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膀胱癌中NRP2与上皮-间质转化及放化疗耐药性的关联

Linking NRP2 With EMT and Chemoradioresistance in Bladder Cancer.

作者信息

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

机构信息

Faculty of Medicine and University Hospital Carl Gustav Carus, OncoRay-National Center for Radiation Research in Oncology, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.

Faculty of Medicine, Institute for Immunology, Technische Universität Dresden, Dresden, Germany.

出版信息

Front Oncol. 2020 Jan 21;9:1461. doi: 10.3389/fonc.2019.01461. eCollection 2019.

DOI:10.3389/fonc.2019.01461
PMID:32038994
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6986262/
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 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.

摘要

神经纤毛蛋白-2（NRP2）是膀胱癌（BCa）患者生存率降低的一个预后指标。NRP2与其主要配体血管内皮生长因子（VEGF）-C一起，对于接受经尿道切除术的BCa患者在放化疗后的治疗结果是一个预测因素。因此，我们研究了在具有或缺乏内源性NRP2表达的BCa细胞系RT112中，顺铂化疗联合放射治疗的益处，以评估NRP2作为潜在治疗靶点的可能性。我们在BCa患者的癌症基因组图谱（TCGA）队列以及一组15个人类BCa细胞系中，发现了NRP2与胶质瘤相关癌基因家族锌指2（GLI2）转录本之间存在高度相关性。此外，我们使用BCa模型展示了转化生长因子-β1（TGFβ1）对NRP2和GLI2表达水平的依赖性调节。由于已证明NRP2可结合TGFβ1、与TGFβ受体结合并增强TGFβ1信号传导，我们使用上皮-间质转化（EMT）检测法结合包含84个与EMT相关基因的PCR分析阵列，评估了下游信号通路。随后在NRP2基因敲除和敲低模型中进行的靶点验证显示，分泌性磷蛋白1（SPP1/OPN/骨桥蛋白）是受NRP2正向调节的下游靶点。

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