Abstract
BackgroundNeuropilin-1 (NRP-1) is a transmembrane glycoprotein participating in the growth and metastasis of cancer cells as multifunctional co-receptors by interacting with the signaling pathways. However, its role in gastric cancer has not yet been clarified. This study aims to investigate whether NRP-1 expression is associated with the clinicopathology of gastric cancer, and involved in the growth and metastasis of gastric cancer cells.MethodsNRP-1 expression in clinical gastric cancer specimens was examined by immunohistochemistry and its association with clinicopathology analyzed. The expression of NRP-1 in a panel of human gastric cancer cells was examined by real-time RT-PCR and immunoblotting. Stable transfectants depleted of NRP-1, termed MGC-803-NRPlow, were generated from MGC-803 cells. Cell proliferation was analyzed by the Cell Counting Kit-8 and Bromodeoxyuridine incorporation assays, and migrating ability analyzed by migration assays. The xenograft model was used to assess the effects of NRP-1 depletion on tumorigenesis, growth, metastasis and therapeutic potentials. The role of NRP-1 as co-receptors in the signaling pathways stimulated by ligands was examined. The key molecules involved in cell proliferation, migration and related signaling pathways were detected by immunoblotting.ResultsGastric cancer tissues expressed higher levels of NRP-1 compared to normal gastric mucosa. Its expression correlated with clinical staging, tumor differentiation and pathological types. NRP-1 depletion inhibited cell proliferation by inducing cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2. NRP-1 depletion reduced the ability of cells to migrate by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumorigenesis, tumor growth and lung metastasis by inhibiting cell proliferation and tumor angiogenesis in situ. Therapeutic NRP-1 shRNA inhibited the growth of established BGC823 tumors. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective recombinant human VEGF-165, EGF and HGF proteins.ConclusionsThe present results indicate that NRP-1 may be a potentially valuable biomarker and therapeutic target for gastric cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0291-5) contains supplementary material, which is available to authorized users.
Highlights
Neuropilin-1 (NRP-1) is a transmembrane glycoprotein participating in the growth and metastasis of cancer cells as multifunctional co-receptors by interacting with the signaling pathways
The present results have demonstrated that depletion of NRP-1 inhibited the proliferation of gastric cancer cells by inducing cell cycle arrest in the G1/S phase through upregulating p27 and downregulating cyclin E and CDK2
We showed that NRP-1 depletion inhibited vascular endothelial growth factor (VEGF)-activated VEGF/VEGFR2 pathway, which is crucial for tumor angiogenesis by regulating the phosphorylation of Focal adhesion kinase (FAK) [28], a key factor in cell migration and metastasis [29]
Summary
Neuropilin-1 (NRP-1) is a transmembrane glycoprotein participating in the growth and metastasis of cancer cells as multifunctional co-receptors by interacting with the signaling pathways. This study aims to investigate whether NRP-1 expression is associated with the clinicopathology of gastric cancer, and involved in the growth and metastasis of gastric cancer cells. It is known that NRP-1 acts as multifunctional co-receptors participating in the initiation, growth and metastasis of cancer cells [1]. Specific inhibition of NRP-1 has been shown to suppress the growth and metastasis of several types of cancer cells [5,6,7,8,9]. The mechanisms for the role of NRP-1 in cancer progression rely on its interactions with several key signaling pathways in cancer cells. The above three cellular signaling pathways are all shown to be involved in the progression of gastric cancer [15,16,17,18]
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