Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation
Open accessAbstract
The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbeta's role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after a long latency. Deletion of IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.
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STAT3 may serve as a common signalling node in development of HCC associated with diverse etiologies, including viral infection, and metabolic and hormonal dysregulation.
“In defining a central role for STAT3 in FGF19-driven hepatocarcinogenesis, the data presented in this report extend previous findings on the causal role played by STAT3 in hepatocellular tumorigenesis4445, and suggest that STAT3 may serve as a common signalling node in the development of HCC associated with diverse etiologies, including viral infection, and metabolic and hormonal dysregulation.”
From Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis (2017) · cites this paper as [44]
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- Authors
- He, G., Yu, G.-Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavljevic, M., Leffert, H. L., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Kyoto University (JP)
- Medical University of Vienna (AT)
- Corresponding author
- Karin, Michael
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2010-03
- Volume
- 17
- Issue
- 3
- Pages
- 286-297
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2841312
- OpenAlex
- W2052656103
- Cited by
- 427
- References
- 4
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 25 · 2023: 12 · 2022: 26 · 2021: 26 · 2020: 25 · 2019: 28 · 2018: 34 · 2017: 27 · 2016: 29 · 2015: 15 · 2014: 33 · 2013: 38 · 2012: 37
- FWCI
- 12.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA118165, CA113602, R21CA161510, R01CA113602, CA118165)
- National Institute of Allergy and Infectious Diseases (R21AI067354)
- National Institute of Environmental Health Sciences (P42ES010337, ES-006376, R01ES006376)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- IKKβ, NF-κB, STAT3, hepatocellular carcinoma, hepatocarcinogenesis, oxidative stress, reactive oxygen species, JNK, tumor progression, hepatocyte-specific deletion, cancer stem cells, compensatory proliferation, hepatocyte death, cell-autonomous signaling
- MeSH terms
- Animals, Humans, Liver Neoplasms, Male, Mice, Inbred C57BL, Transcriptional Activation, NF-kappa B, Gene Deletion, Oxidative Stress, Hepatocytes, STAT3 Transcription Factor, Mice, I-kappa B Kinase
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