Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

Abstract

Neuropilin-2 (NRP2) is a prognostic indicator for reduced survival in bladder cancer (BCa) patients. Together with its major ligand, vascular endothelial growth factor (VEGF)-C, NRP2 expression is a predictive factor for treatment outcome in response to radiochemotherapy in BCa patients who underwent transurethral resection. Therefore, we investigated the benefit of combining cisplatin-based chemotherapy with irradiation treatment in the BCa cell line RT112 exhibiting or lacking endogenous NRP2 expression in order to evaluate NRP2 as potential therapeutic target. We have identified a high correlation of NRP2 and the glioma-associated oncogene family zinc finger 2 (GLI2) transcripts in the cancer genome atlas (TCGA) cohort of BCa patients and a panel of 15 human BCa cell lines. Furthermore, we used in vitro BCa models to show the transforming growth factor-beta 1 (TGFβ1)-dependent regulation of NRP2 and GLI2 expression levels. Since NRP2 was shown to bind TGFβ1, associate with TGFβ receptors, and enhance TGFβ1 signaling, we evaluated downstream signaling pathways using an epithelial-to-mesenchymal transition (EMT)-assay in combination with a PCR profiling array containing 84 genes related to EMT. Subsequent target validation in NRP2 knockout and knockdown models revealed secreted phosphoprotein 1 (SPP1/OPN/Osteopontin) as a downstream target positively regulated by NRP2.

A Bioinformatics Model of Human Diseases on the Basis of Differentially Expressed Genes (of Domestic Versus Wild Animals) That Are Orthologs of Human Genes Associated with Reproductive-Potential Changes

“…Human gene NRP2 produces neuropilin 2, the downregulation of which improves survival after radiochemotherapy [ 83 ], thereby raising reproductive potential consistently with wolf orthologous gene downregulation in microevolution [ 28 ] ( Table 4 ). Conversely, an NRP2 excess causes post-traumatic vascular neointimal hyperplasia [ 84 ] ( Table 4 ).…”

Neuropilin-2 and Its Transcript Variants Correlate with Clinical Outcome in Bladder Cancer

“…A multivariate Cox regression analysis also revealed NRP2 as an independent prognostic factor for OS in this cohort [ 12 ]. The role of NRP2 in the therapy response was corroborated in vitro where we showed that NRP2 downregulation sensitized BLCA cells to radiochemotherapy [ 31 ]. However, the prognostic value of NRP2 may be limited to MIBC.…”

“…Furthermore, our current study investigated NRP2 gene expression while Keck et al investigated NRP2 protein levels [ 12 ]. In light of our reports indicating post-transcriptional regulation that may influence NRP2 protein levels [ 31 ], a direct comparison of immunohistochemical NRP2 staining with mRNA expression should be performed in the future to clarify this issue. However, our current study was particularly focused on messenger expression as we were interested in the potential involvement of NRP2 isoforms/transcript variants in UBC but no isoform-specific antibodies are commercially available yet.…”

RAD18 promotes colorectal cancer metastasis by activating the epithelial‑mesenchymal transition pathway

“…EMT changes the polarity of the cells, deconstructs the cell connections, adjusts the motility of cells, and modifies the cytoskeleton, changes that together may contribute to the promotion of tumor cell metastasis (14). To evaluate whether EMT occurs requires the detection of relevant molecular markers such as E-cadherin, N-cadherin, and vimentin (15). Hence, we further examined the role of EMT-related molecular markers in the context of RAD18-mediated invasion and migration of CRC cells.…”