MBNL1/circNTRK2/PAX5 通路通过编码一种新蛋白 NTRK2-243aa 调节胶质母细胞瘤细胞的有氧糖酵解,Cell Death & Disease

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MBNL1/circNTRK2/PAX5 通路通过编码一种新蛋白 NTRK2-243aa 调节胶质母细胞瘤细胞的有氧糖酵解
Cell Death & Disease ( IF 8.1 ) Pub Date : 2022-09-05 , DOI: 10.1038/s41419-022-05219-4
Yubo Zhao _{1,

2,

3} , Jian Song _{1,

2,

3} , Weiwei Dong _{1,

2,

3} , Xiaobai Liu _{1,

2,

3} , Chunqing Yang _{1,

2,

3} , Di Wang _{1,

2,

3} , Yixue Xue ₄ , Xuelei Ruan ₄ , Libo Liu ₄ , Ping Wang ₄ , Mengyang Zhang ₄ , Yunhui Liu _{1,

2,

3}

Affiliation

多形性胶质母细胞瘤 (GBM) 是人类中枢神经系统最常见的肿瘤。有氧糖酵解与肿瘤发展和恶性行为密切相关。在这项研究中，我们发现 MBNL1、circNTRK2 和 NTRK2-243aa 在 GBM 中显着下调并抑制糖酵解，而 PAX5 上调并促进糖酵解。在功能上，MBNL1 通过与 NTRK2 结合促进 circNTRK2 的表达pre-mRNA，使用 RNA pull-down 和新生 RNA 免疫沉淀分析验证。采用质谱、蛋白质印迹和免疫荧光染色方法检测 NTRK2-243aa 的表达。NTRK2-243aa——由 circNTRK2 编码——在 Y102 处磷酸化 PAX5，导致 PAX5 的半衰期缩短，这已通过体外激酶和 MG132 拯救试验验证。此外，PAX5 通过结合其启动子区域在转录上促进 PKM2 和 HK2 的表达，荧光素酶报告基因和染色质免疫沉淀测定证实了这一点。最后，MBNL1 和 circNTRK2 的过表达结合 PAX5 敲低有效地抑制了 GBM 异种移植肿瘤的形成，并显着延长了原位裸鼠的存活期。

"点击查看英文标题和摘要"

The MBNL1/circNTRK2/PAX5 pathway regulates aerobic glycolysis in glioblastoma cells by encoding a novel protein NTRK2-243aa

Glioblastoma multiforme (GBM) is the most common tumor of the human central nervous system. Aerobic glycolysis has been strongly related to tumor development and malignant behavior. In this study, we found that MBNL1, circNTRK2, and NTRK2-243aa were markedly downregulated and inhibited glycolysis in GBM, whereas PAX5 was upregulated and promoted glycolysis. Functionally, MBNL1 promoted the expression of circNTRK2 by binding to NTRK2 pre-mRNA, as validated using RNA pull-down and nascent RNA immunoprecipitation assays. Mass spectrometry, western blotting, and immunofluorescence staining methods were used to detect the expression of NTRK2-243aa. NTRK2-243aa—encoded by circNTRK2—phosphorylated PAX5 at Y102, leading to the attenuation of the half-life of PAX5, as validated by in vitro kinase and MG132 rescue assays. Besides, PAX5 transcriptionally facilitated the expression of PKM2 and HK2 by binding to their promoter regions, as verified by luciferase reporter and chromatin immunoprecipitation assays. Finally, overexpression of MBNL1 and circNTRK2 combined with PAX5 knockdown effectively inhibited the formation of GBM xenograft tumors and significantly prolonged the survival of orthotopic nude mice. We have delineated that the MBNL1/circNTRK2/PAX5 pathway plays a crucial role in regulating GBM glycolysis and could provide potential targets and alternative strategies for the treatment of GBM.

更新日期：2022-09-06

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