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High-throughput mRNA-sequence of MCM7 and SHCBP1 knock down hepatocytes with IL-1β stimulation

ABSTRACT: Liver fibrosis, characterized by the excessive deposition of extracellular matrix, remains a formidable challenge due to its complex and poorly understood mechanisms. In this study, we aimed to elucidate the role of Minichromosome Maintenance Complex Component 7 (MCM7) and SHC SH2-Domain Binding Protein 1 (SHCBP1) in liver fibrosis, focusing on their regulatory network and interaction. Stable hepatocyte cell lines with knockdown of MCM7 and SHCBP1 were constructed and subsequently stimulated with IL-1β to mimic inflammatory conditions. RNA sequencing was conducted to identify differentially expressed genes and pathways affected by the knockdown. Our analysis revealed significant changes in gene expression profiles, particularly in pathways related to fibrosis and inflammation. We discovered that MCM7 interacts with SHCBP1, which in turn binds to RACGAP1. This interaction activates the SHCBP1-RACGAP1-STAT3 signaling axis, leading to increased IL11 expression. Elevated IL11 levels contribute to the activation of hepatic stellate cells and the progression of liver fibrosis. The findings demonstrate that MCM7 is an important regulatory factor in liver fibrosis and promotes IL11 expression through the SHCBP1-RACGAP1-STAT3 signaling pathway, driving hepatic stellate cell (HSC) activation and fibrosis progression. Overall, our findings highlight a mechanistic pathway where MCM7 and SHCBP1 collaborate to regulate IL11 expression, thereby influencing liver fibrosis progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275059 | GEO | 2025/08/09

REPOSITORIES: GEO

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Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.

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High-throughput mRNA-sequence of MCM7 and SHCBP1 knock down hepatocytes with IL-1β stimulation

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