Gene Summary

Gene:NRP1; neuropilin 1
Aliases: NP1, NRP, BDCA4, CD304, VEGF165R
Summary:This gene encodes one of two neuropilins, which contain specific protein domains which allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contains a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors; they affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members. Several alternatively spliced transcript variants that encode different protein isoforms have been described for this gene. [provided by RefSeq, Oct 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NRP1 (cancer-related)

Lv Y, Hou X, Zhang Q, et al.
Untargeted Metabolomics Study of the In Vitro Anti-Hepatoma Effect of Saikosaponin d in Combination with NRP-1 Knockdown.
Molecules. 2019; 24(7) [PubMed] Free Access to Full Article Related Publications
Saikosaponin d (SSd) is one of the main active ingredients in Radix Bupleuri. In our study, network pharmacology databases and metabolomics were used in combination to explore the new targets and reveal the in-depth mechanism of SSd. A total of 35 potential targets were chosen through database searching (HIT and TCMID), literature mining, or chemical similarity predicting (Pubchem). Out of these obtained targets, Neuropilin-1 (NRP-1) was selected for further research based on the degree of molecular docking scores and novelty. Cell viability and wound healing assays demonstrated that SSd combined with NRP-1 knockdown could significantly enhance the damage of HepG2. Metabolomics analysis was then performed to explore the underlying mechanism. The overall difference between groups was quantitatively evaluated by the metabolite deregulation score (MDS). Results showed that NRP-1 knockdown exhibited the lowest MDS, which demonstrated that the metabolic profile experienced the slightest interference. However, SSd alone, or NRP-1 knockdown in combination with SSd, were both significantly influenced. Differential metabolites mainly involved short- or long-chain carnitines and phospholipids. Further metabolic pathway analysis revealed that disturbed lipid transportation and phospholipid metabolism probably contributed to the enhanced anti-hepatoma effect by NRP-1 knockdown in combination with SSd. Taken together, in this study, we provided possible interaction mechanisms between SSd and its predicted target NRP-1.

Zhang L, Chen Y, Li C, et al.
RNA binding protein PUM2 promotes the stemness of breast cancer cells via competitively binding to neuropilin-1 (NRP-1) mRNA with miR-376a.
Biomed Pharmacother. 2019; 114:108772 [PubMed] Related Publications
Others and ours studies have established the promoting roles of NRP-1 (neuropilin-1) in breast cancer, however, the underlying mechanisms by which NRP-1 is regulated are still confused. Here, bioinformatics analysis indicated that RNA binding protein PUM2 could bind to NRP-1 mRNA. Clinical samples showed that PUM2 expression was significantly increased in breast cancer tissues, negatively correlated with the overall survival and relapse-free survival of breast cancer patients, and positively correlated with NRP-1 expression. Meanwhile, PUM2 expression was remarkably increased in non-adherent spheroids. in vitro experiments demonstrated that PUM2 knockdown attenuated the stemness of breast cancer cells, evident by the decrease of spheroid formation capacity, ALDH1 activity and stemness marker expression. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter analysis indicated that PUM2 competitively bound to NRP 3'UTR with miR-376a, which had been previously confirmed by us to suppress the stemness of breast cancer cells, and increased NRP-1 mRNA stability and expression. Furthermore, ectopic expression of NRP-1 or miR-376a knockdown rescued the inhibitory effects of NRP-1 knockdown on the stemness of breast cancer cells. Thus, our results suggest that PUM2 could facilitate the stemness of breast cancer cells by competitively binding to NRP-1 3'UTR with miR-376a.

Wang G, Shi B, Fu Y, et al.
Hypomethylated gene NRP1 is co-expressed with PDGFRB and associated with poor overall survival in gastric cancer patients.
Biomed Pharmacother. 2019; 111:1334-1341 [PubMed] Related Publications
Gastric cancer (GC) has been an increasingly serious problem in public health. However, there is still a lack of efficient approach to diagnosis and treatment in time, especially in the field of targeted therapy. Increasing evidences demonstrated that DNA methylation plays an essential role in tumorigenesis and progression of GC. Thus the present study aims to identify DNA methylation-based prognostic biomarkers in GC. Two methylation array datasets (GSE25869 and GSE30601) and RNA-seq based gene profiling dataset (TCGA-STAD) were employed for exploring candidate DNA methylation-based biomarkers. Univariate Cox regression analysis was used to select the most efficient prognostic genes in GC patients. Weighted gene correlation network analysis (WGCNA) was performed to screen the cluster of co-expressed genes. As a result, our data proved that NRP1 was a hypomethylated / upregulated gene in GC tissues, and PDGFRB was strongly co-expressed with it. Both of them were significantly associated with the overall survival of patients. More importantly, high expression levels of NRP1 and PDGFRB were associated with malignant phenotypes in GC patients, including Laurén histological diffuse type and higher histological grade. Patients carrying high expression level of NRP1 and PDGFRB had a nearly two-fold increased death risk than others. In summary, the hypomethylated gene, NRP1, and its co-expressed gene, PDGFRB, were significantly correlated with tumor malignant phenotypes, which might serve as potential prognostic biomarkers for GC patients.

