Involvement of ERK1/2 activation in the gene expression of senescence-associated secretory factors in human hepatic stellate cells
Open accessAbstract
Senescent hepatic stellate cells (senescent HSCs) are found in patients with liver cirrhosis and have been thought to be involved in the development of hepatocellular carcinoma (HCC) in mice via the senescence-associated secretory proteins. However, in humans, which secretory proteins are involved and what regulate their expression remain unclear. In the current study, we characterized senescence-associated β-galactosidase-positive senescent human HSCs (hHSCs) induced by repetitive passaging. They exhibited enhanced expression of 14 genes for secretory protein and persistent phosphorylation of ERK1/2 protein but not JNK or p38 MAPK proteins. Enhanced nuclear ERK1/2 phosphorylation was observed in senescent hHSCs. Treatment of the senescent hHSCs with ERK1/2 inhibitor, SCH772984, significantly decreased the levels of angiopoietin like 4 (ANGPTL4), C-C motif chemokine ligand 7 (CCL7), Interleukin-8 (IL-8), platelet factor 4 variant 1 (PF4V1), and TNF superfamily member 15 (TNFSF15) mRNA levels in a dose-dependent manner. The enhanced phosphorylation of ERK1/2 and expression of ANGPTL4, IL-8 and PF4V1 genes were observed in both of senescent human dermal fibroblasts and X-ray-induced senescent hHSCs. However, transient ERK1/2 activation induced by epidermal growth factor could not mimic the gene profile of the senescent hHSCs. These results revealed involvement of ERK1/2 signaling in the regulation of senescence-associated secretory factors, suggesting that simultaneous inductio…
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Ssb1 inhibits STAT3 phosphorylation in activated HSC-T6 cells without influencing other possible binding proteins such as PI3K, AKT, and MAPK3.
“Our study revealed that Ssb1 inhibited STAT3 phosphorylation in the activated HSC‐T6 cells without influencing other possible binding proteins, such as PI3K, AKT, and MAPK3 [48, 49].”
From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [48]
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Cell senescence in liver diseases: pathological mechanism and theranostic opportunity
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“Our study revealed that Ssb1 inhibited STAT3 phosphorylation in the activated HSC-T6 cells without influencing other possible binding proteins, such as PI3K, AKT, and MAPK3 [48, 49].”
- Authors
- Odagiri, N., Matsubara, T., Higuchi, M., Takada, S., Urushima, H., Sato-Matsubara, M., Teranishi, Y., Yoshizato, K., Kawada, N., & Ikeda, K.
- Affiliations
- Osaka City University (JP)
- Corresponding author
- Matsubara, Tsutomu
- ORCID
- Venue
- Molecular and Cellular Biochemistry
- Published
- 2018-11-13
- Volume
- 455
- Issue
- 1-2
- Pages
- 7-19
- ISSN
- 0300-8177 (ISSN-L)
- 1573-4919
- OpenAlex
- W2900629513
- Cited by
- 17
- References
- 8
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2022: 2 · 2021: 3 · 2020: 3
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Molecular and Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Osaka City University (Osaka City University) (acceptedVersion, other-oa)
- Institutional Repositories DataBase (IRDB) (submittedVersion, other-oa)
- Funders
- The Uehara Memorial Foundation
- The Osaka Medical Research Foundation for Intractable Diseases
- The Tokyo Biochemical Research Foundation
- The Osaka City University Strategic Research Grant 2016 for young researchers
- JSPS KAKENHI (JP26870501, JP17K18012)
- Research Program on Hepatitis from the Japan Agency for Medical Research and Development (16fk0210104h0001)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- hepatic stellate cells, cellular senescence, senescence-associated secretory phenotype, ERK signaling, ANGPTL4, interleukin-8, TNFSF15, CCL7, liver cirrhosis, hepatocellular carcinoma, epidermal growth factor, dermal fibroblasts
- MeSH terms
- Cell Line, Enzyme Activation, Gene Expression Regulation, Humans, Cellular Senescence, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 3, Hepatic Stellate Cells
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