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.
Highlights
Bladder cancer (BCa) is the 9th most common malignancy in the world with the highest incidence in Europe and North America [1]
This observation, together with the strong correlation of both transcripts, tempted us to investigate the relationship of NRP2 and glioma-associated oncogene family zinc finger 2 (GLI2) in more detail by selecting two BCa cell lines, namely, J82 and HS853T, showing robust mRNA levels of both NRP2 and GLI2 (Supplementary Figure 1C) for knockdown experiments
Since GLI1 levels are directly dependent on the expression of GLI2, we cannot fully exclude the possibility that changes in NRP2 could be mediated through GLI1 or other downstream targets of GLI2 despite the fact that correlation between NRP2 and GLI2 is by far highest compared to GLI1 or GLI3 in a patient cohort
Summary
Bladder cancer (BCa) is the 9th most common malignancy in the world with the highest incidence in Europe and North America [1]. Linking NRP2 With EMT and Chemoradioresistance of the bladder tumor (TURBT) and adjuvant intravesical Bacillus Calmette-Guérin (BCG) or chemotherapy, the treatment options for the more aggressive MIBC consist of neoadjuvant and adjuvant cisplatin treatment and radical cystectomy. Despite the aggressive therapy regimen, MIBC has a 50% risk to progress to metastatic disease. The average survival time in these patients is 14–15 months [3], and no curative treatment option is available for these patients. Immune checkpoint inhibition has become available in patients with metastatic disease. New therapy options are urgently needed for this disease stage. Radiochemotherapy has emerged as a promising new option for improving locoregional control and being able to preserve the bladder and quality of life [4,5,6]
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