Oplawski M, Dziobek K, Grabarek B, et al.
Expression of NRP-1 and NRP-2 in Endometrial Cancer.
Curr Pharm Biotechnol. 2019; 20(3):254-260 [PubMed] Related Publications
BACKGROUND: Neuropilins (NRPs) participate in many processes related to cancer development such as angiogenesis, lymphangiogenesis and metastasis. Although endometrial cancer is one of the most common gynecological cancers, it has not been studied in terms of NRPs expression.
OBJECTIVE: The aim of this study was to investigate the potential utility of NRPs as important factors in the diagnosis and treatment of endometrial cancer.
METHODS: Our study consisted of 45 women diagnosed with endometrial cancer at the following degrees of histological differentiation: G1, 17; G2, 15; G3, 13 cases. The control group included 15 women without neoplastic changes. The immunohistochemical reactions were evaluated using light microscopy.
RESULTS: We did not detect the expression of NRP-1 and NRP-2 in the control group. NRP-1 expression was found exclusively in cancer cells. It was higher in G2 and G3 and reached about 190% of G1. NRP-2 expression was observed in the endothelium and was similar across all three cancer grades. In cancer cells, NRP-2 expression increased with the degree of histological differentiation.
CONCLUSION: NRP1 and NRP2 are candidates for complementary diagnostic molecular markers and promising new targets for molecular, personalized anticancer therapies.

Niland S, Eble JA
Neuropilins in the Context of Tumor Vasculature.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
Neuropilin-1 and Neuropilin-2 form a small family of plasma membrane spanning receptors originally identified by the binding of semaphorin and vascular endothelial growth factor. Having no cytosolic protein kinase domain, they function predominantly as co-receptors of other receptors for various ligands. As such, they critically modulate the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. This review highlights the diverse neuropilin ligands and interacting partners on endothelial cells, which are relevant in the context of the tumor vasculature and the tumor microenvironment. In addition to tumor cells, the latter contains cancer-associated fibroblasts, immune cells, and endothelial cells. Based on the prevalent neuropilin-mediated interactions, the suitability of various neuropilin-targeted substances for influencing tumor angiogenesis as a possible building block of a tumor therapy is discussed.

Tang H, Jiang L, Zhu C, et al.
Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma.
Oncogene. 2019; 38(17):3119-3133 [PubMed] Related Publications
Esophageal squamous cells carcinoma (ESCC) is a major common thoracic tumor characterized by distinctly high incidences and mortality rates. Despite advances in multimodality therapy, the mortality rate of ESCC remains high and understanding of molecular alterations leading to the development and progression of ESCC is still very limited. In this study, a new tumor suppressor candidate, cell adhesion molecule with homology to L1CAM (CHL1), located at 3p26 which was frequently deleted in ESCC was identified. Reduced expression of CHL1 correlated with poor differentiation, increased invasion, and lymph-node metastasis, advanced tumor stage, and decreased overall survival. Methylation-specific PCR and FISH assays revealed that down-regulation of CHL1 in both ESCC cell lines and clinical samples were associated with promoter hypermethylation and loss of heterozygosity. Functional studies using lentiviral-based overexpression and knockdown systems provided direct support of CHL1 to function as an important tumor suppressor with both anti-proliferation and anti-metastasis abilities, through Merlin and SEMA3B-Np1-mediated inhibition of AKT signaling pathway. Further characterization of CHL1 may provide a novel therapeutic target in ESCC treatment.

