ArticleFrontiers in physiology2015
Interplay of Matrix Stiffness and c-SRC in Hepatic Fibrosis.
Article in Frontiers in physiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 42 citations in OpenAlex.
- From Quiescence to Activation: The Reciprocal Regulation of Ras and Rho Signaling in Hepatic Stellate Cells.Cells · 2025Article
- Metabolomic Profiling and Network Toxicology: Mechanistic Insights into Effect of Gossypol Acetate Isomers in Uterine Fibroids and Liver Injury.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.The Journal of pathology · 2023Article
- Mechanobiology of portal hypertension.JHEP reports : innovation in hepatology · 2023Review
- The Dual-Mode Transition of Myofibroblasts Derived from Hepatic Stellate Cells in Liver Fibrosis.International journal of molecular sciences · 2023Article
- Extracellular matrix stiffness aggravates urethral stricture through Igfbp3/Smad pathway.Scientific reports · 2023Article
- Role of c-Src and reactive oxygen species in cardiovascular diseases.Molecular genetics and genomics : MGG · 2023Review
- The relationship between cancer and biomechanics.Frontiers in oncology · 2023Review
- Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease.Frontiers in physiology · 2023Review
- Hydrostatic pressure induces profibrotic properties in hepatic stellate cells via the RhoA/ROCK signaling pathway.FEBS open bio · 2022Article
- Evaluation of the Mechanism of Jiedu Huazhuo Quyu Formula in Treating Wilson's Disease-Associated Liver Fibrosis by Network Pharmacology Analysis and Molecular Dynamics Simulation.Evidence-based complementary and alternative medicine : eCAM · 2022Article
- Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy.JHEP reports : innovation in hepatology · 2021Review
- Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure.Nature reviews. Gastroenterology & hepatology · 2021Review
- Regulation of Fibroblast Cell Polarity by Src Tyrosine Kinase.Biomedicines · 2021Article
- Extracellular Matrix Remodeling in Chronic Liver Disease.Current tissue microenvironment reports · 2021Review
- Mechano-Signaling Aspects of Hepatocellular Carcinoma.Journal of Cancer · 2021Review
- Caveolin1 Tyrosine-14 Phosphorylation: Role in Cellular Responsiveness to Mechanical Cues.The Journal of membrane biology · 2020Review
- cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease.Biomolecules · 2020Review
- Fibrillar Collagen Type I Participates in the Survival and Aggregation of Primary Hepatocytes Cultured on Soft Hydrogels.Biomimetics (Basel, Switzerland) · 2020Article
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Authors and funding
11 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionIn liver fibrosis activation of hepatic stellate cells (HSC) comprises phenotypical change into profibrotic and myofibroplastic cells with increased contraction and secretion of extracellular matrix (ECM) proteins. The small GTPase RhoA orchestrates cytoskeleton formation, migration, and mobility via non-receptor tyrosine-protein kinase c-SRC (cellular sarcoma) in different cells. Furthermore, RhoA and its downstream effector Rho-kinase also play a crucial role in hepatic stellate cells and hepatic fibrogenesis. Matrix stiffness promotes HSC activation via cytoskeleton modulation. This study investigated the interaction of c-SRC and RhoA under different matrix stiffness conditions.
methodsLiver fibrosis was induced in rats using bile duct ligation (BDL), thioacetamide (TAA) or carbon tetrachloride (CCl4) models. mRNA levels of albumin, PDGF-R, RHOA, COL1A1, and αSMA were analyzed via qRT-PCR. Western Blots using phospho-specific antibodies against p-c-SRC418 and p-c-SRC530 analyzed the levels of activating and inactivating c-SRC, respectively. LX2 cells and hepatocytes were cultured on acrylamide gels of 1 and 12 kPa or on plastic to mimic non-fibrotic, fibrotic, or cirrhotic environments then exposed to SRC-inhibitor PP2. Overexpression of RhoA was performed by transfection using RhoA-plasmids. Additionally, samples from cirrhotic patients and controls were collected at liver transplantations and tumor resections were analyzed for RhoA and c-SRC protein expression by Western Blot.
resultsTranscription of albumin and RhoA was decreased, whereas transcription and activation of c-SRC was increased in hepatocytes cultured on 12 kPa compared to 1 kPa gels. LX2 cells cultured on 12 kPa gels showed upregulation of RHOA, COL1A1, and αSMA mRNA levels. Inhibition of c-SRC by PP2 in LX2 cells led to an increase in COL1A1 and αSMA most prominently in 12 kPa gels. In LX2 cells with RhoA overexpression, c-SRC inhibition by PP2 failed to improve fibrosis. RhoA expression was significantly elevated in human and experimental liver fibrosis, while c-SRC was inactivated.
conclusionsThis study shows that c-SRC is inactive in activated myofibroblast-like HSC in liver cirrhosis. Inactivation of c-SRC is mediated by a crosstalk with RhoA upon hepatic stellate cell activation and fibrosis progression.
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