The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo.
Activated oncogenic signaling is central to the development of nearly all forms of cancer, including the most common class of primary brain tumor, glioma. Research over the last two decades has revealed the particular importance of the Akt pathway, and its molecular antagonist PTEN (phosphatase and tensin homolog), in the process of gliomagenesis. Recent studies have also demonstrated that microRNAs (miRNAs) may be responsible for the modulation of cancer-implicated genes in tumors. Here we report the identification miR-26a as a direct regulator of PTEN expression. We also show that miR-26a is frequently amplified at the DNA level in human glioma, most often in association with monoallelic PTEN loss. Finally, we demonstrate that miR-26a-mediated PTEN repression in a murine glioma model both enhances de novo tumor formation and precludes loss of heterozygosity and the PTEN locus. Our results document a new epigenetic mechanism for PTEN regulation in glioma and further highlight dysregulation of Akt signaling as crucial to the development of these tumors.
Huse
Jason T
JT
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Brennan
Cameron
C
Hambardzumyan
Dolores
D
Wee
Boyoung
B
Pena
John
J
Rouhanifard
Sara H
SH
Sohn-Lee
Cherin
C
le Sage
Carlos
C
Agami
Reuven
R
Tuschl
Thomas
T
Holland
Eric C
EC
D000818:Animals; D002478:Cells, Cultured; D004265:DNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000503:physiopathology*; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*
D004265:DNA Helicases; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; C528163:MIRN26 microRNA, human; C494929:PTEN protein, human; C487757:Pten protein, mouse