+ depletion. This suggests GCK functions as a tumor suppressor gene and may be involved in HCC development. In conclusion, these data provide valuable clues for further investigations of the process of tumorigenesis in human cancer.

scholarly journals Genome-Wide CRISPR Screening Identifies the Tumor Suppressor Candidate OVCA2 As a Determinant of Tolerance to Acetaldehyde

2019 ◽  
Vol 169 (1) ◽  
pp. 235-245 ◽  
Author(s):  
Amin Sobh ◽  
Alex Loguinov ◽  
Alessia Stornetta ◽  
Silvia Balbo ◽  
Abderrahmane Tagmount ◽  
...  
Keyword(s):  
Dna Repair ◽  
Tumor Suppressor ◽  
K562 Cells ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Genome Wide ◽  
A Genome ◽  
Cellular Sensitivity ◽  
Genes Encoding ◽  
Increased Sensitivity

Abstract Acetaldehyde, a metabolite of ethanol, is a cellular toxicant and a human carcinogen. A genome-wide CRISPR-based loss-of-function screen in erythroleukemic K562 cells revealed candidate genetic contributors affecting acetaldehyde cytotoxicity. Secondary screening exposing cells to a lower acetaldehyde dose simultaneously validated multiple candidate genes whose loss results in increased sensitivity to acetaldehyde. Disruption of genes encoding components of various DNA repair pathways increased cellular sensitivity to acetaldehyde. Unexpectedly, the tumor suppressor gene OVCA2, whose function is unknown, was identified in our screen as a determinant of acetaldehyde tolerance. Disruption of the OVCA2 gene resulted in increased acetaldehyde sensitivity and higher accumulation of the acetaldehyde-derived DNA adduct N2-ethylidene-dG. Together these results are consistent with a role for OVCA2 in adduct removal and/or DNA repair.

Genetic Events Responsible for Colorectal Tumorigenesis: Achievements and Challenges

1993 ◽  
Vol 79 (4) ◽  
pp. 235-243 ◽  
Author(s):  
Boris Kopnin
Keyword(s):  
Tumor Suppressor ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Colorectal Carcinogenesis ◽  
Genetic Changes ◽  
Colorectal Tumorigenesis ◽  
Ras Genes ◽  
Carcinoma Cell Lines ◽  
Kinase C ◽  
Multistep Process

Colorectal carcinogenesis is a multistep process that is accompanied by accumulation of changes in proto-oncogenes and tumor-suppressor genes. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes, as well as other genomic alterations appear at characteristic stages of tumor development and are observed in most neoplasms. However, consideration of each of these abnormalities leaves many unanswered questions. The striking data on recurrent amplification of the RB tumor-suppressor gene as well as suppressive activities of protein kinase C and activated RAS genes, at least in some colon carcinoma cell lines, suggest the unusual effects of some signalling pathways in colonic epithelial cells. The results obtained to date indicate that distinct sets of genetic changes may underlie the development of colorectal tumors.

scholarly journals The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0145792 ◽  
Author(s):  
Wendy M. McKimpson ◽  
Ziqiang Yuan ◽  
Min Zheng ◽  
Judy S. Crabtree ◽  
Steven K. Libutti ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Tissue Specific ◽  
Specific Manner

An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

2008 ◽  
Vol 68 (23) ◽  
pp. 9945-9953 ◽  
Author(s):  
Paul N. Kongkham ◽  
Paul A. Northcott ◽  
Young Shin Ra ◽  
Yukiko Nakahara ◽  
Todd G. Mainprize ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Pediatric Medulloblastoma ◽  
Genome Wide

scholarly journals Integrated Genome Wide Association Study (GWAS) Identifies SNPs Associated with Outcome in Pediatric AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2758-2758
Author(s):  
Abdelrahman H Elsayed ◽  
Huiyun Wu ◽  
Xueyuan Cao ◽  
Soheil Meshinchi ◽  
Raul Ribeiro ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Solid Tumors ◽  
Rna Binding ◽  
Prognostic Significance ◽  
Integrated Analysis ◽  
Call Rate ◽  
Multiple Snps ◽  
Genome Wide ◽  
A Genome ◽  
Pediatric Aml

