Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
Clinical research & lab center, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
Theranostics. 2021 Jul 25;11(17):8535-8549. doi: 10.7150/thno.61452. eCollection 2021.
Neuroligin-3 (NLGN3) is necessary and sufficient to promote glioma cell growth. The recruitment of Gαi1/3 to the ligand-activated receptor tyrosine kinases (RTKs) is essential for mediating oncogenic signaling. Various genetic strategies were utilized to examine the requirement of Gαi1/3 in NLGN3-driven glioma cell growth. NLGN3-induced Akt-mTORC1 and Erk activation was inhibited by decreasing Gαi1/3 expression. In contrast ectopic Gαi1/3 overexpression enhanced NLGN3-induced signaling. In glioma cells, NLGN3-induced cell growth, proliferation and migration were attenuated by Gαi1/3 depletion with shRNA, but facilitated with Gαi1/3 overexpression. Significantly, Gαi1/3 silencing inhibited orthotopic growth of patient-derived glioma xenografts in mouse brain, whereas forced Gαi1/3-overexpression in primary glioma xenografts significantly enhanced growth. The growth of brain-metastatic human lung cancer cells in mouse brain was largely inhibited with Gαi1/3 silencing. It was however expedited with ectopic Gαi1/3 overexpression. In human glioma Gαi3 upregulation was detected, correlating with poor prognosis. Gαi1/3 mediation of NLGN3-induced signaling is essential for neuronal-driven glioma growth
神经连接蛋白 3（NLGN3）对于促进神经胶质瘤细胞的生长是必要且充分的。配体激活的受体酪氨酸激酶（RTKs）募集 Gαi1/3 对于介导致癌信号至关重要。 利用各种遗传策略来检查 Gαi1/3 在 NLGN3 驱动的神经胶质瘤细胞生长中的需求。 通过降低 Gαi1/3 表达，抑制了 NLGN3 诱导的 Akt-mTORC1 和 Erk 激活。相比之下，外源性 Gαi1/3 过表达增强了 NLGN3 诱导的信号。在神经胶质瘤细胞中，通过 shRNA 耗尽 Gαi1/3 可减弱 NLGN3 诱导的细胞生长、增殖和迁移，但通过 Gαi1/3 过表达则促进了这些作用。重要的是，Gαi1/3 沉默抑制了患者来源的神经胶质瘤异种移植在小鼠大脑中的原位生长，而在原发性神经胶质瘤异种移植中强制 Gαi1/3 过表达则显著增强了生长。用 Gαi1/3 沉默抑制了脑转移的人类肺癌细胞在小鼠大脑中的生长，但通过外源性 Gαi1/3 过表达则加速了其生长。在人类神经胶质瘤中检测到 Gαi3 的上调，与预后不良相关。Gαi1/3 介导的 NLGN3 诱导的信号对于神经元驱动的神经胶质瘤生长是必要的。
