脑胶质瘤细胞中TGF-β1调控c-Myc的分子机理研究

Glioma is the most common brain tumor, which featured as highly invasive and destructive. The main role of TGF-β1 in glioma is to control the cell proliferation, metastasis, invasion, angiogenesis and immune escape. It can depress the transcription of c-Myc via Smad3, one of the members involved in the TGF-β1 signaling pathway. MXI1, an important tumor suppressor, could also directly depress c-Myc. In our previous studies, we found that TGF-β1 could regulate MXI1 via its 3'UTR. Through a large-scale interaction screening, we discovered two miRNAs, miR-24 and miR-27a could bind the 3'UTR of MXI1. These miRNAs can also be regulated by TGF-β1. Therefore, we hypothesized that there is a novel signaling pathway from TGF-β1 to c-Myc mediated by miRNAs. This project is aimed to find those transcription factors, which are regulated by TGF-β1 and are responsible for the regulation of the two miRNAs. With the experiments of cell proliferation, metastasis, invasion and tumor formation, we are going to study of the functions of the miRNAs and transcription factors involved in the pathway in vitro and in vivo. These experiments will provide the theoretical basis for illustrating the mechanism of tumorigenesis and also for searching new therapeutical targets in glioma.

脑胶质瘤是颅内肿瘤中最多见的一种，具有高侵袭性和破坏性。TGF-β在脑胶质细胞中的主要作用是控制细胞的生长、迁移、侵袭、血管再生以及免疫逃逸，通过其信号通路上的Smad3抑制c-Myc基因的转录。MXI1能够直接负调控c-Myc，是重要的抑癌基因。我们发现TGF-β1 通过MXI1 3'-UTR调控该基因的表达水平，较大规模筛选发现同一个簇的miR-24和-27a都能够结合MXI1基因的 3'-UTR，而它们受TGF-β1调控。从而我们推测在TGF-β1与c-Myc之间可能存在miRNA介导的新分子通路。本项目旨在寻找受TGF-β1调控，且能够调控这两个miRNAs的转录因子，从而阐明TGF-β1对 c-Myc调控的新分子通路。通过细胞增殖、迁移、侵袭和体内成瘤等实验对通路中miRNAs及转录因子的功能进行深入研究，为阐明胶质瘤发生的分子机制、并为寻找临床治疗的新靶点提供理论基础。

脑胶质瘤是颅内肿瘤中最多见的一种，具有高侵袭性和破坏性。TGF-β在脑胶质细胞中的主要作用是控制细胞的生长、迁移、侵袭、血管再生以及免疫逃逸，通过其信号通路上的Smad3抑制c-Myc基因的转录。MXI1能够直接负调控c-Myc，是重要的抑癌基因。通过大规模筛选和细胞、裸鼠模型两方面的验证实验，揭示了TGF-β1/RUNX1/miRNA/MXI1/c-Myc调控通路和MXI1和cMyc之间相互抑制的分子环路，从而阐明TGF-β1对 c-Myc调控的新分子通路。完善了胶质瘤细胞增殖的分子机制。通过miRNA和转录因子在细胞和裸鼠模型上的功能分析，明确了在胶质瘤中miR-155，miR-24-3p, miR-27a-3p通过调控MXI1和cMyc进而促进细胞增殖的作用，进一步的研究表明TGF-β1/RUNX1调控轴能够通过对miRNA的调控从而对胶质瘤细胞的增殖产生影响。这些结果为阐明胶质瘤发生的分子机制、并为寻找临床治疗的新靶点提供理论基础。