microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma.
Tumorigenesis involves multistep genetic alterations. To elucidate the microRNA (miRNA)-gene interaction network in carcinogenesis, we examined their genome-wide expression profiles in 96 pairs of tumor/non-tumor tissues from hepatocellular carcinoma (HCC). Comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that increased expression of miR-122 seed-matched genes leads to a loss of mitochondrial metabolic function. Furthermore, the miR-122 secondary targets, which decrease in expression, are good prognostic markers for HCC. Transcriptome profiling data from additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. The HCC findings can be recapitulated in mouse liver by silencing miR-122 with antagomir treatment followed by gene-expression microarray analysis. In vitro miR-122 data further provided a direct link between induction of miR-122-controlled genes and impairment of mitochondrial metabolism. In conclusion, miR-122 regulates mitochondrial metabolism and its loss may be detrimental to sustaining critical liver function and contribute to morbidity and mortality of liver cancer patients.
Burchard
Julja
J
Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck and Co., Inc., Seattle, WA, USA.
Zhang
Chunsheng
C
Liu
Angela M
AM
Poon
Ronnie T P
RT
Lee
Nikki P Y
NP
Wong
Kwong-Fai
KF
Sham
Pak C
PC
Lam
Brian Y
BY
Ferguson
Mark D
MD
Tokiwa
George
G
Smith
Ryan
R
Leeson
Brendan
B
Beard
Rebecca
R
Lamb
John R
JR
Lim
Lee
L
Mao
Mao
M
Dai
Hongyue
H
Luk
John M
JM
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D050259:Genes, Mitochondrial / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D015854:Up-Regulation / Q000235:genetics
C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger