Morpholino-mediated splice switching of NELFE suppresses hepatocellular carcinoma cell phenotypes in vitro and in vivo
Year: 2026
Type: article
Abstract: exon 10 and identifies patients with a trend toward longer recurrence-free survival and lower NELFE expression in their tumors. Mechanistically, the variant reduces U2AF2 occupancy at intron 9, likely through an indirect effect on splice-site recognition rather than direct disruption of U2AF2 binding. Recognizing exon 10 as a targetable splice event, we designed morpholino (MO) antisense oligonucleotides against its splice junctions that phenocopied the variant, lowering NELFE protein expression and impairing malignant phenotypes across HCC cell lines spanning diverse etiologies and NELFE expression levels. Delivered by ultrasound-targeted microbubble destruction (UTMD) in orthotopic liver tumors, NELFE MOs significantly reduced tumor burden and extended survival. These findings establish a naturally occurring splicing event as the basis for a localized, splice-switching therapeutic strategy for HCC.
Authors: Laura M. Reynolds, Ryan Lamm, Kai Zhang, Anna E. Barry-Wolbers, Alvaro Lucci, Brittany N. Ruiz, Corinne E. Wessner, Trish Nguyen, Kayla M. Hammond, Christoph Eckert, Ji-Bin Liu, Pongsakorn Choochuen, Kai Ying Hong, Wei Jiang, Marshonna Forgues, Gaia M. Palazzo, Daniel Lin, Adam S. Bodzin, Ashesh P. Shah, Xin Wei Wang, Sean P. Martin, Nicolas L. Fawzi, Matthias M. Gaida, John R. Eisenbrey, Hien Dang
Institutions: Thomas Jefferson University, University Medical Center of the Johannes Gutenberg University Mainz, Translationale Onkologie an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz, National Cancer Institute, Center for Cancer Research, Pennsylvania State University, Brown University
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,900
OpenAlex ID: W7215107835