The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis
Open accessAbstract
Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/β-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/β-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/β-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations.
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“Notch signaling is also considered a mediator of the Hippo/YAP (Yes-Associated Protein) pathway. The activation of YAP leads to an increase in Notch receptor expression, which in turn triggers Notch signaling and translocation of Notch intracellular domain into the nucleus[57].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [57]
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Metadata
- Authors
- Kim, W., Khan, S. K., Gvozdenovic-Jeremic, J., Kim, Y., Dahlman, J., Kim, H., Park, O., Ishitani, T., Jho, E.-H., Gao, B., & Yang, Y.
- Affiliations
- National Institutes of Health (US)
- University of Seoul (KR)
- Kyushu University (JP)
- Venue
- Journal of Clinical Investigation
- Published
- 2016-11-21
- Volume
- 127
- Issue
- 1
- Pages
- 137-152
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5199712
- OpenAlex
- W2556760701
- Cited by
- 244
- References
- 82
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 23 · 2023: 31 · 2022: 29 · 2021: 37 · 2020: 34 · 2019: 22 · 2018: 26 · 2017: 9
- FWCI
- 13.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- Hippo signaling pathway, Wnt/β-catenin signaling, Notch signaling, hepatocellular carcinoma, hepatocarcinogenesis, YAP/TAZ, STAT3, MST1, MST2, hepatomegaly, tumor initiation, signaling networks
- MeSH terms
- Hippo Signaling Pathway, Serine-Threonine Kinase 3, YAP-Signaling Proteins, Hippo Kinases, Animals, Carcinoma, Hepatocellular, Liver Neoplasms, Experimental, Phosphoproteins, Proto-Oncogene Proteins, Hepatocyte Growth Factor, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, STAT3 Transcription Factor, beta Catenin, Mice, Receptors, Notch, Wnt Signaling Pathway
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