Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
08 Jul 2024
08 Jul 2024
Historique:
received:
05
09
2023
accepted:
30
05
2024
revised:
03
05
2024
medline:
9
7
2024
pubmed:
9
7
2024
entrez:
8
7
2024
Statut:
aheadofprint
Résumé
The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol, termed the Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual development of severe hypoxia seen in vivo to mimic conditions observed in primary tumors. Cells subjected to LTHY underwent a non-canonical epithelial to mesenchymal transition (EMT) based on miRNA and mRNA signatures as well as displayed EMT-like morphological changes. Concomitant to this, we report production of a novel truncated isoform of WT1 transcription factor (tWt1), a non-canonical EMT driver, with expression driven by a yet undescribed intronic promoter through hypoxia-responsive elements (HREs). We further demonstrated that tWt1 initiates translation from an intron-derived start codon, retains proper subcellular localization and DNA binding. A similar tWt1 is also expressed in LTHY-cultured human cancer cell lines as well as primary cancers and predicts long-term patient survival. Our study not only demonstrates the importance of culture conditions that better mimic those observed in primary cancers, especially with regards to hypoxia, but also identifies a novel isoform of WT1 which correlates with poor long-term survival in ovarian cancer.
Identifiants
pubmed: 38977895
doi: 10.1038/s41417-024-00795-3
pii: 10.1038/s41417-024-00795-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : MOP133726
Organisme : Cancer Research Society (Société de Recherche sur le Cancer)
ID : 20464
Organisme : Cancer Research Society (Société de Recherche sur le Cancer)
ID : 20464
Informations de copyright
© 2024. The Author(s).
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