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miR-15a/miR-16-1 expression inversely correlates with cyclin D1 levels in Men1 pituitary NETs

Kate E Lines1, Paul J Newey2, Christopher J Yates3

  • 1K Lines, University of Oxford, Radcliffe Department of Medicine, Oxford Centre for Diabetes Endocrinology and Metabolism, Oxford, United Kingdom of Great Britain and Northern Ireland.

The Journal of Endocrinology
|November 4, 2018
PubMed

Insights

Loss of menin in Multiple Endocrine Neoplasia type 1 (MEN1) is linked to decreased tumor suppressor microRNAs (miRNAs) like miR-15a, miR-16-1, and let-7a in pituitary tumors. This suggests miRNAs play a role in MEN1 tumor development.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Multiple Endocrine Neoplasia type 1 (MEN1) is an inherited disorder causing tumors in endocrine glands, linked to MEN1 gene mutations.
  • The tumor suppressor protein menin, encoded by MEN1, has roles in cell regulation, but its function in MEN1 tumorigenesis is unclear.
  • MicroRNAs (miRNAs) regulate gene expression and are implicated in tumor development, yet their specific role in MEN1-associated tumors and relation to menin is not fully understood.

Purpose of the Study:

  • To investigate the expression of specific miRNAs (miR-15a, miR-16-1, let-7a) in pituitary tumors from mice with a heterozygous knockout of the Men1 gene (Men1+/-).
  • To explore the relationship between these miRNAs and menin expression in the context of MEN1-associated pituitary tumorigenesis.

Main Methods:

  • Analysis of miR-15a, miR-16-1, and let-7a expression in pituitary tumors of Men1+/- mice compared to wild-type (WT) controls.
  • Correlation analysis between miRNA expression and cyclin D1 (a known target) expression.
  • Investigating the effect of menin knockdown on miR-15a expression in human (HeLa) and mouse (AtT20) cell lines.

Main Results:

  • Significant downregulation of miR-15a (2.3-fold), miR-16-1 (2.1-fold), and let-7a (1.6-fold) was observed in Men1+/- mouse pituitary tumors.
  • miR-15a and miR-16-1 expression showed an inverse correlation with the pro-tumourigenic target cyclin D1.
  • Knockdown of menin in cell lines led to a significant decrease in miR-15a expression, suggesting a direct link.

Conclusions:

  • The study identifies downregulation of tumor suppressor miRNAs (miR-15a, miR-16-1, let-7a) in MEN1-associated pituitary tumors.
  • These findings suggest that reduced menin expression contributes to miRNA dysregulation, potentially driving pituitary tumor development in MEN1.
  • The results highlight a novel mechanism involving miRNA alterations in MEN1 tumorigenesis, with implications for understanding pituitary tumor formation.

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