泛素连接酶TRIM59调控胶质瘤发生发展的分子机制

Gliomablstoma is the most common and malignant tumor in central neuron system. EGFR is a driver of gliomagenesis. Although many studies for EGFR-driven gliomagenesis have been performed, the progress of clinical treatment of glioma patients is dismal. It is urgent to discover the mechanisms by which EGFR drives glioma progress. Previous we found that EGFR upregulated TRIM59 expression through SOX9, and enhanced the assocation between TRIM59 and STAT3; knockdown of TRIM59 using shRNAs inhibited EGFR-driven glioma cell proliferation, migration, colony formation, tumor growth in the brain of mice and phospho-STAT3, whereas it upregulated TC45 protein expression, a protein tyrosine phosphatase. We further found that TRIM59 can bind with TC45. IHC analysis also showed tha phospho-EGFR, TRIM59 and phospho-STAT3 were co-expressed in clinical specimens of GBM. We hypothesize that EGFR-upregulated and SOX9-dependent TRIM59 binds with TC45. TRIM59 promotes TC45 ubiquitination and degradation, leading to repress TC45 to dephosphorylate STAT3, resulting in high STAT3.phosphorylation and promoting glioma tumorigensis. Our project will deeply explore the mechanisms by which TRIM59 regulates EGFR-driven gliomagensis and glioma stem cell stemness. Binding with clinical specimen analysis, we will also address the roles of TRIM59 in clinical. This will help not only to understand the molecular mechanisms of EGFR-driven gliomagenesis, but also to provide potential research basis for clinical diagnosis and therapy.

胶质瘤是最常见最恶性的神经系统肿瘤，而EGFR是胶质瘤发生发展的关键驱动分子。尽管对EGFR调控的下游信号进行了大量研究，但临床应用效果不佳，故迫切需要深入揭示其分子机制。我们前期研究发现泛素连接酶TRIM59表达与胶质瘤的发展正相关，TRIM59高表达的病人预后较差；EGFR上调TRIM59表达依赖于SOX9，敲除TRIM59明显抑制EGFR调节的胶质瘤增殖、STAT3磷酸化而上调酪氨酸磷酸酶TC45表达。故假设：EGFR通过SOX9上调TRIM59表达，促进TRIM59泛素化降解磷酸酶TC45，抑制TC45对STAT3的去磷酸化，维持STAT3高磷酸化活性，激活下游基因的表达，促进胶质瘤的增殖及肿瘤干细胞的干性维持。本项目将在前期基础上，利用胶质瘤细胞、肿瘤干细胞及临床标本，结合原位移植瘤模型、组学分析等方法揭示该假说。本项目将有助于揭示胶质瘤增殖的新机制，为临床提供新的肿瘤靶向位点。

胶质瘤是最常见最恶性的中枢神经系统肿瘤，而EGFR是胶质瘤发生发展的关键驱动分子之一。尽管对EGFR调控的下游信号进行了大量研究，但临床应用效果不佳，故迫切需要深入揭示其分子机制，为临床诊断治疗提供新靶点新思路。.通过本项目的研究，取得如下成果：1）在胶质瘤中，EGFR激活促进CDK5与TRIM59 结合, 并使TRIM59的S308氨基酸位点发生磷酸化，促进向细胞核内转移。核TRIM59泛素化降解异型组蛋白macroH2A1，促进磷酸化STAT3与其靶基因启动子结合。同时，TRIM59入核后通过抑制磷酸酶TC45去磷酸化STAT3，两方面共同作用维持STAT3信号通路的异常激活，从而导致肿瘤的恶性增殖。相关成果发表在（Cancer Res 2018；Nat. Commun.2019）；2）我们还发现在胶质瘤中，EGFR特异上调H3K23乙酰化，乙酰化的H3K23结合TRIM24,招募STAT3与染色质结合，增强STAT3信号活性，促进胶质瘤恶性增殖及其肿瘤干细胞干性维持 （Nat. Commun.2017; Cancer Res.2017）; 3）发现SHP-2的小分子抑制剂SHP099可以通过血脑屏障特异靶向胶质瘤干细胞，脂质抑制剂G0S2调控胶质瘤干细胞的抗辐射能力，TGF‐β诱导的LncRNA LINC00115信号通路在促进胶质瘤肿瘤增殖侵袭和干性维持中的作用等，相关文章发表在Neuro Oncol（2019），J EXP CLIN CANC RES（2019）和EMBO Rep（2019）。另外，我们也为研究肿瘤发生机制以及治疗建立了体外iPS平台。