MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways.
MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17~92 expression is frequently found in human cancers, mainly due to gene amplification and Myc-mediated transcriptional upregulation. Here we show that B cell-specific miR-17~92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17~92. We experimentally identified miR-17~92 target genes by PAR-CLIP and validated select target genes in miR-17~92 transgenic mice. These analyses demonstrate that miR-17~92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NFκB pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17~92-driven lymphoma cells exhibited constitutive activation of the PI3K and NFκB pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17~92 as a powerful cancer driver that coordinates the activation of multiple oncogenic pathways, and demonstrate for the first time that chemical inhibition of miRNA downstream pathways has therapeutic value in treating cancers caused by miRNA dysregulation.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Hyun Yong
HY
Jin
Hiroyo
H
Oda
Maoyi
M
Lai
Rebecca L
RL
Skalsky
Kelly
K
Bethel
Jovan
J
Shepherd
Seung Goo
SG
Kang
Wen-Hsien
WH
Liu
Mohsen
M
Sabouri-Ghomi
Bryan R
BR
Cullen
Klaus
K
Rajewsky
Changchun
C
Xiao
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D062085:RNA, Long Noncoding; D015203:Reproducibility of Results
D018398:Homeodomain Proteins; D007093:Imidazoles; D035683:MicroRNAs; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011810:Quinoxalines; D062085:RNA, Long Noncoding; C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; C568997:MIR17HG, human; C064658:RAG-1 protein; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol