title: Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway.
abstract: 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.
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Palumbo
authors.forename: F R
authors.initials: FR
authors.lastname: Faucz
authors.forename: M
authors.initials: M
authors.lastname: Azevedo
authors.forename: P
authors.initials: P
authors.lastname: Xekouki
authors.forename: D
authors.initials: D
authors.lastname: Iliopoulos
authors.forename: C A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D052680:Corticotrophs / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015175:Prolactinoma / Q000235:genetics / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D052683:Somatotrophs / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D035683:MicroRNAs; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C545189:MIRN128 microRNA, human; C528163:MIRN26 microRNA, human