MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors.
MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice. We found that miR-136, miR-376a, and miR-31 were each prominently overexpressed in murine lung cancers. Real-time RT-PCR and in situ hybridization (ISH) assays confirmed these miRNA expression profiles in paired normal-malignant lung tissues from mice and humans. Engineered knockdown of miR-31, but not other highlighted miRNAs, substantially repressed lung cancer cell growth and tumorigenicity in a dose-dependent manner. Using a bioinformatics approach, we identified miR-31 target mRNAs and independently confirmed them as direct targets in human and mouse lung cancer cell lines. These targets included the tumor-suppressive genes large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A), and expression of each was augmented by miR-31 knockdown. Their engineered repression antagonized miR-31-mediated growth inhibition. Notably, miR-31 and these target mRNAs were inversely expressed in mouse and human lung cancers, underscoring their biologic relevance. The clinical relevance of miR-31 expression was further independently and comprehensively validated using an array containing normal and malignant human lung tissues. Together, these findings revealed that miR-31 acts as an oncogenic miRNA (oncomir) in lung cancer by targeting specific tumor suppressors for repression.
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Xi
X
Liu
Lorenzo F
LF
Sempere
Haoxu
H
Ouyang
Vincent A
VA
Memoli
Angeline S
AS
Andrew
Yue
Y
Luo
Eugene
E
Demidenko
Murray
M
Korc
Wei
W
Shi
Meir
M
Preis
Konstantin H
KH
Dragnev
Hua
H
Li
James
J
Direnzo
Mads
M
Bak
Sarah J
SJ
Freemantle
Sakari
S
Kauppinen
Ethan
E
Dmitrovsky
D000818:Animals; D019295:Computational Biology; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
C577037:MIRN136 microRNA, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse; C512974:PPP2R2A protein, human; D025521:Tumor Suppressor Proteins; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2