Tominaga K, Minato H, Murayama T, et al.
Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.
Proc Natl Acad Sci U S A. 2019; 116(2):625-630 [PubMed] Free Access to Full Article Related Publications
Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of

Grun D, Adhikary G, Eckert RL
NRP-1 interacts with GIPC1 and SYX to activate p38 MAPK signaling and cancer stem cell survival.
Mol Carcinog. 2019; 58(4):488-499 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Epidermal cancer stem cells (ECS cells) comprise a limited population of cells that form aggressive, rapidly growing, and highly vascularized tumors. VEGF-A/NRP-1 signaling is a key driver of the ECS cell phenotype and aggressive tumor formation. However, relatively less is known regarding the downstream events following VEGF-A/NRP-1 interaction. In the present study, we show that VEGF-A/NRP-1, GIPC1, and Syx interact to increase RhoA-dependent p38 MAPK activity to enhance ECS cell spheroid formation, invasion, migration, and angiogenic potential. Inhibition or knockdown of NRP-1, GIPC1 or Syx attenuates RhoA and p38 activity to reduce the ECS cell phenotype, and NRP-1 knockout, or pharmacologic inhibition of VEGF-A/NRP-1 interaction or RhoA activity, reduces p38 MAPK activity and tumor growth. Moreover, expression of wild-type or constitutively-active RhoA, or p38, in NRP1-knockout cells, restores p38 activity and the ECS cell phenotype. These findings suggest that NRP-1 forms a complex with GIPC1 and Syx to activate RhoA/ROCK-dependent p38 activity to enhance the ECS cell phenotype and tumor formation.

Hellec C, Diawara M, Carpentier M, et al.
The Pro-Tumoral Activity of Heparan Sulfate 3-
Molecules. 2018; 23(10) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Heparan sulfate 3-

Kiso M, Tanaka S, Saji S, et al.
Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network.
Int J Cancer. 2018; 143(11):2905-2918 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF-related molecular mechanisms on breast cancer cells. VEGF-knocked-out MDA-MB-231 cells (231

Chen ZP, Wei JC, Wang Q, et al.
Long non‑coding RNA 00152 functions as a competing endogenous RNA to regulate NRP1 expression by sponging with miRNA‑206 in colorectal cancer.
Int J Oncol. 2018; 53(3):1227-1236 [PubMed] Related Publications
Colorectal cancer (CRC) is the third most common type of cancer; however, the molecular mechanisms underlying colorectal tumor metastasis and growth remain elusive. Recently, accumulating evidence has indicated that long non‑coding RNAs (lncRNAs) play a critical role in CRC progression and metastasis; however, the biological role and clinical significance of lncRNA 00152 (lnc00152) in CRC remains largely unknown. Thus, in this study, lnc00152 expression was measured in 80 human CRC tissue samples, 40 non‑cancerous tissue samples, and 3 CRC cell lines (SW480, SW620 and LoVo) using RT‑qPCR. We examined the effects of lnc00152 on CRC cells following transfection with lnc00152 overexpression plasmid or respective siRNA in vitro and in vivo. Luciferase assays revealed the mechanism driving competitive endogenous RNA (ceRNA). We identified that lnc00152 was aberrantly overexpressed in colorectal tumors and cancer cells and that lnc00152 was modulated by miRNA‑206. lnc00152 overexpression enhanced the proliferative and invasive ability of CRC cells in vitro, promoted tumor growth in vivo, and was associated with the shorter overall survival of patients with CRC. In addition, lnc00152 overexpression promoted epithelial-mesenchymal transition (EMT) and increased neuropilin‑1 (NRP1) expression in the CRC cells. By contrast, lnc00152 silencing exerted a counteractive effect. Collectively, these findings demonstrate the critical role of lnc00152 in tumor growth and progression in CRC, and identify a novel therapeutic target associated with CRC development and progression.

Wang X, Hu H, Liu H
RNA binding protein Lin28B confers gastric cancer cells stemness via directly binding to NRP-1.
Biomed Pharmacother. 2018; 104:383-389 [PubMed] Related Publications
This work aims to explore the roles and related mechanisms of RNA binding protein Lin28B in gastric cancer cells stemness. We found that Lin28B expression was negatively correlated with the overall survival (OS) of gastric cancer patients, and significantly increased in gastric cancer cells compared with that in gastric epithelial cells. Lin28B overexpression increased spheroid formation, expression of gastric cancer stemness-related markers, and decreased cisplatin sensitivity in gastric cancer cells. Mechanistically, Lin28B could directly bind to NRP-1 3'UTR, thus increasing NRP-1 mRNA stability and expression, and activate the downstream Wnt/β-catenin signaling. Knockdown of NRP-1 or treatment with Wnt/β-catenin antagonist could rescue the promotive effects of Lin28B on gastric cancer stemness. Thus, thes results indicate that Lin28B could facilitate gastric cancer stemness via directly binding to NRP-1 3'UTR and activating the downstream Wnt/β-catenin signaling.

