Activation of STAT3 by the Hepatitis C Virus Core Protein Leads to Cellular Transformation
Open accessAbstract
The signal transducer and activator of transcription (STAT) family proteins are transcription factors critical in mediating cytokine signaling. Among them, STAT3 is often constitutively phosphorylated and activated in human cancers and in transformed cell lines and is implicated in tumorigenesis. However, cause of the persistent activation of STAT3 in human tumor cells is largely unknown. The hepatitis C virus (HCV) is a major etiological agent of non-A and non-B hepatitis, and chronic infection by HCV is associated with development of liver cirrhosis and hepatocellular carcinoma. HCV core protein is proposed to be responsible for the virus-induced transformation. We now report that HCV core protein directly interacts with and activates STAT3 through phosphorylation of the critical tyrosine residue. Activation of STAT3 by the HCV core in NIH-3T3 cells resulted in rapid proliferation and up-regulation of Bcl-XL and cyclin-D1. Additional expression of STAT3 in HCV core-expressing cells resulted in anchorage-independent growth and tumorigenesis. We propose that the HCV core protein cooperates with STAT3, which leads to cellular transformation.
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Hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3.
“Both hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3 (328–330), while HTLV-I, Epstein–Barr virus and papilloma virus activate STAT3 and NF-κB (311, 331, 332).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [328]
The Results section (‘The HCV-Core Protein Induces Activation of STAT3’; page not available) reports STAT3 activation by HCV core protein and stronger activation with the full-length HCV genome. The Introduction mentions HBV proteins only in a comparison of other signaling assays; our copy does not show that HBV activates STAT3. Thus, this source supports the HCV part, not the HBV part. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHCV core protein interacts with STAT3, a transcription factor involved in mediating cytokine signalling.
“HCV core protein interacts with the signal transducer and activator of transcription 3 (STAT3) protein36, a transcription factor involved in mediating cytokine signalling37.”
From Inflammation and cancer (2002) · cites this paper as [36]
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“Both hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3 (328–330), while HTLV-I, Epstein– Barr virus and papilloma virus activate STAT3 and NF-κ B (311, 331, 332).”
BackgroundSignal transduction of inflammatory cytokines and tumor development
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- Authors
- Yoshida, T., Hanada, T., Tokuhisa, T., Kosai, K.-I., Sata, M., Kohara, M., & Yoshimura, A.
- Affiliations
- Kurume University (JP)
- Kyushu University (JP)
- Chiba University (JP)
- Gifu University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Yoshimura, Akihiko
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2002-09-02
- Volume
- 196
- Issue
- 5
- Pages
- 641-653
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2194001
- OpenAlex
- W2161994461
- Cited by
- 236
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 14 · 2015: 7 · 2014: 12 · 2013: 11 · 2012: 11
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- STAT3, HCV core protein, STAT3 phosphorylation, cell transformation, viral oncogenesis, hepatocellular carcinoma, Bcl-xL, cyclin D1, anchorage-independent growth, carcinogenesis, NIH3T3 cells, tyrosine kinase signaling
- MeSH terms
- Animals, Cell Line, Cell Transformation, Neoplastic, DNA-Binding Proteins, DNA, Viral, Humans, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Nude, Mice, Transgenic, Neoplasms, Experimental, Transfection, Tumor Stem Cell Assay, Viral Core Proteins, Trans-Activators, Hepacivirus, 3T3 Cells, DNA, Complementary, STAT3 Transcription Factor, Mice
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