2. Academic Validation
  3. Coordinated expression of retained introns and poison exons in renal cell carcinoma

Coordinated expression of retained introns and poison exons in renal cell carcinoma

  • Cell Rep. 2025 Aug 26;44(8):115985. doi: 10.1016/j.celrep.2025.115985.
José C Martínez 1,  Mi Zhou 2,  Gilbert Giri 3,  Yi-Hsuan Tsai 2,  Meghan M Rowley 4,  Grant A Goda 5,  Maria M Aleman 6,  William Y Kim 7,  Daniel Dominguez 8
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Hematology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
  • 4 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 5 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA.
  • 6 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC, USA.
  • 7 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: wykim@med.unc.edu.
  • 8 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: didoming@email.unc.edu.
PMID: 40682778 DOI: 10.1016/j.celrep.2025.115985
Abstract

The regulation and impact of tumor-specific isoforms in Cancer is challenging to understand, with unclear links between oncogenic signaling and mRNA processing and decay. Using transcriptomic analyses and experimental validation, we demonstrate that clear cell renal cell carcinoma (ccRCC) tumors exhibit coordinated intron retention (IR) and poison exon (PE) inclusion, generating transcripts targeted by nonsense-mediated decay (NMD). ccRCC tumors segregate into two subtypes based on IR: tumors with low IR levels and those with high IR levels, the latter associated with aggressive clinical features and poorer survival. We identify mammalian target of rapamycin (mTOR) signaling as a key modulator of IR and PE inclusion, showing mTOR inhibition significantly increases NMD-targeted isoforms, linking mTOR signaling with RNA surveillance pathways. Additionally, tumors with high IR levels exhibit increased T cell infiltration signatures. Collectively, these findings reveal a mechanism by which aggressive ccRCC tumors sustain aberrant RNA isoforms, offering insights for biomarker and therapeutic development.

Keywords

CP: Cancer; CP: Genomics; cancer genomics; clear cell renal cell carcinoma; immunotherapy; intron retention; mTOR; nonsense-mediated decay; poison exons.

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