Ishizuka Y, Koshinaga T, Hirano T, et al.
NRP1 knockdown promotes the migration and invasion of human neuroblastoma-derived SK‑N‑AS cells via the activation of β1 integrin expression.
Int J Oncol. 2018; 53(1):159-166 [PubMed] Related Publications
Neuropilin 1 (NRP1) is a transmembrane glycoprotein, which regulates many aspects of cellular function by functioning as co-receptor of various ligands. Recent studies have suggested that NRP1 promotes tumorigenesis, not only by activating the growth of tumor vessels, but also by activating the growth or migration of tumor cells themselves. The present study was performed to elucidate the roles of NRP1 in the development and/or progression of neuroblastoma (NB). In contrast to previous observations in various types of cancer, the analysis of public datasets indicated that lower levels of NRP1 expression were significantly associated with a shorter survival period of patients with NB. Consistent with this finding, wound-healing assay and Matrigel invasion assay revealed that NB cells in which NRP1 was knocked down exhibited increased migratory and invasive abilities. Further analyses indicated that β1 integrin expression was markedly increased in NB cells in which NRP1 was knocked down, and NB cells in which β1 integrin was knocked down exhibited decreased migratory and invasive abilities. The results presented herein indicate that NRP1 exerts tumor suppressive effects in NB, at least in part by regulating the expression of β1 integrin.

Naik A, Al-Yahyaee A, Abdullah N, et al.
Neuropilin-1 promotes the oncogenic Tenascin-C/integrin β3 pathway and modulates chemoresistance in breast cancer cells.
BMC Cancer. 2018; 18(1):533 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, however transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored.
METHODS: BT-474 NRP-1 variant cells were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell line. RNA sequencing and qRT-PCR were conducted to identify differentially expressed genes. The role of an upregulated oncogene, Tenascin C (TNC) and its associated pathway was investigated by siRNA-mediated knockdown. Resistant variants of the control and BT-474 NRP-1 cells were generated by sequential treatment with four cycles of Adriamycin/Cyclophosphamide (4xAC) followed by four cycles of Paclitaxel (4xAC + 4xPAC).
RESULTS: NRP-1 overexpression increased cellular tumorigenic behavior. RNA sequencing identified upregulation of an oncogene, Tenascin-C (TNC) and downregulation of several tumor suppressors in BT-474 NRP-1 cells. Additionally, protein analysis indicated activation of the TNC-associated integrin β3 (ITGB3) pathway via focal adhesion kinase (FAK), Akt (Ser473) and nuclear factor kappa B (NF-kB) p65. siRNA-mediated TNC knockdown ablated the migratory capacity of BT-474 NRP-1 cells and inactivated FAK/Akt473 signaling. NRP-1 overexpressing cells downregulated breast cancer resistance protein (BCRP/ABCG2). Consequently, sequential treatment with Adriamycin/Cyclophosphamide (AC) cytotoxic drugs to generate resistant cells indicated that BT-474 NRP-1 cells increased sensitivity to treatment by inactivating NRP-1/ITGB3/FAK/Akt/NF-kB p65 signaling compared to wild-type BT-474 resistant cells.
CONCLUSIONS: We thus report a novel mechanism correlating high baseline NRP-1 with upregulated TNC/ITGB3 signaling, but decreased ABCG2 expression, which sensitizes BT-474 NRP-1 cells to Adriamycin/Cyclophosphamide. The study emphasizes on the targetability of the NRP-1/ITGB3 axis and its potential as a predictive biomarker for chemotherapy response.

