Neuropilin-2 expression is inhibited by secreted Wnt antagonists and its down-regulation is associated with reduced tumor growth and metastasis in osteosarcoma

Tao Ji,Carol Lin,Alexander Christ,Yi Guo,Bang H Hoang,Ramez Eskander,Kapjun Kim,Peter Mcqueen,Xiaolin Zi,Samia Ghaffar

doi:10.1186/s12943-015-0359-4

Abstract

BackgroundNeuropilin 2 (NRP2) isa multi-functional co-receptor to many receptors, including VEGF receptor, c-Met and others. NRP2 has recently been implicated in tumor angiogenesis, growth, and metastasis of many other cancers. However, its role in osteosarcoma remains poorly understood.ResultsNRP2 was overexpressed in osteosarcoma cell lines and tissues, and associated with poor survival of osteosarcoma patients. Knockdown of NRP2 expression by short-hairpin (Sh) RNA resulted in reduced tumor growth, metastasis, and blood vessel formation of osteosarcoma. Knockdown of NRP2 expression by ShRNA also inhibited the recruitment of HUVEC cells to osteosarcoma cells. Inhibition of Wnt signaling by overexpression of secreted Wnt antagonists soluble LRP5, Frzb, and WIF1 markedly down-regulated mRNA and protein expression of NRP2 in osteosarcoma cell lines.ConclusionsRegulation of NRP2 receptor expression may represent a novel approach for treatment of osteosarcoma through retarding osteosarcoma growth, metastasis and blood vessel formation. In addition, down-regulation of NRP2 expression can be achieved by expression of secreted Wnt antagonists.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0359-4) contains supplementary material, which is available to authorized users.

Highlights

Neuropilin 2 (NRP2) isa multi-functional co-receptor to many receptors, including vascular endothelial growth factor (VEGF) receptor, c-Met and others
By knocking down NRP2 using ShRNA, we examined the potential role of NRP2 in modulating tumor growth, invasion, metastasis and blood vessel formation in OS
NRP2 expression is correlated with metastasis and poor prognosis of OS Compared to normal osteoblasts (NHOst), mRNA levels of NRP2 are significantly increased in 6/7 OS cell lines and protein levels are elevated in all tested cell lines (Figure 1A & B)

Summary

Introduction

Neuropilin 2 (NRP2) isa multi-functional co-receptor to many receptors, including VEGF receptor, c-Met and others. Neuropilins, including neuropilin-1 (NRP1) and neuropilin-2 (NRP2), are multi-functional coreceptors for class 3 semaphorins (SEMA) and vascular endothelial growth factor (VEGF), essential for both neuronal guidance and cardiovascular development [2,3]. NRP1 and 2 were involved in the regulation of endothelial cell properties and mediate sprouting of blood vessel and lymphatic vessels, respectively [7,8]. These findings showed the crucial role of NRP1 and 2 in the development of the vascular and lymphatic systems, respectively

Methods

Results

Conclusion