β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.
In: The American journal of pathology, Jg. 189 (2019-05-01), Heft 5, S. 1091-1104
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Zugriff:
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.
(Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.
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Autor/in / Beteiligte Person: | Min, Q ; Molina, L ; Li, J ; Adebayo Michael, AO ; Russell, JO ; Preziosi, ME ; Singh, S ; Poddar, M ; Matz-Soja, M ; Ranganathan, S ; Bell, AW ; Gebhardt, R ; Gaunitz, F ; Yu, J ; Tao, J ; Monga, SP |
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Zeitschrift: | The American journal of pathology, Jg. 189 (2019-05-01), Heft 5, S. 1091-1104 |
Veröffentlichung: | 2011-: New York : Elsevier ; <i>Original Publication</i>: Philadelphia [etc.] American Assn. of Pathologists [etc.], 2019 |
Medientyp: | academicJournal |
ISSN: | 1525-2191 (electronic) |
DOI: | 10.1016/j.ajpath.2019.02.002 |
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