Zang Y, Yu R, Bai Y, Chen X
MicroRNA-9 suppresses cancer proliferation and cell cycle progression in acute lymphoblastic leukemia with inverse association of neuropilin-1.
J Cell Biochem. 2018; 119(8):6604-6613 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is one of the most common and most malign childhood cancers. In this work, we investigated the expression and function of human mature microRNA-9 (miR-9) in ALL. In ALL in vitro cell lines and in situ clinical specimens, gene expression of miR-9 was tested by qRT-PCR. MiR-9 was overexpressed in CEM/C1 and Molt-3 cells to investigate its possible anti-cancer effects on ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. The possible downstream target of miR-9, neuropilin-1 (NRP1), was examined by dual-luciferase activity assay, qRT-PCR, and Western blot. NRP1was upregulated in miR-9-overexpressed CEM/C1 and Molt-3 cells to investigate the functional involvement of NRP1 in miR-9-mediated regulation on ALL in vitro proliferation and cell-cycle progression. MiR-9 was downregulated in ALL cell lines and leukemic T-cells of ALL patients. Lentivirus-mediated miR-9 overexpression inhibited ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. NRP1 was confirmed be the downstream target of miR-9, and inversely modulated by miR-9 in ALL. NRP1 upregulation reversed the anti-cancer regulations of miR-9 on ALL in vitro proliferation and cell-cycle progression. MiR-9 is downregulated in ALL. Overexpressing miR-9 may inhibit ALL development, possible through its downstream target of NRP1.

Zhang G, Chen L, Khan AA, et al.
miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis.
Int J Cancer. 2018; 143(3):635-644 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM remains lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In our study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. First, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing. Then, by dual luciferase reporter gene, we found miR-124-3p can specially bind to the 3'UTR region of the NRP-1 thus suppresses its expression. Moreover, miR-124-3p overexpression significantly inhibited GBM cell proliferation, migration and tumor angiogenesis which resulted in GBM apoptosis and cell cycle arrest, putatively via NRP-1 mediated PI3K/Akt/NFκB pathways activation in GBM cells. Meanwhile, miR-124-3p overexpression also suppressed tumor growth and reduced tumor angiogenesis when targeted by NRP-1 in a PDX model. Furthermore, NRP-1 mAb exerted synergistic inhibitory effects with miR-124-3p overexpression in GBM. Thus, we discovered that miR-124-3p acts as the upstream suppressor of NRP-1 which promotes GBM cell development and growth by PI3K/Akt/NFκB pathway. The miR-124-3p/NRP-1/GIPC1 pathway as a new pathway has a vital role in GBM, and it could be considered as the potential target for malignant gliomas in future.

Vivekanandhan S, Mukhopadhyay D
Genetic status of KRAS influences Transforming Growth Factor-beta (TGF-β) signaling: An insight into Neuropilin-1 (NRP1) mediated tumorigenesis.
Semin Cancer Biol. 2019; 54:72-79 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Oncogenic RAS and deregulated transforming growth factor-beta (TGF)-β signaling have been implicated in several cancers. So far, attempts to target either one of them therapeutically have been futile as both of them are involved in multiple fundamental cellular processes and the normal forms are expressed by almost all cells. Hence, their inhibition would disrupt several physiological processes. Besides, their downregulation stimulates the tumor cells to develop adaptive mechanisms and would most likely be ineffective as therapeutic targets. Furthermore, growing literature suggests that both of these signaling pathways converge to enhance tumor development. Therefore, a lot of interest has been generated to explore the areas where these pathways interface that might identify new molecules that could potentially serve as novel therapeutic targets. In this review, we focus on such convergent signaling and cross-interaction that is mediated by neuropilin-1 (NRP1), a receptor that can interact with multiple growth factors including TGF-β for promoting tumorigenesis process.

Guillem V, Calabuig M, Brunet S, et al.
Bone marrow VEGFC expression is associated with multilineage dysplasia and several prognostic markers in adult acute myeloid leukemia, but not with survival.
Leuk Lymphoma. 2018; 59(10):2383-2393 [PubMed] Related Publications
Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC. We also found an association between VEGFC expression and the patient cytogenetic risk group, with those with a worse prognosis having higher VEGFC expression levels. No correlation was observed between VEGFC expression and survival or complete remission. VEGFC expression strongly correlated with expression of the VEGF receptors FLT1, KDR, and NRP1. Thus, in this series, VEGFC expression was increased in AML-MRC and in subgroups with a poorer prognosis, but has no impact on survival.

