曹聪课题组发现Gαi1蛋白上游关键基因

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。

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 & Cell 2022a/b [3, 4]，Science Signaling， 2009 [5]，Oncogene 2018, 2021 [6, 7]，IJBS 2022 [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；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，苏州大学曹聪课题组在Protein & Cell在线发表了题为YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation 的研究论文，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。

原文链接：https://doi.org/10.1093/procel/pwac011

参考文献

1. Yao J, Wu XY, Yu Q, Yang SF, Yuan J, Zhang ZQ, Xue JS, Jiang Q, Chen MB, Xue GH, Cao C: The requirement of phosphoenolpyruvate carboxykinase 1 for angiogenesis in vitro and in vivo. Sci Adv 2022, 8:eabn6928.

2. Marshall J, Zhou XZ, Chen G, Yang SQ, Li Y, Wang Y, Zhang ZQ, Jiang Q, Birnbaumer L, Cao C: Antidepression action of BDNF requires and is mimicked by Galphai1/3 expression in the hippocampus. Proc Natl Acad Sci U S A 2018, 115:E3549-E3558.

3. Liu F, Chen G, Zhou L, Wang Y, Zhang Z, Qin X, Cao C: YME1L overexpression exerts pro-tumorigenic activity in glioma by promoting Gαi1 expression and Akt activation. Protein Cell 2022.

4. Xu G, Qi L-n, Zhang M-q, Li X-y, Chai J-l, Zhang Z-q, Chen X, Wang Q, Li K-r, Cao C: Gαi1/3 mediation of Akt-mTOR activation is important for RSPO3-induced angiogenesis. Protein & Cell 2022.

5. Cao C, Huang X, Han Y, Wan Y, Birnbaumer L, Feng GS, Marshall J, Jiang M, Chu WM: Galpha(i1) and Galpha(i3) are required for epidermal growth factor-mediated activation of the Akt-mTORC1 pathway. Sci Signal 2009, 2:ra17.

6. Liu YY, Chen MB, Cheng L, Zhang ZQ, Yu ZQ, Jiang Q, Chen G, Cao C: microRNA-200a downregulation in human glioma leads to Galphai1 over-expression, Akt activation, and cell proliferation. Oncogene 2018, 37:2890-2902.

7. Lv Y, Wang Y, Song Y, Wang SS, Cheng KW, Zhang ZQ, Yao J, Zhou LN, Ling ZY, Cao C: LncRNA PINK1-AS promotes G alpha i1-driven gastric cancer tumorigenesis by sponging microRNA-200a. Oncogene 2021, 40:3826-3844.

8. Bian ZJ, Shan HJ, Zhu YR, Shi C, Chen MB, Huang YM, Wang XD, Zhou XZ, Cao C: Identification of Galphai3 as a promising target for osteosarcoma treatment. Int J Biol Sci2022, 18:1508-1520.

9. Wang Y, Liu YY, Chen MB, Cheng KW, Qi LN, Zhang ZQ, Peng Y, Li KR, Liu F, Chen G, Cao C: Neuronal-driven glioma growth requires Galphai1 and Galphai3. Theranostics 2021, 11:8535-8549.

10. Bai JY, Li Y, Xue GH, Li KR, Zheng YF, Zhang ZQ, Jiang Q, Liu YY, Zhou XZ, Cao C: Requirement of Galphai1 and Galphai3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response. Theranostics 2021, 11:4894-4909.

11. Sun J, Huang W, Yang SF, Zhang XP, Yu Q, Zhang ZQ, Yao J, Li KR, Jiang Q, Cao C: Galphai1 and Galphai3mediate VEGF-induced VEGFR2 endocytosis, signaling and angiogenesis. Theranostics 2018, 8:4695-4709.

12. Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, Langer T: The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol 2014, 204:919-929.

13. Stiburek L, Cesnekova J, Kostkova O, Fornuskova D, Vinsova K, Wenchich L, Houstek J, Zeman J: YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol Biol Cell 2012, 23:1010-1023.

转载须知

【非原创文章】本文著作权归文章作者所有，欢迎个人转发分享，未经作者的允许禁止转载，作者拥有所有法定权利，违者必究。