RRC ID 57639
Author Matsumoto S, Yamamichi T, Shinzawa K, Kasahara Y, Nojima S, Kodama T, Obika S, Takehara T, Morii E, Okuyama H, Kikuchi A.
Title GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling.
Journal Nat Commun
Abstract The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. Here we show that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/β-catenin signaling in HB patients. GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of β-catenin, YAP, and c-Met induces HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppresses marker gene expression and HB-like liver tumorigenesis, and instead enhances TGFβ signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppress the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a target molecule of Wnt/β-catenin signaling and required for HB progression.
Volume 10(1)
Pages 3882
Published 2019-8-28
DOI 10.1038/s41467-019-11533-x
PII 10.1038/s41467-019-11533-x
PMID 31462641
PMC PMC6713762
MeSH Adolescent Animals Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Carcinogenesis Cell Line, Tumor Cell Proliferation Child Child, Preschool Gene Expression Regulation, Neoplastic Hepatoblastoma / genetics Hepatoblastoma / metabolism* Humans Infant Infant, Newborn Liver Neoplasms / genetics Liver Neoplasms / metabolism* Liver Neoplasms / pathology Male Mice Mice, Nude Molecular Targeted Therapy Neoplasm Proteins / genetics* Neoplasm Proteins / metabolism Neoplasm Transplantation Oligonucleotides, Antisense / pharmacology Oligonucleotides, Antisense / therapeutic use Transforming Growth Factor beta / metabolism* Wnt Signaling Pathway* beta Catenin / metabolism
IF 11.878
Times Cited 3
Resource
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)