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Skipping Exon-v6 from CD44v6-Containing Isoforms Influences Chemotherapy Response and Self-Renewal Capacity of Gastric Cancer Cells

by 1,2,†, 1,2,3,†, 1,2,4 and 1,2,4,*
1
i3s–Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal
2
IPATIMUP–Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
3
Doctoral Programme in Biomedicine, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal
4
FMUP–Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(9), 2378; https://doi.org/10.3390/cancers12092378
Received: 3 July 2020 / Revised: 13 August 2020 / Accepted: 18 August 2020 / Published: 22 August 2020
(This article belongs to the Section Molecular Cancer Biology)
De novo expressed CD44 isoforms containing exon-v6 are frequently associated with gastric cancer (GC) aggressiveness, and may predict chemotherapy response in vitro. Whether exon-v6 itself is responsible for conferring these properties to CD44v6-containing isoforms remains to be elucidated. CRISPR/Cas9 and Phosphorodiamidate Morpholino oligomers (PMOs) were used to induce specific exon-v6 skipping, maintaining the CD44 reading frame, in two GC cell lines endogenously expressing CD44v6. Cisplatin and 5-fluorouracil treatment response, and self-renewal ability was compared between CRISPR/Cas9-edited, CD44v6 knockdown and mock cells. We obtained homozygous genome-edited cell lines with exon-v6 deletion. Edited cells transcribed CD44v isoforms presenting in frame v5–v7 splicing, mimicking exon-v6 skipping. Results showed that removing specifically exon-v6 sensitizes cells to cisplatin and impairs cells’ self-renewal ability, similarly to CD44v6 knockdown. In parallel, we also tested a clinically feasible approach for transient exon-v6 skipping with a PMO-based strategy. We demonstrate that exon-v6 specific removal from CD44v isoforms increases cell sensitivity to cisplatin and impairs GC cells self-renewal. We trust that a PMO approach designed towards CD44v6 overexpressing GC cells may be a suitable approach to sensitize tumor cells for conventional therapy. View Full-Text
Keywords: CRISPR/Cas9; chemoresistance; exon skipping; morpholinos; cell survival; stomach neoplasms CRISPR/Cas9; chemoresistance; exon skipping; morpholinos; cell survival; stomach neoplasms
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MDPI and ACS Style

Lobo, S.; Pereira, C.; Oliveira, C.; Almeida, G.M. Skipping Exon-v6 from CD44v6-Containing Isoforms Influences Chemotherapy Response and Self-Renewal Capacity of Gastric Cancer Cells. Cancers 2020, 12, 2378. https://doi.org/10.3390/cancers12092378

AMA Style

Lobo S, Pereira C, Oliveira C, Almeida GM. Skipping Exon-v6 from CD44v6-Containing Isoforms Influences Chemotherapy Response and Self-Renewal Capacity of Gastric Cancer Cells. Cancers. 2020; 12(9):2378. https://doi.org/10.3390/cancers12092378

Chicago/Turabian Style

Lobo, Silvana, Carla Pereira, Carla Oliveira, and Gabriela M. Almeida 2020. "Skipping Exon-v6 from CD44v6-Containing Isoforms Influences Chemotherapy Response and Self-Renewal Capacity of Gastric Cancer Cells" Cancers 12, no. 9: 2378. https://doi.org/10.3390/cancers12092378

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