Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.
Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.
Cairo
Stefano
S
Oncogenesis and Molecular Virology Unit, Institut Pasteur, Paris Cedex 15, France.
Armengol
Carolina
C
De Reyniès
Aurélien
A
Wei
Yu
Y
Thomas
Emilie
E
Renard
Claire-Angélique
CA
Goga
Andrei
A
Balakrishnan
Asha
A
Semeraro
Michaela
M
Gresh
Lionel
L
Pontoglio
Marco
M
Strick-Marchand
Hélène
H
Levillayer
Florence
F
Nouet
Yann
Y
Rickman
David
D
Gauthier
Frédéric
F
Branchereau
Sophie
S
Brugières
Laurence
L
Laithier
Véronique
V
Bouvier
Raymonde
R
Boman
Françoise
F
Basso
Giuseppe
G
Michiels
Jean-François
JF
Hofman
Paul
P
Arbez-Gindre
Francine
F
Jouan
Hélène
H
Rousselet-Chapeau
Marie-Christine
MC
Berrebi
Dominique
D
Marcellin
Luc
L
Plenat
François
F
Zachar
Dominique
D
Joubert
Madeleine
M
Selves
Janick
J
Pasquier
Dominique
D
Bioulac-Sage
Paulette
P
Grotzer
Michael
M
Childs
Margaret
M
Fabre
Monique
M
Buendia
Marie-Annick
MA
D000818:Animals; D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D051176:beta Catenin