Antisense transcription from lentiviral gene targeting linked to an integrated stress response in colorectal cancer cells.
MT: Oligonucleotides
Therapies and Applications
antisense reads
colorectal cancer
ephrinB2
gene therapy
integrated stress response
lentiviral vector
shRNA
vector integration
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
14 Jun 2022
14 Jun 2022
Historique:
received:
03
02
2022
accepted:
12
05
2022
entrez:
13
6
2022
pubmed:
14
6
2022
medline:
14
6
2022
Statut:
epublish
Résumé
Advances in gene therapy research have resulted in the successful development of new therapies for clinical use. Here, we explored a gene targeting approach to deplete ephrinB2 from colorectal cancer cells using an inducible lentiviral vector. EphrinB2, a transmembrane ephrin ligand, promotes colorectal cancer cell growth and viability and predicts poor patient survival when expressed at high levels in colorectal cancer tissues. We discovered that lentiviral vector integration and expression in the host DNA frequently drive divergent host gene transcription, generating antisense reads coupled with splicing events and generation of chimeric vector/host transcripts. Antisense transcription of host DNA was linked to development of an integrated stress response and cell death. Despite recent successes, off-target effects remain a concern in genetic medicine. Our results provide evidence that divergent gene transcription is a previously unrecognized off-target effect of lentiviral vector integration with built-in properties for regulation of gene expression.
Identifiants
pubmed: 35694213
doi: 10.1016/j.omtn.2022.05.029
pii: S2162-2531(22)00142-1
pmc: PMC9163427
doi:
Types de publication
Journal Article
Langues
eng
Pagination
877-891Déclaration de conflit d'intérêts
All authors declare no competing interests.
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