Cited by 244Hippo pathway signaling and YAP/TAZWnt/β-catenin signaling in development and cancerLiver physiology and pathology

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Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

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Kim, Wantae, Khan, Sanjoy Kumar, Gvozdenovic-Jeremic, Jelena, Kim, Youngeun, Dahlman, Jason, Kim, Hanjun, Park, Ogyi, Ishitani, Tohru, Jho, Eek-hoon, Gao, Bin, Yang, Yingzi·2016·Journal of Clinical Investigation

DOI 10.1172/jci88486PMC PMC5199712

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Abstract

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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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)
ORCID: Kim, Wantae
Kim, Youngeun
Kim, Hanjun
Ishitani, Tohru
Jho, Eek-hoon
Gao, Bin
Yang, Yingzi
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2016-11-21
Volume: 127
Issue: 1
Pages: 137-152
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci88486
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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Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

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