神经胶质母细胞瘤（GBM）等高级别胶质瘤是颅内常见肿瘤，致死致率高，预后极差。近年来对胶质瘤的治疗有所突破，但总的生存期仅能延长数月。一系列的促癌基因表达及功能异常和胶质瘤发生、发展密切相关。目前研究聚焦于探究新的关键信号通路和分子靶点。
18新利体育 神经18新利备用网站 所曹聪课题组多年来研究证实G蛋白抑制性α亚单位1和3（Gαi1/3蛋白）是多个信号通路中的关键分子。在多个细胞及生长因子刺激下，Gαi1/3蛋白和受体酪氨酸激酶（RTKs）等受体结合，并介导下游信号（PI3K-Akt-mTOR及Erk-MAPK等）转导（Science Advances 2022[1], PNAS 2018[2], Protein & Cell2022a/b[3, 4]，Science Signaling， 2009 [5]，Oncogene2018, 2021 [6, 7]，IJBS2022[8]，Theranostics 2018，2021a/b[9-11]等论文）。课题组前期研究发现胶质瘤患者肿瘤组织标本中Gαi1/3表达显著上调；敲减、敲除Gαi1/3后可显著抑制胶质瘤细胞体外及在小鼠颅内生长（Oncogene2018[6]，Theranostics 2021a[9]）。但Gαi1/3蛋白表达调控的分子机制并不明确。
YME1L（YME1 Like 1 ATPase）是AAA家族ATP酶的主要成员，位于线粒体内膜[12]。YME1L对维持线粒体的形态、功能和可塑性至关重要[13]。YME1L在线粒体内膜内组装成同源寡聚物，参与降解线粒体蛋白：包括脂质转运蛋白、线粒体内膜易位蛋白及OPA1等等；YME1L缺失导致线粒体分裂增加，线粒体碎片化；YME1L还参与细胞增殖并抑制细胞凋亡 [13]。但YME1L在人类胶质瘤中的表达和潜在功能仍不清楚。
2022年10月19日，18新利体育 曹聪课题组在Protein & Cell（IF=15.328）在线发表了题为“YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation”研究论文，该研究揭示了YME1L通过促进Gαi1蛋白表达和下游Akt活化促胶质瘤细胞生长。
结合TCGA数据库和患者组织标本发现，YME1L在胶质瘤组织中表达显著上调，且仅在线粒体中富集。在体外培养的人胶质瘤细胞中，运用病毒shRNA敲减或CRISPR/Cas9方法敲除YME1L显著抑制细胞的生长、增殖和迁移，并诱导细胞线粒体损伤和细胞凋亡；而运用病毒载体过表达YME1L则促胶质瘤细胞生长。机制研究发现，胶质瘤细胞中敲减及敲除YME1L后，Gαi1表达下调，下游Akt抑制；而过表达YME1L后，Gαi1表达水平增加，Akt激活。
Gαi1过表达或导入持续活化的Akt（caAkt1）减轻YME1L敲除后抗胶质瘤细胞作用。在体研究发现，YME1L敲除后的人胶质瘤细胞在小鼠颅内生长显著抑制；肿瘤组织内Gαi1表达下调，Akt活化抑制。综上，YME1L通过介导Gαi1-Akt信号激活促胶质瘤细胞生长，该通路或是胶质瘤的一个重要新的治疗靶点。
论文受国家自然科学基金优秀青年基金和面上项目等资助。
原文链接：https://doi.org/10.1093/procel/pwac011
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