Wang J, Huang Y, Zhang J, et al.
NRP-2 in tumor lymphangiogenesis and lymphatic metastasis.
Cancer Lett. 2018; 418:176-184 [PubMed] Related Publications
Neuropilin-2 (NRP-2) not only functions as a receptor for semaphorins, a family of neural axon guidance factors, but also interacts with VEGFs, a family of vascular endothelial growth factors. As an independent receptor or a co-receptor, NRP-2 binds to ligands VEGF-C/D, activates the VEGF-C/D-NRP-2 signaling axis, and further regulates lymphangiogenesis-associated factors in both lymphatic endothelial cells (LECs) and some tumor cells during tumor progression. Via VEGF-C/D-NRP-2 axis, NRP-2 induces LEC proliferation, reconstruction and lymphangiogenesis and subsequently promotes tumor cell migration, invasion and lymphatic metastasis. There are similarities and differences among NRP-1, NRP-2 and VEGFR-3 in chemical structure, ligand specificity, chromosomal location, soluble protein forms, cellular functions and expression profiles. High expression of NRP-2 in LECs and tumor cells has been observed in different anatomic sites, histological patterns and progression stages of various tumors, especially during tumor lymphangiogenesis and lymphatic metastasis, and therefore the NRP-2 and VEGF-C/D-NRP-2 axis are closely related to tumor development, progression, invasion, and metastasis. In addition, it is important for prognosis of tumor. The studies on NRP-2 targeted therapy have recently achieved some successes, utilizing NRP-2 blocking antibodies, NRP-2 inhibitory peptides, soluble NRP-2 antagonists, small molecule inhibitors and various NRP-2 gene therapeutic strategies.

Chen C, Chi H, Min L, Junhua Z
Downregulation of guanine nucleotide-binding protein beta 1 (GNB1) is associated with worsened prognosis of clearcell renal cell carcinoma and is related to VEGF signaling pathway.
J BUON. 2017 Nov-Dec; 22(6):1441-1446 [PubMed] Related Publications
PURPOSE: Clear-cell renal cell carcinoma (ccRCC) is characterized by genetic abnormalities, while the role of Guanine Nucleotide-Binding Protein Beta 1 (GNB1) in ccRCC has not been studied. We thus aimed to evaluate the expression and prognostic value of GNB1 in ccRCC.
METHODS: A two-stage study (exploration and validation) was conducted using in silico and immunohistochemical (IHC) scoring of ccRCC samples from our institute, to evaluate the association between GNB1 expression and clinicopathological parameters of ccRCC patients. Pathway analyses were performed for genes coexpressed with GNB1 using the KOBAS platform to profile the function of GNB1 and IHC validation.
RESULTS: In the exploration stage, data from TCGA ccRCC dataset were reproduced, which contained 537 patients with ccRCC and found that downregulation of GNB1 was significantly associated with worse prognosis. IHC staining from the Human Protein Atlas showed significantly downregulation of GNB1 in ccRCC tissue compared with normal kidney. Pathway analysis showed significantly altered vascular endothelial growth factor (VEGF) signaling pathways among which expressions of 3 genes (WASF2, NRP1, and HIP1) were significantly associated with GNB1 expression, respectively. In the validation stage, included were 80 ccRCC samples and GNB1 expression was scored using IHC positivity. GNB1 expression was negatively associated with tumor stage, lymph node invasion, metastasis, older age, and increased tumor grade. Female gender and receiving neoadjuvant therapy were also associated with decreased GNB1 expression. The expressions of WASF2, NRP1 and HIP1 were also studied and found that they were significantly associated with GNB1.
CONCLUSION: GNB1 was downregulated in ccRCC. Decreased GNB1 expression was associated with worsened disease characteristics and prognosis. GNB1 was related with VEGF signaling in ccRCC, implying a therapeutic potential of this factor.

Abaza HM, Alfeky MAA, Eissa DS, et al.
Neuropilin-1/CD304 Expression by Flow Cytometry in Pediatric Precursor B-Acute Lymphoblastic Leukemia: A Minimal Residual Disease and Potential Prognostic Marker.
J Pediatr Hematol Oncol. 2018; 40(3):200-207 [PubMed] Related Publications
Flow cytometry (FCM) is used for quantification of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) through discriminating leukemic B-lymphoblasts from normal B-cell precursor counterparts "hematogones." Neuropilin-1 (NRP-1)/CD304 is a vascular endothelial growth factor receptor implicated in the progression of hematological malignancies. We evaluated NRP-1/CD304 as MRD and prognostic marker in pediatric precursor B-ALL using FCM. Seventy children with precursor B-ALL and 40 control children were enrolled. CD304 percentage and fluorescence intensity were significantly higher in precursor B-ALL at diagnosis compared with controls. In total, 28 of 70 (40%) precursor B-ALL patients at diagnosis were CD304 (group A), whereas 42/70 (60%) patients were CD304 (group B). Group A showed higher incidence of lymphadenopathy and TEL-AML1 fusion gene than group B. CD304 was reevaluated in group A patients at day 28 postinduction chemotherapy which revealed 12/28 (42.9%) patients with persistent CD304 expression (MRD; group A1) and 16/28 (57.1%) patients who turned CD304 (MRD; group A2). At diagnosis, group A1 showed lower incidence of TEL-AML1 fusion gene and higher risk stratification than group A2. NRP-1/CD304 expression by FCM is efficient in discriminating leukemic B-lymphoblasts from hematogones, a stable leukemia-associated phenotype for MRD monitoring, and a putative poor prognostic marker in pediatric precursor B-ALL.

