RNA-binding Protein DAZAP1 Promotes Gastric Cancer Metastasis by Enhancing NOTCH1 and JAG1 mRNA Stability

Background: DAZ-associated protein 1 (DAZAP1), an RNA-binding protein (RBP) and a modulator of alternative splicing, participates in tumorigenesis. However, the potential oncogenic function and mechanism of DAZAP1 in gastric cancer (GC) are still unknown.Methods: Gene expression analysis, including messenger RNA (mRNA) and protein levels by quantitative RT-PCR, western blot (WB), immunofluorescence, immunohistochemistry (IHC), in situ hybridization (ISH) assays, tissue microarrays assay (TMA), RNA immunoprecipitation (RIP) and sequencing (RIP-seq) analysis, and mRNA stability assays were assessed. Functional analyses-colony forming, EdU assay, wound healing, migration, and invasive abilities of GC cells-were performed.Finding: DAZAP1 displayed a significant upregulation in GC cells and acted as an oncogene. Additionally, DAZAP1 overexpression is positively correlated with tumor progression and poor survival in individuals with GC. Functionally, DAZAP overexpression promotes growth, epithelial-mesenchymal transition (EMT), and metastasis of GC cells. Mechanistically, RBPs-DAZAP1 physically bind to NOTCH1 or JAG1 mRNA to regulate its stability using RIP-seq analyses. In addition, forced expression of DAZAP1 facilitated NOTCH1- and/or JAG1-mediated metastasis through EMT in GC cells. Besides, the changes in NOTCH1 or JAG1 expression were positively correlated with DAZAP1 expression levels when DAZAP1 was silenced or enhanced in GC. Finally, DAZAP1 modulated the activation of the NOTCH/JAG1 signaling pathway.