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.

No abstract

As a co-receptor for vascular endothelial growth factor (VEGF), Neuropilin-1 (NRP-1) plays an important role in angiogenesis and malignant progression of many human cancers. However, the role of NRP-1 in hepatocellular carcinoma (HCC) is not well understood. The study aimed to detected the expression of Neuropilin-1 in HCC and investigate the association between its expression and the clinicopathological characteristics and prognosis of HCC. Quantitative real-time PCR (qRT-PCR), Western blot, Immunofluorescence and immunohistochemistry (IHC) analyses were performed to characterize the expression of NRP-1 in HCC cell lines and tissues. The association of NRP-1 expression with the clinicopathological characteristics and the prognosis was subsequently assessed. qRT-PCR and Western blot assays revealed that the expression of NRP-1 in HCC was significantly increased relative to that of normal live cells and tissues (P < 0.05,and <0.001, respectively). In addition, high expression of NRP-1 was significantly associated with intrahepatic metastasis (P = 0.036), Edmondson grade (P = 0.007), TNM classification (P = 0.0031), and portal vein invasion (P = 0.004). Furthermore, the HCC patients with high NRP-1 expression had shorter overall survival (OS), and recurrence-free survival (RFS), whereas, patients with low NRP-1 expression had better OS and RFS (P = 0.0035, and 0.0048, respectively). These data indicate that NRP-1 expression may play an important role in the progression of HCC, and that high NRP-1 expression suggests unfavorable clinicopathological characteristics and survival in HCC patients.

Neuropilin-1 (NRP-1) is a nontyrosine kinase coreceptor for semaphorin 3A and the vascular endothelial growth factor involved in tumor angiogenesis, growth, and metastasis and is regarded as a promising target for cancer therapy. In the present study, we investigated the effects of an anti-NRP-1 monoclonal antibody (mAb) that we generated for MCF7 breast cancer cellular adhesion studies. MTT, colony formation, and adhesion assays showed that our anti-NRP-1 mAb dose-dependently inhibited MCF7 proliferation and fibronectin adhesion, leading to a rounded cellular morphology. Further, rhodamine phalloidin stain revealed that fibronectin-dependent formation of actin stress fibers was inhibited by anti-NRP-1 mAb. Immunoprecipitation and western blot showed that anti-NRP-1 mAb treatment inhibited the formation of NRP-1-α5β1 integrin complexes and suppressed the phosphorylation of focal adhesion kinase and p130cas in MCF7 cells. These findings contribute to further understanding the NRP-1 function in cell adhesion and tumor metastasis. Moreover, our anti-NRP-1 mAb is a prospective drug candidate for tumor treatment.

This article reports the effect of Neuropilin-1 monoclonal antibody (NRP-1 MAb) on glioma cell lines in vitro and the effect on nude mice bearing glioma tumor (U87) in vivo. MTT, the scratch test and transwell test were used to evaluate the inhibitory effect of NRP-1 MAb on glioma cell lines. The tissue distribution and tumor targeting capability of NRP-1 MAb in U87 Xenografts nude mice was determined in Optical Imaging. Anti-glioma experiment was carried out by NRP-1 MAb on U87 Xenografts nude mice. NRP-1 MAb was showed to inhibit the proliferation, migration and invasion of glioma cells. NRP-1 MAb can specifically target the tumor in U87 Xenografts nude mice and reduce the proliferation activity of the tumor. The results of this study indicate that NRP-1 MAb can inhibit the proliferation, migration and metastasis of glioma cell lines and can target the glioma tumor to reduce tumor growth. Therefore, NRP-1 MAb may be an effective agent for glioma-targeted therapy.

BackgroundChemokine ligand 13 (CXCL13) is believed to play a role in the recruitment of B cells in the central nervous system during neuroinflammation. Neurosyphilis is a group of clinical syndromes of the central nervous system caused by Treponema pallidum (T. pallidum) infection. The relationship between CXCL13 and neurosyphilis still needs further study. In our study, CSF and serum CXCL13 concentrations were detected among 40 neurosyphilis patients, 31 syphilis/non-neurosyphilis patients, 26 non-syphilis/other central nervous system diseases patients. Serum CXCL13 concentrations were detected in 49 healthy persons. All enrolled persons were HIV-negative. Receiver operating characteristic (ROC) analysis was performed to determine the threshold value that could distinguish neurosyphilis from syphilis.ResultsWe found that the CSF CXCL13 concentrations and CXCL13 quotient (QCXCL13) were significantly increased in neurosyphilis patients compared to syphilis/non-neurosyphilis (χ2 = 21.802, P < 0.001) and non-syphilis patients (χ2 = 7.677, P = 0.002). ROC curve analyses revealed that CSF CXCL13 concentrations and QCXCL13 could serve as valuable biomarkers for differentiating neurosyphilis from non-neurosyphilis/syphilis.ConclusionsThe CSF CXCL13 and QCXCL13 could serve as valuable biomarkers for differentiating neurosyphilis from non-neurosyphilis/syphilis in HIV-negative patients.

Glioma occurs due to multi-gene abnormalities. Neuropilin-1 (NRP-1), as a transmembrane protein, involves in glioma proliferation, invasion, and migration, as well as tumor angiogenesis. The cytoplasmic protein, GAIP/RGS19-interacting protein (GIPC1), could regulate the clathrin-vesicles trafficking and recycling. Here, we show that NRP-1 co-localizes and co-immunoprecipitates with GIPC1, and the C-terminal SEA-COOH motif of NRP-1 interacts specially with the named from three proteins: PSD-95 (a 95 kDa protein involved in signaling at the post-synaptic density), DLG (the Drosophila melanogaster Discs Large protein) and ZO-1 (the zonula occludens 1 protein involved in maintenance of epithelial polarity) (PDZ) domain of GIPC1 in glioma cells. Knockdown of GIPC1 by small interfering RNA (siRNA) significantly reduces the proliferation and invasion of glioma cells in vitro and increases its apoptosis. Furthermore, si-GIPC1 prevents the action of adaptor proteins adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) and p130Cas and inhibits the downstream kirsten rat sarcoma viral oncogene homolog (KRAS)-ERK signaling pathway. This study demonstrated that NRP-1/GIPC1 pathway plays a vital role in glioma progression, and it is a potential important target for multi-gene combined therapeutics.

To study the house price dynamics in China, this paper extends the traditional life-cycle model by incorporating land supply, regime shifts and government regulation factors. The models are estimated with an error correction framework using quarterly data from 2000 to 2007 in Beijing. The conclusions are as follows. (1) There exits a stable co-integration relationship between house price and fundamentals; land supply and financial regimes are also important determinants of long-run equilibrium house prices. (2) Short-run dynamics depend on changes of fundamentals and the adjustment process of housing market. Land supply has a significant impact on house price fluctuations while demand factors such as user costs, income and residential mortgage loan have greater influences. The adjustment speed of real house prices to the long-run equilibrium has been reduced significantly since 2005 which means exogenous shocks can cause prolonged deviation of real house prices from the equilibrium level.