Stattic

Glioma is marked by swift cell proliferation, extensive invasion and poor outcomes. Serine protease inhibitor H1 (SERPINH1) encoding heat shock protein 47, a collagen-specific molecular chaperone, plays a role in a number of cancers. However, its definite role in glioma remains unclear. The aim of the present study was to investigate the role of SERPINH1 in glioma progression, especially its impact on cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT). The glioma cell lines LN229, T98, U251 and U87MG were transfected with lentivirus for stable knockdown or overexpression of SERPINH1. Assays assessing cell proliferation, migration and invasion were conducted to investigate the role of SERPINH1 in these processes. Bioinformatic analysis was conducted using The Cancer Genome Atlas and the Chinese Glioma Genome Atlas databases to identify potential molecular pathways associated with SERPINH1. Western blotting (WB) was employed to examine the expression of significant proteins in the JAK1/STAT3 signaling pathway and EMT markers. Nude mice were used for in vivo experiments to evaluate tumor growth and changes related to EMT. Overexpression of SERPINH1 notably increased glioma cell proliferation, migration and invasion, whereas knockdown suppressed these activities. Bioinformatic analyses revealed that SERPINH1 is closely associated with the JAK1/STAT3 signaling pathway and EMT-related genes. WB results confirmed that SERPINH1 regulates the activation of JAK1/STAT3 and influences the levels of EMT markers such as N- and E-cadherin. The JAK1/STAT3 agonist RO8191 partially rescued glioma cell behavior in the SERPINH1 knockdown group, while the inhibitor STATTIC partially weakened the enhanced effects in the SERPINH1 overexpression group. In vivo, SERPINH1 overexpression accelerated tumor growth and EMT progression, while knockdown resulted in a reduction in tumor size and the expression of EMT markers. SERPINH1 is essential for glioma progression, enhancing cell proliferation, migration, invasion and EMT by activating the JAK1/STAT3 signaling pathway. These results indicate that targeting SERPINH1 could provide a promising new approach for glioma therapy.

Hippocampal neural stem/progenitor cells (HNPCs) in the hippocampus can differentiate into neurons and astrocytes, and are regulated by complex signaling pathways, such as the NOTCH1-signal transducer and activator of transcription 3 (STAT3) axis, which are crucial for cell fate determination. However, the exact molecular mechanism underlying HNPC differentiation remains unclear. This study investigated the role of NOTCH1-STAT3 pathway in HNPC differentiation into neuronal and astrocytic lineages during embryonic development. Mouse HNPCs were cultured with basic fibroblast and epidermal growth factors to promote proliferation. Differentiation was assessed using western blotting, immunofluorescence, RNA sequencing (RNA-seq), and reverse transcription-quantitative PCR to analyze gene expression. The roles of NOTCH1 and STAT3 in cell fate were assessed using their respective inhibitors, DAPT and Stattic, respectively. Immunoprecipitation was performed to investigate the interactions between NOTCH1 and STAT3. Proliferative conditions induced a shift from neurogenesis to astrocytic differentiation in HNPCs, as demonstrated by the increased GFAP and decreased TUJ1 levels. RNA-seq and gene ontology analyses revealed the upregulation of astrocyte-related genes and suppression of neurogenesis. NOTCH1 signaling promoted astrocytic differentiation through elevated DLL1 expression. Additionally, the inhibition of STAT3 or NOTCH1 reduced GFAP expression, whereas NOTCH1 knockdown reduced STAT3 activation, suggesting that NOTCH1 regulates astrocytic fate via STAT3 in proliferating HNPCs. These findings reveal the regulatory mechanisms of neural differentiation, emphasizing the critical role of the NOTCH1-STAT3 signaling axis in astrocytic differentiation of HNPCs, thereby enhancing our understanding of the molecular basis of neural cell fate decisions during brain development.