Abstract Acute myeloid leukemia (AML) treatment response remains poorly understood. Although multiple studies have focused on understanding the transcriptomic and epigenetic landscape of AML, a genome-wide analysis of SNPs in pediatric AML has not yet been investigated in depth. Thus, we sought to identify genetic variants predictive of AML response, relapse, and survival in pediatric AML patients. For this study, we generated genome-wide SNP data patients (n=160) treated on the multicenter AML02 clinical trial (ClinicalTrials.gov Identifier: NCT00136084) using Infinium Omni 2.5M Exome Beadchip. Standard GWAS QC procedure was followed in order to remove SNPs with call rate < 95%, monomorphic SNPs, SNPs with MAF<5% and samples with call rate<95%. Following QC, a risk-adjusted multi-outcome integrative GWAS was performed to identify SNPs associated with minimal residual disease (MRD) following induction I, relapse-free survival (RFS) and overall survival (OS). We performed a risk-adjusted analysis to identify 21 SNPs mapping to 14 genes at an endpoint-integrative p value <2x10-5. Table 1 provides list of genes with SNPs significantly associated with MRD, RFS, OS as well as in the integrated analysis at <2x10-5. Of interest multiple SNPs in DICER1, which is a key enzyme required for the biogenesis of microRNAs and small interfering RNAs were significantly associated with clinical outcome with promise integrated analysis at p = 0.000011, supported by associations with MRD, RFS and OS at p <0.002 (Figure 1A). DICER1 is over-expressed in AML with its expression under the influence of hematopoietic transcript factor, GATA1. RAI14, a retinoic acid induced 14 is a prognostic marker of poor response in solid tumors and has been associated with development of drug resistance. Multiple SNPs in RAI14 were significantly associated with clinical endpoints. Figure 1B shows RAI14 SNP rs336474 with C allele significantly associated with better RFS (p= 0.027) and OS (p=0.007), with an integrated p= 0.000004. SNP in upstream of RBFOX1, a RNA binding fox-1 homolog 1 and within intron of GRIN2A, glutamate ionotropic receptor NMDA type subunit 2A were significantly associated with MRD, RFS and OS (all p<0.005) and integrated p =0.00001 (Figure 1C). SNPs within genes involved in pyrimidine metabolism such as UPP2, a uridine phosphorylase; tumor suppressor genes such as JPH3, which codes for junctophilin; LILRB4 which encodes for a Leukocyte Immunoglobulin Like Receptor B4, that regulates inflammatory responses and cytotoxicity; HACE1 a potential tumor suppressor involved in the solid tumors pathophysiology; ANK2, an ankyrin family protein with role in cell proliferation and motility; BIRC8, which is implicated in CML disease progression etc. In conclusion, our results demonstrate significance of genome-wide investigation of SNPs to identify novel and clinically relevant SNPs of prognostic significance in childhood AML. We will present the in depth results of our integrated GWAS analysis as well as validation in independent patient cohorts. In summary, our results constitute one of the first integrated GWAS analyses to identify SNPs of prognostic significance in pediatric AML. Acknowledgments: We are thankful for funding from NIH R01-CA139246 and ALSAC. Disclosures No relevant conflicts of interest to declare.

scholarly journals A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene

2008 ◽  
Vol 22 (21) ◽  
pp. 2932-2940 ◽  
Author(s):  
S. Gobeil ◽  
X. Zhu ◽  
C. J. Doillon ◽  
M. R. Green
Keyword(s):  
Suppressor Gene ◽  
Metastasis Suppressor ◽  
Melanoma Metastasis ◽  
Metastasis Suppressor Gene ◽  
Genome Wide ◽  
A Genome ◽  
Shrna Screen
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