Role of NRP1 in Bladder Cancer Pathogenesis and Progression

<jats:p>Bladder urothelial carcinoma (BC) is a fatal invasive malignancy and the most common malignancy of the urinary system. In the current study, we investigated the function and mechanisms of Neuropilin-1 (NRP1), the co-receptor for vascular endothelial growth factor, in BC pathogenesis and progression. The expression of NRP1 was evaluated using data extracted from GEO and HPA databases and examined in BC cell lines. The effect on proliferation, apoptosis, angiogenesis, migration, and invasion of BC cells were validated after <jats:italic>NRP1</jats:italic> knockdown. After identifying differentially expressed genes (DEGs) induced by <jats:italic>NRP1</jats:italic> silencing, GO/KEGG and IPA<jats:sup>®</jats:sup> bioinformatics analyses were performed and specific predicted pathways and targets were confirmed <jats:italic>in vitro.</jats:italic> Additionally, the co-expressed genes and ceRNA network were predicted using data downloaded from CCLE and TCGA databases, respectively. High expression of NRP1 was observed in BC tissues and cells. <jats:italic>NRP1</jats:italic> knockdown promoted apoptosis and suppressed proliferation, angiogenesis, migration, and invasion of BC cells. Additionally, after <jats:italic>NRP1</jats:italic> silencing the activity of MAPK signaling and molecular mechanisms of cancer pathways were predicted by KEGG and IPA<jats:sup>®</jats:sup> pathway analysis and validated using western blot in BC cells. <jats:italic>NRP1</jats:italic> knockdown also affected various biological functions, including antiviral response, immune response, cell cycle, proliferation and migration of cells, and neovascularisation. Furthermore, the main upstream molecule of the DEGs induced by <jats:italic>NRP1</jats:italic> knockdown may be <jats:italic>NUPR1</jats:italic>, and <jats:italic>NRP1</jats:italic> was also the downstream target of <jats:italic>NUPR1</jats:italic> and essential for regulation of <jats:italic>FOXP3</jats:italic> expression to activate neovascularisation. <jats:italic>DCBLD2</jats:italic> was positively regulated by <jats:italic>NRP1</jats:italic>, and PPAR signaling was significantly associated with low <jats:italic>NRP1</jats:italic> expression. We also found that NRP1 was a predicted target of miR-204, miR-143, miR-145, and miR-195 in BC development. Our data provide evidence for the biological function and molecular aetiology of NRP1 in BC and for the first time demonstrated an association between NRP1 and NUPR1, FOXP3, and DCBLD2. Specifically, downregulation of <jats:italic>NRP1</jats:italic> contributes to BC progression, which is associated with activation of MAPK signaling and molecular mechanisms involved in cancer pathways. Therefore, NRP1 may serve as a target for new therapeutic strategies to treat BC and other cancers.</jats:p>