RUNX1 通过 TGFβ 通路依赖性方式促进胶质母细胞瘤的间质亚型形成。
RUNX1 contributes to the mesenchymal subtype of glioblastoma in a TGFβ pathway-dependent manner.
机构信息
Lab of Neuro-oncology, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
Department of Neurosurgery, the Affiliated Hospital of Qingdao University, Qingdao, China.
出版信息
Cell Death Dis. 2019 Nov 21;10(12):877. doi: 10.1038/s41419-019-2108-x.
Runt-Related Transcription Factor 1 (RUNX1) is highly expressed in the Mesenchymal (Mes) subtype of glioblastoma (GBM). However, the specific molecular mechanism of RUNX1 in Mes GBM remains largely elusive. In this study, cell and tumor tissue typing were performed by RNA-sequencing. Co-immunoprecipitation (co-IP) and immunofluorescence (IF) were employed to identify members of the RUNX1 transcriptional protein complex. Bioinformatics analysis, chromatin immunoprecipitation (ChIP), and luciferase reporter experiments were utilized to verify target genes. Analyses of The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) verified the expression levels and prognoses associated with RUNX1/p-SMAD3/SUV39H1 target genes. In vivo patient-derived xenograft (PDX) studies and in vitro functional studies verified the impact of RUNX1 on the occurrence and development of GBM. The results showed that RUNX1 was upregulated in Mes GBM cell lines, tissues and patients and promoted proliferation and invasion in GBM in a TGFβ pathway-dependent manner in vivo and in vitro. We found and verified that BCL3 and MGP are transcriptionally activated by p-SMAD3 /RUNX1, while MXI1 is transcriptionally suppressed by the RUNX1/SUV39H1-H3K9me3 axis. This finding offers a theoretical rationale for using molecular markers and choosing therapeutic targets for the Mes type of GBM.
Runt 相关转录因子 1（RUNX1）在间充质（Mes）型胶质母细胞瘤（GBM）中高度表达。然而，RUNX1 在 Mes GBM 中的具体分子机制在很大程度上仍未被揭示。在这项研究中，通过 RNA 测序进行了细胞和肿瘤组织分型。共免疫沉淀（co-IP）和免疫荧光（IF）用于鉴定 RUNX1 转录蛋白复合物的成员。生物信息学分析、染色质免疫沉淀（ChIP）和荧光素酶报告实验用于验证靶基因。对癌症基因组图谱（TCGA）和中国胶质瘤基因组图谱（CGGA）的分析验证了与 RUNX1/p-SMAD3/SUV39H1 靶基因相关的表达水平和预后。体内患者来源的异种移植（PDX）研究和体外功能研究验证了 RUNX1 对 GBM 发生和发展的影响。结果表明，RUNX1 在 Mes GBM 细胞系、组织和患者中上调，并在体内和体外以 TGFβ 途径依赖性方式促进 GBM 的增殖和侵袭。我们发现并验证了 BCL3 和 MGP 被 p-SMAD3/RUNX1 转录激活，而 MXI1 被 RUNX1/SUV39H1-H3K9me3 轴转录抑制。这一发现为使用分子标记和选择 Mes 型 GBM 的治疗靶点提供了理论依据。
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