Jimenez-Hernandez LE, Vazquez-Santillan K, Castro-Oropeza R, et al.
NRP1-positive lung cancer cells possess tumor-initiating properties.
Oncol Rep. 2018; 39(1):349-357 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Tumor-initiating cells possess the capacity for self-renewal and to create heterogeneous cell lineages within a tumor. Therefore, the identification and isolation of cancer stem cells is an essential step in the analysis of their biology. The aim of the present study was to determine whether the cell surface protein neuropilin 1 (NRP1) can be used as a biomarker of stem-like cells in lung cancer tumors. For this purpose, NRP1-negative (NRP1-) and NRP1-positive (NRP1+) cell subpopulations from two lung cancer cell lines were sorted by flow cytometry. The NRP1+ cell subpopulation showed an increased expression of pluripotency markers OCT-4, Bmi-1 and NANOG, as well as higher cell migration, clonogenic and self-renewal capacities. NRP1 gene knockdown resulted not only in a decreased expression of stemness markers but also in a decrease in the clonogenic, cell migration and self-renewal potential. In addition, the NRP1+ cell subpopulation exhibited dysregulated expression of epithelial-to-mesenchymal transition-associated genes, including the ΔNp63 isoform protein, a previously reported characteristic of cancer stem cells. Notably, a genome-wide expression analysis of NRP1-knockdown cells revealed a potential new NRP1 pathway involving OLFML3 and genes associated with mitochondrial function. In conclusion, we demonstrated that NRP1+ lung cancer cells have tumor-initiating properties. NRP1 could be a useful biomarker for tumor-initiating cells in lung cancer tumors.

Ren Y, Sagers JE, Landegger LD, et al.
Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas.
Sci Rep. 2017; 7(1):12922 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS.

Vivekanandhan S, Yang L, Cao Y, et al.
Genetic status of KRAS modulates the role of Neuropilin-1 in tumorigenesis.
Sci Rep. 2017; 7(1):12877 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Neuropilin-1 (NRP1), a non-tyrosine kinase receptor, is overexpressed in many cancers including pancreatic and lung cancers. Inhibition of NRP1 expression, however, has differing pro-tumor vs. anti-tumor effects, depending on the cancer types. To understand the differential role of NRP1 in tumorigenesis process, we utilized cells from two different cancer types, pancreatic and lung, each containing either wild type KRAS (KRAS

Vellinga TT, Kranenburg O, Frenkel N, et al.
Lymphangiogenic Gene Expression Is Associated With Lymph Node Recurrence and Poor Prognosis After Partial Hepatectomy for Colorectal Liver Metastasis.
Ann Surg. 2017; 266(5):765-771 [PubMed] Related Publications
OBJECTIVES: To investigate the relevance of lymphangiogenic gene expression in primary and liver metastasis of colorectal cancer (CRC) and identify determinants of lymphatic invasion.
BACKGROUND: Lymphatic development promoting vascular endothelial growth factor C (VEGFC) is associated with poor outcome in primary CRC. For colorectal liver metastasis (CRLM), intrahepatic lymph invasion and lymph node metastasis are poor prognostic factors. Exact biological factors promoting lymphatic involvement remain elusive, just as the association with molecular subtypes of CRC.
METHODS: We designed a lymphangiogenic gene set (VEGFC, Nrp-2, PDPN, LYVE-1, MRC1, CCL-21) and applied it to large datasets of CRC. Gene expression of the lymphangiogenic signature was assessed in resected CRLM specimens by Rt-QPCR. In vitro experiments were performed with colon cancer cell line Colo320 (high Nrp-2 expression) and human dermal microvascular lymphatic endothelial cells (LECs).
RESULTS: Lymphangiogenic gene expression was associated with poor prognosis in both primary and liver metastasis of CRC. CRLM with high expression of consensus molecular subtype-4 identifier genes also exhibited high lymphangiogenic gene expression. Lymph node recurrence following CRLM resection was associated with high expression of VEGFC and Nrp-2. Blocking Nrp-2 significantly reduced invasion of Colo320 cells through an LEC monolayer.
CONCLUSIONS: Lymphangiogenic gene expression is correlated with worse prognosis and consensus molecular subtype-4 in both primary and liver metastatic CRC. VEGFC and Nrp-2 expression may be predictive of lymph node involvement in recurrence after resection of CRLM. Nrp-2, expressed on both tumor and LECs, may have a mechanistic role in lymphatic invasion and is a potential novel target in CRC.

