Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer

Alexander Schulz, Ielizaveta Gorodetska, Rayk Behrendt, Susanne Fuessel, Kati Erdmann, Sarah Foerster, Kaustubh Datta, Thomas Mayr, Anna Dubrovska, Michael H. Muders

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
Article number1461
JournalFrontiers in Oncology
Volume9
DOIs
StatePublished - Jan 21 2020

Keywords

  • J82
  • Neuropilin-2 (NRP2)
  • RT112
  • bladder cancer
  • epithelial-to-mesenchymal transition (EMT)
  • glioma-associated oncogene family zinc finger 2 (GLI2)
  • osteopontin (OPN)
  • secreted phosphoprotein 1 (SPP1)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schulz, A., Gorodetska, I., Behrendt, R., Fuessel, S., Erdmann, K., Foerster, S., Datta, K., Mayr, T., Dubrovska, A., & Muders, M. H. (2020). Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer. Frontiers in Oncology, 9, [1461]. https://doi.org/10.3389/fonc.2019.01461