Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway

Oncogene. 2013 Mar 28;32(13):1651-9. doi: 10.1038/onc.2012.190. Epub 2012 May 21.


MicroRNAs (miRNAs) have been involved in the pathogenesis of different types of cancer; however, their function in pituitary tumorigenesis remains poorly understood. Cyclic-AMP-dependent protein kinase-defective pituitaries occasionally form aggressive growth-hormone (GH)-producing pituitary tumors in the background of hyperplasia caused by haploinsufficiency of the protein kinase's main regulatory subunit, PRKAR1A. The molecular basis for this development remains unknown. We have identified a 17-miRNA signature of pituitary tumors formed in the background of hyperplasia (caused in half of the cases by PRKAR1A-mutations). We selected two miRNAs on the basis of their functional screen analysis: inhibition of miR-26b expression and upregulation of miR-128 suppressed the colony formation ability and invasiveness of pituitary tumor cells. Furthermore, we identified that miR-26b and miR-128 affected pituitary tumor cell behavior through regulation of their direct targets, PTEN and BMI1, respectively. In addition, we found that miR-128 through BMI1 direct binding on the PTEN promoter affected PTEN expression levels and AKT activity in the pituitary tumor cells. Our in vivo data revealed that inhibition of miR-26b and overexpression of miR-128 could suppress pituitary GH3 tumor growth in xenografts. Taken together, we have identified a miRNA signature for GH-producing pituitary tumors and found that miR-26b and miR-128 regulate the activity of the PTEN-AKT pathway in these tumors. This is the first suggestion of the possible involvement of miRNAs regulating the PTEN-AKT pathway in GH-producing pituitary tumor formation in the context of hyperplasia or due to germline PRKAR1A defects. MiR-26b suppression and miR-128 upregulation could have therapeutic potential in GH-producing pituitary tumor patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoma / genetics
  • Adenoma / pathology*
  • Animals
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Corticotrophs / metabolism
  • Corticotrophs / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Growth Hormone-Secreting Pituitary Adenoma / genetics
  • Growth Hormone-Secreting Pituitary Adenoma / pathology*
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / pharmacology
  • MicroRNAs / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism
  • Oncogene Protein v-akt / physiology*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • PTEN Phosphohydrolase / physiology*
  • Prolactinoma / genetics
  • Prolactinoma / pathology
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Somatotrophs / drug effects
  • Somatotrophs / metabolism
  • Somatotrophs / pathology


  • MIRN128 microRNA, human
  • MIRN26A microRNA, human
  • MicroRNAs
  • Oncogene Protein v-akt
  • PTEN Phosphohydrolase