Molecular Oncology (Oct 2024)

Spliceosomic dysregulation in pancreatic cancer uncovers splicing factors PRPF8 and RBMX as novel candidate actionable targets

  • Emilia Alors‐Pérez,
  • Ricardo Blázquez‐Encinas,
  • María Trinidad Moreno‐Montilla,
  • Víctor García‐Vioque,
  • Juan Manuel Jiménez‐Vacas,
  • Andrea Mafficini,
  • Iranzu González‐Borja,
  • Claudio Luchini,
  • Juan M. Sánchez‐Hidalgo,
  • Marina E. Sánchez‐Frías,
  • Sergio Pedraza‐Arevalo,
  • Antonio Romero‐Ruiz,
  • Rita T. Lawlor,
  • Antonio Viúdez,
  • Manuel D. Gahete,
  • Aldo Scarpa,
  • Álvaro Arjona‐Sánchez,
  • Raúl M. Luque,
  • Alejandro Ibáñez‐Costa,
  • Justo P. Castaño

DOI
https://doi.org/10.1002/1878-0261.13658
Journal volume & issue
Vol. 18, no. 10
pp. 2524 – 2540

Abstract

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Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early‐diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre‐mRNA processing factor 8 (PRPF8) and RNA‐binding motif protein X‐linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non‐tumor levels and resulted in decreased key tumor‐related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets.

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