Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer.
Myc activation has been implicated in the pathogenesis of hepatoblastoma (HB), a rare embryonal neoplasm derived from liver progenitor cells. Here, microRNA (miR) expression profiling of 65 HBs evidenced differential patterns related to developmental stage and Myc activity. Undifferentiated aggressive HBs overexpressed the miR-371-3 cluster with concomitant down-regulation of the miR-100/let-7a-2/miR-125b-1 cluster, evoking an ES cell expression profile. ChIP and Myc inhibition assays in hepatoma cells demonstrated that both miR clusters are regulated by Myc in an opposite manner. We show that the two miR clusters exert antagonistic effects on cell proliferation and tumorigenicity. Moreover, their combined deregulation cooperated in modulating the hepatic tumor phenotype, implicating stem cell-like regulation of Myc-dependent miRs in poorly differentiated HBs. Importantly, a four-miR signature representative of these clusters efficiently stratified HB patients, and when applied to 241 hepatocellular carcinomas (HCCs), it identified invasive tumors with a poor prognosis. Our data argue that Myc-driven reprogramming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells.
Oncogenesis and Molecular Virology Unit, Institut Pasteur, 75015 Paris, France.
Stefano
S
Cairo
Yipeng
Y
Wang
Aurélien
A
de Reyniès
Karine
K
Duroure
Jennifer
J
Dahan
Marie-José
MJ
Redon
Monique
M
Fabre
Michael
M
McClelland
Xin W
XW
Wang
Carlo M
CM
Croce
Marie-Annick
MA
Buendia
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005602:France; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018197:Hepatoblastoma / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc