MicroRNA-34c is associated with emphysema severity and modulates SERPINE1 expression.
BACKGROUND
MicroRNAs (MiRNA) are small non-coding RNAs that regulate gene expression. The aim of this study was to identify miRNAs differentially expressed between mild and moderately emphysematous lung, as well as their functional target mRNAs. Resected lung from patients with COPD undergoing lung cancer surgery was profiled using miRNA (Agilent Human miRNA profiler G4470 V1.01) and mRNA (OperonV2.0) microarrays. Cells of lung origin (BEAS-2B and HFL1) were profiled using mRNA microarrays (Illumina HumanHT-12 V3) after in vitro manipulation.


RESULTS
COPD patients had mean (SD) age 68 (6) years, FEV1 72 (17)% predicted and gas transfer (KCO) 70 (10)% predicted. Five miRNAs (miR-34c, miR-34b, miR-149, miR-133a and miR-133b) were significantly down-regulated in lung from patients with moderate compared to mild emphysema as defined by gas transfer (p < 0.01). In vitro upregulation of miR-34c in respiratory cells led to down-regulation of predicted target mRNAs, including SERPINE1, MAP4K4, ZNF3, ALDOA and HNF4A. The fold change in ex-vivo expression of all five predicted target genes inversely correlated with that of miR-34c in emphysematous lung, but this relationship was strongest for SERPINE1 (p = 0.05).


CONCLUSIONS
Differences in miRNA expression are associated with emphysema severity in COPD patients. MiR-34c modulates expression of its putative target gene, SERPINE1, in vitro in respiratory cell lines and ex vivo in emphysematous lung tissue.
Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, QLD 4032, Australia. ss.francis@uqconnect.edu.au.
Santiyagu M
SM
Savarimuthu Francis
Morgan R
MR
Davidson
Maxine E
ME
Tan
Casey M
CM
Wright
Belinda E
BE
Clarke
Edwina E
EE
Duhig
Rayleen V
RV
Bowman
Nicholas K
NK
Hayward
Kwun M
KM
Fong
Ian A
IA
Yang
D000368:Aged; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004646:Emphysema / Q000235:genetics*; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D014162:Transfection; D015854:Up-Regulation
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human