MicroRNA-338 inhibits growth, invasion and metastasis of gastric cancer by targeting NRP1 expression.

Yang Peng,Xiao-Ling Wu,Lu-Lu Wang,Lu-Chun Li,Yan-Min Liu,Chih-Hsin Tang

doi:10.1371/journal.pone.0094422

Abstract

NRP1 as multifunctional non-tyrosine-kinase receptors play critical roles in tumor progression. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, particularly cancer. It remains unclear whether miRNAs can regulate the expression of NRP1. The goal of this study was to identify miRNAs that could inhibit the growth, invasion and metastasis of gastric cancer by targeting NRP1 expression. We found that miR-338 expression was reduced in gastric cancer cell lines and in gastric cancer tissues. Moreover, we found that miR-338 inhibited gastric cancer cell migration, invasion, proliferation and promoted apoptosis by targeting NRP1 expression. As an upstream regulator of NRP1, miR-338 directly targets NRP1. The forced expression of miR-338 inhibited the phosphorylation of Erk1/2, P38 MAPK and Akt; however, the expression of phosphorylated Erk1/2, P38 MAPK and Akt was restored by the overexpression of NRP1. In AGS cells infected with miR-338 or transfected with SiNRP1, the protein levels of fibronectin, vimentin, N-cadherin and SNAIL were decreased, but the expression of E-cadherin was increased. The expression of mesenchymal markers in miR-338-expressing cells was restored to normal levels by the restoration of NRP1 expression. In vivo, miR-338 also decreased tumor growth and suppressed D-MVA by targeting NRP1. Therefore, we conclude that miR-338 acts as a novel tumor suppressor gene in gastric cancer. miR-338 can decrease migratory, invasive, proliferative and apoptotic behaviors, as well as gastric cancer EMT, by attenuating the expression of NRP1.

Highlights

Neuropilins, including neuropilin1 (NRP1) and neuropilin2 (NRP2), are multifunctional non-tyrosine-kinase receptors that were first identified based on their critical roles in the developing nervous system[1]
NRP1 can be a coreceptor of other growth factors, which elucidates why vascular endothelial growth factor (VEGF) can signal through neuropilins in the absence of VEGFR-1or VEGFR-2[8,9]
We found that gastric cancer cell migration, invasion, proliferation and apoptosis were restored in the AGS cell line with forced miR-338 expression and NRP1 restoration (Figure 3G–3J)

Summary

Introduction

Neuropilins, including neuropilin (NRP1) and neuropilin (NRP2), are multifunctional non-tyrosine-kinase receptors that were first identified based on their critical roles in the developing nervous system[1]. Subsequent investigations identified NRP-1 as a receptor for the vascular endothelial growth factor (VEGF)-A isoform VEGF-165 in both endothelial cells and some tumor cells [4,5]. Research revealed that NRP1 could affect the growth of tumors as a coreceptor of VEGFR [5]. Scientists later found that NRP1 could boost tumorangiogenesis, accelerate tumor growth and curb tumor apoptosis without VEGFR [7]. As a coreceptor of TbRI/TbRII, NRP1 can curb tumor apoptosis and accelerate tumor growth via both canonical and non-canonical signaling [10]. NRP1, as a coreceptor of PDGFR/cmet, can boost tumorangiogenesis via P38MAPK and ERK signaling[11]

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