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Am J Pathol. 2019 May;189(5):1091-1104. doi: 10.1016/j.ajpath.2019.02.002. Epub 2019 Feb 19.

β-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.

Author information

1
Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
2
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
3
Department of Gynecology, Shiyan Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, China.
4
Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.
5
Division of Pediatric Pathology, Department of Pathology, Children's Hospital, Pittburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania.
6
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania.
7
Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
8
Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China; Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Science, Jinan, China. Electronic address: sdyujinming@163.com.
9
Department of Gynecology, Shiyan Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, China; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania.
10
Department of Gynecology, Shiyan Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, China; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania. Electronic address: smonga@pitt.edu.

Erratum in

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.

PMID:
30794807
PMCID:
PMC6521893
[Available on 2020-05-01]
DOI:
10.1016/j.ajpath.2019.02.002

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