Dang Ning-Ning, Li Xiao-Bing, Zhang Mei, Han Chen, Fan Xiao-Yong, Huang Shu-Hong
Department of Dermatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Institute of Basic Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Front Cell Dev Biol. 2021 Aug 16;9:662763. doi: 10.3389/fcell.2021.662763. eCollection 2021.
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.
神经元衍生的突触粘附分子神经连接蛋白-3（NLGN3）在胶质瘤生长中起重要作用。然而，自分泌NLGN3在胶质瘤中的作用尚未得到充分研究。采用免疫组织化学检测NLGN3在胶质瘤中的表达。我们进一步探讨了其在高表达NLGN3的U251和U87细胞中的功能及调控机制。敲低内源性NLGN3可显著降低胶质瘤细胞的增殖、迁移和侵袭能力，并下调PI3K-AKT、ERK1/2和LYN信号通路的活性。相比之下，NLGN3过表达则产生相反的结果。我们的结果进一步证明，LYN作为一种反馈机制促进NLGN3的裂解。这种反馈调节是通过上调负责NLGN3裂解的ADAM10蛋白酶实现的。抑制ADAM10可抑制胶质瘤细胞的增殖、迁移和侵袭；相反，ADAM10的表达与脑内低级别胶质瘤（LGG）较低的可能性相关。我们的研究表明，胶质瘤来源的NLGN3通过上调LYN和ADAM10的活性促进胶质瘤进展，进而促进NLGN3裂解形成正反馈回路。该通路可能为人类胶质瘤的治疗打开一个潜在的治疗窗口。
