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Tytuł pozycji:

Tumorigenic effects of TLX overexpression in HEK 293T cells.

Tytuł:
Tumorigenic effects of TLX overexpression in HEK 293T cells.
Autorzy:
Parris TZ; Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Vizlin-Hodzic D; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Salmela S; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Funa K; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Źródło:
Cancer reports (Hoboken, N.J.) [Cancer Rep (Hoboken)] 2019 Oct; Vol. 2 (5), pp. e1204. Date of Electronic Publication: 2019 Jul 25.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Hoboken, NJ : John Wiley & Sons, Inc., [2018]-
MeSH Terms:
Genomic Instability*
Cell Transformation, Neoplastic/*genetics
Orphan Nuclear Receptors/*metabolism
Cell Proliferation/genetics ; Frameshift Mutation ; G1 Phase Cell Cycle Checkpoints/genetics ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Orphan Nuclear Receptors/genetics ; RNA-Seq ; Up-Regulation
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Contributed Indexing:
Keywords: NR2E1; TLX; cancer; genome instability; nuclear receptors
Substance Nomenclature:
0 (NR2E1 protein, human)
0 (Orphan Nuclear Receptors)
Entry Date(s):
Date Created: 20200729 Date Completed: 20211004 Latest Revision: 20211004
Update Code:
20240104
PubMed Central ID:
PMC7941458
DOI:
10.1002/cnr2.1204
PMID:
32721119
Czasopismo naukowe
Background: The human orphan receptor TLX (NR2E1) is a key regulator of neurogenesis, adult stem cell maintenance, and tumorigenesis. However, little is known about the genetic and transcriptomic events that occur following TLX overexpression in human cell lines.
Aims: Here, we used cytogenetics and RNA sequencing to investigate the effect of TLX overexpression with an inducible vector system in the HEK 293T cell line.
Methods and Results: Conventional spectral karyotyping was used to identify chromosomal abnormalities, followed by fluorescence in situ hybridization (FISH) analysis on chromosome spreads to assess TLX DNA copy number. Illumina paired-end whole transcriptome sequencing was then performed to characterize recurrent genetic variants (single nucleotide polymorphisms (SNPs) and indels), expressed gene fusions, and gene expression profiles. Lastly, flow cytometry was used to analyze cell cycle distribution. Intriguingly, we show that upon transfection with a vector containing the human TLX gene (eGFP-hTLX), an isochromosome forms on the long arm of chromosome 6, thereby resulting in DNA gain of the TLX locus (6q21) and upregulation of TLX. Induction of the eGFP-hTLX vector further increased TLX expression levels, leading to G0-G1 cell cycle arrest, genetic aberrations, modulation of gene expression patterns, and crosstalk with other nuclear receptors (AR, ESR1, ESR2, NR1H4, and NR3C2). We identified a 49-gene signature associated with central nervous system (CNS) development and carcinogenesis, in addition to potentially cancer-driving gene fusions (LARP1-CNOT8 and NSL1-ZDBF2) and deleterious genetic variants (frameshift insertions in the CTSH, DBF4, POSTN, and WDR78 genes).
Conclusion: Taken together, these findings illustrate that TLX may play a pivotal role in tumorigenesis via genomic instability and perturbation of cancer-related processes.
(© 2019 Wiley Periodicals, Inc.)

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