NLGN3 Upregulates Expression of ADAM10 to Promote the Cleavage of NLGN3 via Activating the LYN Pathway in Human Gliomas.

Ning-Ning Dang,Xiao-Bing Li,Shu-Hong Huang,Chen Han,Mei Zhang,Xiao-Yong Fan

doi:10.3389/fcell.2021.662763

Abstract

The neuron derived synaptic adhesion molecular neuroligin-3 (NLGN3) plays an important role in glioma growth. While the role of autocrine NLGN3 in glioma has not been well-studied. The expression of NLGN3 in glioma was detected using immunohistochemistry. We further explored its function and regulatory mechanism in U251 and U87 cells with high expression of NLGN3. Knockdown of endogenous NLGN3 significantly reduced the proliferation, migration, and invasion of glioma cells and down-regulated the activity of the PI3K-AKT, ERK1/2, and LYN signaling pathways. In comparison, overexpression of NLGN3 yielded opposite results. Our results further demonstrate that LYN functions as a feedback mechanism to promote NLGN3 cleavage. This feedback regulation was achieved by upregulating the ADAM10 sheddase responsible for NLGN3 cleavage. Inhibition of ADAM10 suppressed the proliferation, migration, and invasion of glioma cells; oppositely, the expression of ADAM10 was correlated with a higher likelihood of lower grade glioma (LGG) in the brain. Our study demonstrates that glioma-derived NLGN3 promotes glioma progression by upregulating activity of LYN and ADAM10, which in turn promote NLGN3 cleavage to form a positive feedback loop. This pathway may open a potential therapeutic window for the treatment of human glioma.

Highlights

Malignant glioma is the most common type of brain tumors and is both highly invasive and lethal (Stupp and Roila, 2017)
NLGN3 was expressed in all five cell lines, but expression was highest in U251 and U87 cells, so these two cell lines were used for subsequent experiments
What mediates the regulation of the LYN pathway to NLGN3 cleavage? Recent studies have shown that ADAM10 is responsible for NLGN3 shedding from glioma cells, so we further studied the role of ADAM10 in this positive feedback loop (Venkatesh et al, 2017)

Summary

Introduction

Malignant glioma is the most common type of brain tumors and is both highly invasive and lethal (Stupp and Roila, 2017). The Neuroligins (NLs) are a family of cell adhesion molecules located in the postsynaptic membrane of neurons and mediated synapse formation (Cao et al, 2018). These play important roles in the formation of synaptic structures, neurotransmitters release, synaptic recognition, synaptic maturation, and signal transduction (Chubykin et al, 2005; Südhof, 2008; Aiga et al, 2011; Krueger et al, 2012). Researchers found that neuronal activity promotes high-grade glioma (HGG) growth through modulating Neuroligin-3 secretion. Current research is limited to neuron-derived NLGN3 in the brain tumor microenvironment; whether NLGN3 secreted by tumor tissue itself can affect the growth of glioma cells remains unknown. We determined that NLGN3 is highly expressed by glioma tissue itself, but NLGN3’s role and the mechanism involved in glioma progression have not been reported

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