Zhu H, Jiang X, Zhou X, et al.
Neuropilin-1 regulated by miR-320 contributes to the growth and metastasis of cholangiocarcinoma cells.
Liver Int. 2018; 38(1):125-135 [PubMed] Related Publications
BACKGROUND & AIMS: Neuropilin-1 (NRP-1) activates signalling pathways as multifunctional co-receptors in cancer cells. However, its role and how it is regulated by miRNAs in cholangiocarcinoma (CCA) have not yet been investigated.
METHODS: The expression of NRP-1, miR-320 and key molecules involved in cell proliferation, migration and related signalling pathways were detected by immunohistochemistry, immunoblotting and qRT-PCR. Stable transfectants depleted of NRP-1 were generated. The regulatory effect of miR-320 on NRP-1 was evaluated by luciferase reporter assays. Cell proliferation, cell cycle distribution and migration were examined. Xenograft tumour models were established to assess tumourigenesis, tumour growth and lung metastasis.
RESULTS: Cholangiocarcinoma tissues expressed higher levels of NRP-1 than adjacent normal biliary tissues, and its expression negatively correlated with miR-320. NRP-1 depletion inhibited cell proliferation and induced cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2; and reduced cell migration by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumourigenesis, tumour growth and lung metastasis by inhibiting cell proliferation and tumour angiogenesis in experimental animals. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective ligands. MiR-320 negatively regulated the expression of NRP-1 by binding to the 3'-UTR of NRP-1 promoter, and miR-320 mimics inhibited cell proliferation and migration, and the growth of established tumours in animals by downregulating NRP-1.
CONCLUSIONS: The present results indicate that NRP-1 is negatively regulated by miR-320, and both of them may be potentially therapeutic targets for CCA.

Naik A, Al-Zeheimi N, Bakheit CS, et al.
Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study.
Sci Rep. 2017; 7(1):3301 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Circulating plasma and peripheral blood mononuclear (PBMCs) cells provide an informative snapshot of the systemic physiological state. Moreover, they provide a non-invasively accessible compartment to identify biomarkers for personalized medicine in advanced breast cancer. The role of Neuropilin-1 (NRP-1) and its interacting molecules in breast tumor tissue was correlated with cancer progression; however, the clinical impact of their systemic levels was not extensively evaluated. In this cross-sectional study, we found that circulating and tumor tissue expression of NRP-1 and circulating placental growth factor (PlGF) increase in advanced nodal and metastatic breast cancer compared with locally advanced disease. Tumor tissue expression of NRP-1 and PlGF is also upregulated in triple negative breast cancer (TNBC) compared to other subtypes. Conversely, in PBMCs, NRP-1 and its interacting molecules SEMA4A and SNAI1 are significantly downregulated in breast cancer patients compared to healthy controls, indicating a protective role. Moreover, we report differential PBMC expression profiles that correlate inversely with disease stage (SEMA4A, SNAI1, PLXNA1 and VEGFR3) and can differentiate between the TNBC and non-TNBC tumor subtypes (VEGFR3 and PLXNA1). This work supports the importance of NRP-1-associated molecules in circulation to characterize poor prognosis breast cancer and emphasizes on their role as favorable drug targets.

Overacre-Delgoffe AE, Chikina M, Dadey RE, et al.
Interferon-γ Drives T
Cell. 2017; 169(6):1130-1141.e11 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Regulatory T cells (T

Gemmill RM, Nasarre P, Nair-Menon J, et al.
The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer.
Sci Signal. 2017; 10(462) [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non-small cell lung cancer (NSCLC) cell lines, transforming growth factor-β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)-induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus-interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to-mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFβ and correlated with tumor progression in patients.

Tse BWC, Volpert M, Ratther E, et al.
Neuropilin-1 is upregulated in the adaptive response of prostate tumors to androgen-targeted therapies and is prognostic of metastatic progression and patient mortality.
Oncogene. 2017; 36(24):3417-3427 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.

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