Uncovering growth-suppressive MicroRNAs in lung cancer.
OBJECTIVE
MicroRNA (miRNA) expression profiles improve classification, diagnosis, and prognostic information of malignancies, including lung cancer. This study uncovered unique growth-suppressive miRNAs in lung cancer.


METHODS
miRNA arrays were done on normal lung tissues and adenocarcinomas from wild-type and proteasome degradation-resistant cyclin E transgenic mice to reveal repressed miRNAs in lung cancer. Real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays validated these findings. Lung cancer cell lines were derived from each transgenic line (designated as ED-1 and ED-2 cells, respectively). Each highlighted miRNA was independently transfected into these cells. Growth-suppressive mechanisms were explored. Expression of a computationally predicted miRNA target was examined. These miRNAs were studied in a paired normal-malignant human lung tissue bank.


RESULTS
miR-34c, miR-145, and miR-142-5p were repressed in transgenic lung cancers. Findings were confirmed by real-time and semiquantitative reverse transcription-PCR as well as in situ hybridization assays. Similar miRNA profiles occurred in human normal versus malignant lung tissues. Individual overexpression of miR-34c, miR-145, and miR-142-5p in ED-1 and ED-2 cells markedly repressed cell growth. Anti-miR cotransfections antagonized this inhibition. The miR-34c target, cyclin E, was repressed by miR-34c transfection and provided a mechanism for observed growth suppression.


CONCLUSIONS
miR-34c, miR-145, and miR-142-5p were repressed in murine and human lung cancers. Transfection of each miRNA significantly repressed lung cancer cell growth. Thus, these miRNAs were growth suppressive and are proposed to exert antineoplastic effects in the lung.
Liu
Xi
X
Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Sempere
Lorenzo F
LF
Galimberti
Fabrizio
F
Freemantle
Sarah J
SJ
Black
Candice
C
Dragnev
Konstantin H
KH
Ma
Yan
Y
Fiering
Steven
S
Memoli
Vincent
V
Li
Hua
H
DiRenzo
James
J
Korc
Murray
M
Cole
Charles N
CN
Bak
Mads
M
Kauppinen
Sakari
S
Dmitrovsky
Ethan
E
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000032:analysis* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D035683:MicroRNAs