肿瘤微环境中高亚牛磺酸水平通过调控自噬维持胶质瘤干细胞“干性”

Existence of GSCs is the fundamental reason for intractability of glioma. Tumor microenvironment plays an important role on sustaining stemness of GSCs. Recent studies showed that aberrant metabolites generation by cancer cell metabolic reprogramming is an important feature of GSCs niche. While little is known about the effect of metabolites in glioma microenvironment on GSCs. Our previous study revealed that hypotaurine was significantly elevated in glioma tissues, and more importantly, the stress of hypotaurine deprivation induced cell autophagy. Based on the fact that autophagy has great impact on GSCs stemness maitaining, we hypothesize in this project that high level of hypotaurine in glioma microenvironment helps maintaining GSCs stemness via regulating autophagy. To verify this assumption, in this project we will investigate the impact of hypotaurine metabolic pathways on GSCs stemness and autophagy by in vitro and in vivo experiments; reveal the molecular mechanism of autophagy regulation by hypotaurine via mRNA microarray and Chip Assay; and explore the clinical significance of hypotaurine as a biomarker for glioma. The study of this project will provide fundamental theory and novel ideas for glioma therapy by targeting GSCs.

胶质瘤干细胞（Glioma stem cells，GSCs）是胶质瘤难治的根本原因。肿瘤微环境与GSCs“干性”维持密切相关。近期研究表明肿瘤代谢重编程导致的代谢分子异常表达构成了GSCs特有的生存环境。但肿瘤微环境中的代谢分子对GSCs的作用和调控机制尚未知。申请者前期研究中发现亚牛磺酸在胶质瘤组织中显著升高，且亚牛磺酸缺乏应激可启动细胞自噬。基于自噬对GSCs“干性”维持具有重要影响，本项目提出假说：肿瘤微环境中高亚牛磺酸水平通过调控自噬维持GSCs“干性”。为证实这一假说，本项目将利用体内外实验证实亚牛磺酸代谢网络对GSCs“干性”和自噬的影响，利用基因芯片、Chip assay等技术阐明亚牛磺酸调控GSCs自噬的分子机制，探讨其作为胶质瘤生物标记物的临床意义；本项目将对靶向GSCs治疗胶质瘤奠定新理论和提供新思路。

胶质瘤是脑内最常见的恶性肿瘤，具有高致死和致残率等特点，治疗手段缺乏，肿瘤发生发展的分子机制尚不明确。肿瘤微环境中代谢产物的异常对肿瘤生物学行为有重要作用，本项目围绕与亚牛磺酸代谢密切相关的甲硫氨酸代谢，阐明了甲硫氨酸剥夺对胶质瘤细胞生长抑制的作用，其分子机制是通过降低IL1RN的表达，进而导致胶质瘤细胞周期停滞在G1/S期来实现肿瘤抑制作用的。同时围绕“自噬”这一重要细胞生物学特点，在原有计划上进行修改证实了硝唑尼特在体内外可以抑制胶质瘤的增殖，阐明其分子机制是通过抑制晚期溶酶体酸化过程导致抑癌基因ING1⾃噬降解减少，进而促进ING1的升高和细胞周期G0/G1阻滞来实现的。本项目紧跟国际前沿的热点和难点问题，按照预定计划和在新发现的线索之上，围绕肿瘤代谢异常和自噬开展了系列研究，发现了多个胶质瘤的潜在治疗靶点（甲硫氨酸代谢通路，IL1RN, ING1）和具有抗胶质瘤作用的化合物硝唑尼特，由于硝唑尼特具有通过血脑屏障的能力，将来可能是胶质瘤治疗的潜在药物。总之，在本项目的支持下取得了多个原创性和前沿性的成果，为靶向胶质瘤的治疗提供了新的思路和理论基础。