TGF-β/SOX9通路促进胶质瘤发生发展的分子机制研究

Glioma is one of the most common malignant intracranial tumors, The clinical cure rate is low, and the prognosis is poor. So searching the molecular mechanism development has always been a research hot spot. Transforming growth factor beta (TGF-β) signaling pathway is one of the most important intracellular signal transduction pathways for tumor cells. It participates in regulating of many tumor cell life activities. Our previous studies have shown that SOX9 is the key molecular of glioma signal network, which participates in regulating the occurrence of glioma and the stemness of glioma stem cell, we also find that TGF-β can elevate the expression level of SOX9 in glioma cells. It has been reported that SOX9 can regulate various kinases which TGF-β activating, TGF-β factor and TGF-β related receptors can also promote SOX9 expressing level in glioma cells. So we speculated that TGF-β may regulate the occurrence and development of glioma through SOX9. This project aims to clarify the molecular mechanism of TGF-β/SOX9 signaling pathway involved in regulating the glioma invasion, migration and the glioma stem cells stemness maintain through protein interactions combined gene regulation biotechnology. Then clarify the molecular mechanisms of TGF-β/SOX9 signaling pathway involved in regulating the occurrence and development in gliomas. It has great significance for exploring the molecule network of glioma regulation, and it is useful to looking for new therapeutic targets for clinical treatment of glioma.

胶质瘤是严重危害人类健康的常见恶性肿瘤之一，治愈率低，预后差。因此，探究其发生发展分子机制一直是研究热点。转化生长因子β（TGF-β）信号通路是肿瘤中重要的信号通路，参与调控众多肿瘤细胞生物学效应，我们研究发现，SOX9是胶质瘤中信号网络的关键节点，参与调控胶质瘤的发生和胶质瘤干细胞干性维持，且发现TGF-β可以促进胶质瘤细胞中SOX9的表达。据报道，SOX9参与调控TGF-β激活的多种激酶活性，TGF-β因子及其相关配体能够正向调控SOX9的表达。因此我们提出TGF-β可通过促进SOX9的表达而促进胶质瘤发生发展的假说。本项目拟通过蛋白互作结合基因调控技术，阐明TGF-β/SOX9信号通路参与调控胶质瘤侵袭、迁移及胶质瘤干细胞干性维持的分子机制，继而揭示TGF-β/SOX9信号通路参与调控胶质瘤发生发展的分子机制。这对完善胶质瘤调控的分子信号网络及为临床治疗寻找新的治疗靶标均有重要意义。

胶质瘤是最常见的原发性中枢神经系统(CNS)恶性肿瘤，占颅内肿瘤35-40%，其发病分子机制尚不明确，胶质瘤呈恶性浸润性生长，手术很难切除彻底，具有发病率高、复发率高、预后差等特点。SOX9作为干性转录因子是多种信号通路的重要节点，参与调节胶质瘤细胞的增殖、迁移、侵袭以及GSC干性维持和放疗抵抗。转化生长因子β（TGF-β）信号通路是肿瘤中重要的信号通路，参与调控众多肿瘤细胞生物学效应。我们研究发现SOX9在胶质瘤组织中高表达，可以促进胶质瘤细胞的增殖、迁移、侵袭及肿瘤形成，且SOX9高表达患者的生存期相对较短。本项目还发现TGF-β1通过抑制SOX9的蛋白酶体降解来提高胶质瘤细胞中SOX9的表达水平，进而促进胶质瘤细胞的增殖、迁移、侵袭及裸鼠皮下移植瘤的形成，提示在胶质瘤中，TGF-β和SOX9协同发挥促癌作用。此外，我们还发现SOX9在胶质瘤干细胞球中高表达，而敲减SOX9可抑制胶质瘤细胞的克隆形成和干细胞球形成。本项目阐明了TGF-β/SOX9信号通路参与调控胶质瘤增殖、迁移、侵袭、及胶质瘤干细胞干性维持的分子机制，为揭示胶质瘤发病的分子机制提供了新的理论依据，同时为胶质瘤的靶向治疗提供了新的治疗思路和治疗策略。..