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β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis
- Source :
- American Journal of Pathology; May 2019, Vol. 189 Issue: 5 p1091-1104, 14p
- Publication Year :
- 2019
-
Abstract
- Hepatoblastoma (HB), the most common pediatric primary liver neoplasm, shows nuclear localization of β-catenin and yes-associated protein 1 (YAP1) in almost 80% of the cases. Co-expression of constitutively active S127A-YAP1 and ΔN90 deletion-mutant β-catenin (YAP1–ΔN90-β-catenin) causes HB in mice. Because heterogeneity in downstream signaling is being identified owing to mutational differences even in the β-catenin gene alone, we investigated if co-expression of point mutants of β-catenin (S33Y or S45Y) with S127A-YAP1 led to similar tumors as YAP1–ΔN90-β-catenin. Co-expression of S33Y/S45Y–β-catenin and S127A-YAP1 led to activation of Yap and Wnt signaling and development of HB, with 100% mortality by 13 to 14 weeks. Co-expression with YAP1–S45Y/S33Y-β-catenin of the dominant-negative T-cell factor 4 or dominant-negative transcriptional enhanced associate domain 2, the respective surrogate transcription factors, prevented HB development. Although histologically similar, HB in YAP1–S45Y/S33Y-β-catenin, unlike YAP1–ΔN90-β-catenin HB, was glutamine synthetase (GS) positive. However, both ΔN90–β-catenin and point-mutant β-catenin comparably induced GS-luciferase reporter in vitro. Finally, using a previously reported 16-gene signature, it was shown that YAP1–ΔN90-β-catenin HB tumors exhibited genetic similarities with more proliferative, less differentiated, GS-negative HB patient tumors, whereas YAP1–S33Y/S45Y-β-catenin HB exhibited heterogeneity and clustered with both well-differentiated GS-positive and proliferative GS-negative patient tumors. Thus, we demonstrate that β-catenin point mutants can also collaborate with YAP1 in HB development, albeit with a distinct molecular profile from the deletion mutant, which may have implications in both biology and therapy.
Details
- Language :
- English
- ISSN :
- 00029440
- Volume :
- 189
- Issue :
- 5
- Database :
- Supplemental Index
- Journal :
- American Journal of Pathology
- Publication Type :
- Periodical
- Accession number :
- ejs49250408
- Full Text :
- https://doi.org/10.1016/j.ajpath.2019.02.002