{
  "abstract": "Hepatocellular carcinoma (HCC) is among the deadliest cancers worldwide, with rising incidence and few targeted therapies, driving high rates of recurrence and poor survival. Negative elongation factor E (NELFE), an RNA-binding subunit of the NELF complex, acts oncogenically when overexpressed and is associated with worse prognosis in HCC, yet no therapies target it. Here, we identify a rare germline intronic variant in the NELFE locus, NM_002904.6:c.943-110C>T (rs79208225) that promotes skipping of NELFE 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.",
    "Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA.",
    "Institute of Pathology, University Medical Center Mainz, JGU-Mainz, 55131 Mainz, Germany.",
    "TRON, Translational Oncology at the University Medical Center, JGU-Mainz, 55131 Mainz, Germany.",
    "Department of Pathology and Genome Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.",
    "Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.",
    "Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.",
    "Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.",
    "Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.",
    "Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.",
    "Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 25,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Laura M Reynolds"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryan Lamm"
    },
    {
      "affs": [
        0
      ],
      "name": "Kai Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Anna E Barry-Wolbers"
    },
    {
      "affs": [
        0
      ],
      "name": "Alvaro Lucci"
    },
    {
      "affs": [
        0
      ],
      "name": "Brittany N Ruiz"
    },
    {
      "affs": [
        1
      ],
      "name": "Corinne E Wessner"
    },
    {
      "affs": [
        0
      ],
      "name": "Trish Nguyen"
    },
    {
      "affs": [
        0
      ],
      "name": "Kayla M Hammond"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Christoph Eckert"
    },
    {
      "affs": [
        1
      ],
      "name": "Ji-Bin Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Pongsakorn Choochuen"
    },
    {
      "affs": [
        0
      ],
      "name": "Kai Ying Hong"
    },
    {
      "affs": [
        4
      ],
      "name": "Wei Jiang"
    },
    {
      "affs": [
        5
      ],
      "name": "Marshonna Forgues"
    },
    {
      "affs": [
        0
      ],
      "name": "Gaia M Palazzo"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Daniel Lin"
    },
    {
      "affs": [
        0
      ],
      "name": "Adam S Bodzin"
    },
    {
      "affs": [
        0
      ],
      "name": "Ashesh P Shah"
    },
    {
      "affs": [
        5,
        8
      ],
      "name": "Xin Wei Wang"
    },
    {
      "affs": [
        9
      ],
      "name": "Sean P Martin"
    },
    {
      "affs": [
        10
      ],
      "name": "Nicolas L Fawzi"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Matthias M Gaida"
    },
    {
      "affs": [
        1
      ],
      "name": "John R Eisenbrey"
    },
    {
      "affs": [
        0,
        7
      ],
      "name": "Hien Dang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/17z8g7fpk8660.bib",
  "cited_by": 0,
  "doi": "10.1016/j.omtn.2026.103124",
  "fulltext_url": "https://europepmc.org/articles/PMC13694868",
  "id": "17z8g7fpk8660",
  "issns": [
    "2162-2531"
  ],
  "landing_url": "https://europepmc.org/article/MED/42927183",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|RNA Research and Splicing"
    ]
  ],
  "openalex": "W7215107835",
  "pdf_url": "https://europepmc.org/articles/PMC13694868?pdf=render",
  "pmcid": "PMC13694868",
  "pmid": "42927183",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/17z8g7fpk8660.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:18Z",
      "native_id": "MED:42927183",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42927183"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Research and Splicing",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Morpholino-mediated splice switching of NELFE suppresses hepatocellular carcinoma cell phenotypes in vitro and in vivo.",
  "title_text": "Morpholino-mediated splice switching of NELFE suppresses hepatocellular carcinoma cell phenotypes in vitro and in vivo.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:18Z",
  "url": "https://research.draconitic.com/paper/17z8g7fpk8660",
  "venue": "Molecular therapy. Nucleic acids",
  "versions": []
}