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Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Mari C Vázquez-Borrego1,2,3,4, Antonio C Fuentes-Fayos5,6,7,8, Eva Venegas-Moreno9

  • 1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain. z32vabom@uco.es.

Cancers
|September 29, 2019
PubMed

Insights

Altered splicing machinery is common in pituitary neuroendocrine tumors (PitNETs). Targeting SF3B1 with pladienolide-B reduced PitNET cell growth and hormone secretion, suggesting new diagnostic and therapeutic strategies.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Pituitary neuroendocrine tumors (PitNETs) represent a significant portion of brain tumors, often arising sporadically.
  • Aberrant alternative splicing is increasingly recognized as a hallmark of various tumor types.
  • The spliceosome, particularly SF3B1, is a promising therapeutic target, with inhibitors like pladienolide-B showing anti-tumor potential.

Purpose of the Study:

  • To investigate the expression of splicing-machinery components in 261 PitNETs across different subtypes.
  • To evaluate the therapeutic effect of pladienolide-B on PitNET cell proliferation, viability, and hormone secretion.
  • To identify potential diagnostic, prognostic, and therapeutic targets within the splicing machinery for PitNETs.

Main Methods:

  • Analysis of splicing-machinery component expression in 261 human PitNETs (somatotropinomas, non-functioning, corticotropinomas, prolactinomas) and normal pituitaries.
  • In vitro experiments using human PitNET cell cultures and pituitary cell lines (AtT-20/GH3) to assess pladienolide-B effects.
  • Assessment of cell proliferation, viability, and hormone secretion following pladienolide-B treatment.

Main Results:

  • Significant dysregulation of splicing-machinery components was observed in all PitNET subtypes compared to normal tissue.
  • A unique molecular signature of splicing components was identified, capable of distinguishing between normal and tumor tissues within each PitNET subtype.
  • Pladienolide-B treatment effectively reduced proliferation, viability, and hormone secretion in PitNET cell cultures and lines.

Conclusions:

  • The splicing machinery is drastically dysregulated in PitNETs, potentially contributing to tumorigenesis.
  • Splicing-machinery component expression profiles offer potential as diagnostic and prognostic biomarkers for PitNETs.
  • Targeting SF3B1 with pladienolide-B demonstrates therapeutic promise for PitNET treatment.
Keywords:
pituitary neuroendocrine tumorspladienolide-B.spliceosomesplicing

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