Artesi Maria, Kroonen Jerome, Bredel Markus, Nguyen-Khac Minh, Deprez Manuel, Schoysman Laurent, Poulet Christophe, Chakravarti Arnab, Kim Hyunsoo, Scholtens Denise, Seute Tatjana, Rogister Bernard, Bours Vincent, Robe Pierre A
Department of Human Genetics, CBIG/GIGA Research Center, University of Liège, Liège, Belgium (M.A., J.K., M.N.-K., L.S., C.P., V.B., P.A.R.); Department of Neurology and Neurosurgery and T. and P. Bonhenn Neuro-Oncology Laboratory, University Hospital of Utrecht, Utrecht, Netherlands (J.K., L.S., T.S., P.A.R.); Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, Illinois (D.S.); Center for Population Health Sciences, Institute for Public Health and Medicine, Northwestern University, Chicago (D.S.); Division of Neuropathology, University Hospital of Liège, Liège, Belgium (M.D.); Division of Neurobiology, CBIG/GIGA Research Center, University Hospital of Liège, Liège, Belgium (B.R.); Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, Ohio (A.C., P.A.R.); Department of Radiation Oncology, Hazelrig-Salter Radiation Oncology Center and UAB Comprehensive Cancer Center, Birmingham, Alabama (M.B., H.K.).
Neuro Oncol. 2015 Mar;17(3):392-406. doi: 10.1093/neuonc/nou215. Epub 2014 Aug 25.
Glioblastomas remain ominous tumors that almost invariably escape treatment. Connexins are a family of transmembrane, gap junction-forming proteins, some members of which were reported to act as tumor suppressors and to modulate cellular metabolism in response to cytotoxic stress.
We analyzed the copy number and expression of the connexin (Cx)30 gene gap junction beta-6 (GJB6), as well as of its protein immunoreactivity in several public and proprietary repositories of glioblastomas, and their influence on patient survival. We evaluated the effect of the expression of this gap junction protein on the growth, DNA repair and energy metabolism, and treatment resistance of these tumors.
The GJB6 gene was deleted in 25.8% of 751 analyzed tumors and mutated in 15.8% of 158 tumors. Cx30 immunoreactivity was absent in 28.9% of 145 tumors. Restoration of Cx30 expression in human glioblastoma cells reduced their growth in vitro and as xenografts in the striatum of immunodeficient mice. Cx30 immunoreactivity was, however, found to adversely affect survival in 2 independent retrospective cohorts of glioblastoma patients. Cx30 was found in clonogenic assays to protect glioblastoma cells against radiation-induced mortality and to decrease radiation-induced DNA damage. This radioprotection correlated with a heat shock protein 90-dependent mitochondrial translocation of Cx30 following radiation and an improved ATP production following this genotoxic stress.
These results underline the complex relationship between potential tumor suppressors and treatment resistance in glioblastomas and single out GJB6/Cx30 as a potential biomarker and target for therapeutic intervention in these tumors.
胶质母细胞瘤仍然是预后凶险的肿瘤，几乎总是难以治疗。连接蛋白是一类形成跨膜间隙连接的蛋白质，据报道其中一些成员可作为肿瘤抑制因子，并在细胞毒性应激反应中调节细胞代谢。
我们分析了胶质母细胞瘤的几个公共和专有数据库中连接蛋白（Cx）30基因缝隙连接蛋白β-6（GJB6）的拷贝数、表达及其蛋白免疫反应性，以及它们对患者生存的影响。我们评估了这种缝隙连接蛋白的表达对这些肿瘤的生长、DNA修复、能量代谢和治疗抗性的影响。
在751例分析的肿瘤中，25.8%存在GJB6基因缺失，在158例肿瘤中，15.8%发生突变。在145例肿瘤中，28.9%不存在Cx30免疫反应性。在人胶质母细胞瘤细胞中恢复Cx30表达可降低其体外生长以及在免疫缺陷小鼠纹状体中的异种移植生长。然而，在2个独立的胶质母细胞瘤患者回顾性队列中发现，Cx30免疫反应性对生存有不利影响。在克隆形成试验中发现，Cx30可保护胶质母细胞瘤细胞免受辐射诱导的死亡，并减少辐射诱导的DNA损伤。这种辐射防护与辐射后Cx30依赖热休克蛋白90的线粒体易位以及这种基因毒性应激后ATP生成的改善相关。
这些结果强调了胶质母细胞瘤中潜在肿瘤抑制因子与治疗抗性之间的复杂关系，并将GJB6/Cx30确定为这些肿瘤治疗干预的潜在生物标志物和靶点。
