Activation of MYC and CTNNB1 (encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. Approach & Results We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a "Myc/β-catenin signature", composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/β-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.

Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz / A. Bisso, M. Filipuzzi, G.P. Gamarra Figueroa, G. Brumana, F. Biagioni, M. Doni, G. Ceccotti, N. Tanaskovic, M.J. Morelli, V. Pendino, F. Chiacchiera, D. Pasini, D. Olivero, S. Campaner, A. Sabò, B. Amati. - In: HEPATOLOGY. - ISSN 0270-9139. - (2020). [Epub ahead of print] [10.1002/hep.31120]

Cooperation between MYC and β-catenin in liver tumorigenesis requires Yap/Taz

G. Ceccotti;N. Tanaskovic;V. Pendino;D. Pasini;
2020

Abstract

Activation of MYC and CTNNB1 (encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. Approach & Results We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or Apc loss) upon expression of CRE recombinase in the liver, and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes followed by RNA-seq profiling allowed the identification of a "Myc/β-catenin signature", composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably this signature enriched for targets of Yap and Taz, two transcriptional co-activators known to be activated by WNT/β-catenin signaling, and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.
CTNNB1; WNT; hepatocellular carcinoma; mouse models
Settore BIO/11 - Biologia Molecolare
Settore BIO/13 - Biologia Applicata
Settore MED/06 - Oncologia Medica
2020
22-gen-2020
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/727358
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