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GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling

Author

Listed:
  • Shinji Matsumoto

    (Osaka University)

  • Taku Yamamichi

    (Osaka University
    Osaka University)

  • Koei Shinzawa

    (Osaka University)

  • Yuuya Kasahara

    (Osaka University
    Health and Nutrition (NIBIOHN))

  • Satoshi Nojima

    (Osaka University)

  • Takahiro Kodama

    (Osaka University)

  • Satoshi Obika

    (Osaka University
    Health and Nutrition (NIBIOHN))

  • Tetsuo Takehara

    (Osaka University)

  • Eiichi Morii

    (Osaka University)

  • Hiroomi Okuyama

    (Osaka University)

  • Akira Kikuchi

    (Osaka University)

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.

Suggested Citation

  • Shinji Matsumoto & Taku Yamamichi & Koei Shinzawa & Yuuya Kasahara & Satoshi Nojima & Takahiro Kodama & Satoshi Obika & Tetsuo Takehara & Eiichi Morii & Hiroomi Okuyama & Akira Kikuchi, 2019. "GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11533-x
    DOI: 10.1038/s41467-019-11533-x
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