鉴定新的治疗人脑胶质瘤的目标是极其重要的。在这里，我们测试了蛋白质抑制性Gα亚基2（Gαi2）在胶质瘤中的表达、潜在功能和基础机制。生物信息学分析发现，Gαi2表达在人脑胶质瘤中显著升高，与患者存活率差、肿瘤等级较高和野生型IDH状态相关。此外，在局部胶质瘤组织和不同的胶质瘤细胞中，Gαi2的表达也明显增加。在原代和永生化（A172）胶质瘤细胞中，Gαi2 shRNA或敲除（通过Cas9-sgRNA）有效抑制了细胞的生存能力、增殖和移动，并诱导了细胞凋亡。利用慢病毒载体进行异位Gαi2过表达进一步促进了胶质瘤细胞的恶性行为。在原代胶质瘤细胞中，Gαi2的表达水平下降，p65磷酸化、NFκB活性和NFκB通路基因的表达也随之降低，但在Gαi2过表达后却有所增加。在胶质瘤组织和不同的胶质瘤细胞中，Gαi2启动子和特异性蛋白1（Sp1）转录因子之间的结合也增加了。在原代胶质瘤细胞中，Sp1的沉默、敲除或抑制显著降低了Gαi2的表达。体内实验证明，通过AAV肿瘤内注射Gαi2 shRNA可阻碍裸鼠皮下胶质瘤异种移植的生长。此外，Gαi2敲除抑制了裸鼠颅内胶质瘤异种移植。在Gαi2敲除的皮下和颅内胶质瘤异种移植中观察到Gαi2下调、NFκB抑制和凋亡诱导的现象。总之，过度表达的Gαi2通过促进NFκB级联激活可能对胶质瘤细胞的生长起重要作用。 ©作者。

Identification of novel therapeutic oncotargets for human glioma is extremely important. Here we tested expression, potential functions and underlying mechanisms of G protein inhibitory α subunit 2 (Gαi2) in glioma. Bioinformatics analyses revealed that Gαi2 expression is significantly elevated in human glioma, correlating with poor patients' survival, higher tumor grade and wild-type IDH status. Moreover, increased Gαi2 expression was also in local glioma tissues and different glioma cells. In primary and immortalized (A172) glioma cells, Gαi2 shRNA or knockout (KO, by Cas9-sgRNA) potently suppressed viability, proliferation, and mobility, and induced apoptosis. Ectopic Gαi2 overexpression, using a lentiviral construct, further augmented malignant behaviors in glioma cells. p65 phosphorylation, NFκB activity and expression of NFκB pathway genes were decreased in Gαi2-depleted primary glioma cells, but increased following Gαi2 overexpression. There was an increased binding between Gαi2 promoter and Sp1 (specificity protein 1) transcription factor in glioma tissues and different glioma cells. In primary glioma cells Gαi2 expression was significantly reduced following Sp1 silencing, KO or inhibition. In vivo studies revealed that Gαi2 shRNA-expressing AAV intratumoral injection hindered growth of subcutaneous glioma xenografts in nude mice. Moreover, Gαi2 KO inhibited intracranial glioma xenograft in nude mice. Gαi2 depletion, NFκB inhibition and apoptosis induction were observed in subcutaneous and intracranial glioma xenografts with Gαi2 depletion. Together, overexpressed Gαi2 is important for glioma cell growth possibly by promoting NFκB cascade activation.© The author(s).