title: microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck and Co., Inc., Seattle, WA, USA.
authors.forename: Julja
authors.initials: J
authors.lastname: Burchard
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Angela M
authors.initials: AM
authors.lastname: Liu
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Nikki P Y
authors.initials: NP
authors.lastname: Lee
authors.forename: Kwong-Fai
authors.initials: KF
authors.lastname: Wong
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Lam
authors.forename: Mark D
authors.initials: MD
authors.lastname: Ferguson
authors.forename: George
authors.initials: G
authors.lastname: Tokiwa
authors.forename: Ryan
authors.initials: R
authors.lastname: Smith
authors.forename: Brendan
authors.initials: B
authors.lastname: Leeson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Beard
authors.forename: John R
authors.initials: JR
authors.lastname: Lamb
authors.forename: Lee
authors.initials: L
authors.lastname: Lim
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.forename: Hongyue
authors.initials: H
authors.lastname: Dai
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
mesh_terms: 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
chemical_list: C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger